piperidines and piperidine

Piperidines are among the most important synthetic fragments for designing drugs and play a significant role in the pharmaceutical industry. Their derivatives are present in more than twenty classes of pharmaceuticals, as well as alkaloids. The current review summarizes recent scientific literature on intra- and intermolecular reactions leading to the formation of various piperidine derivatives: substituted piperidines, spiropiperidines, condensed piperidines, and piperidinones. Moreover, the pharmaceutical applications of synthetic and natural piperidines were covered, as well as the latest scientific advances in the discovery and biological evaluation of potential drugs containing piperidine moiety. This review is designed to help both novice researchers taking their first steps in this field and experienced scientists looking for suitable substrates for the synthesis of biologically active piperidines.

Topics: Alkaloids; Cyclization; Piperidines; Stereoisomerism

Heterocycles and their derivatives hold an important place in medicinal chemistry due to their vast therapeutic and pharmacological significance and wider implications in drug design and development. Piperidine is a nitrogen-containing heterocyclic moiety that exhibits an array of pharmacological properties. This review discusses the potential of piperidine derivatives against the neurodegenerative disease Alzheimer's. The incidences of Alzheimer's disease are increasing nowadays, and constant efforts are being made to develop a medicinal agent for this disease. We have highlighted the advancement in developing piperidine-based anti-neuronal disease compounds and the profound activities of some major piperidine-bearing drug molecules with their important target site. This review focuses on advancements in the field of natural and synthetic occurring piperidines active against Alzheimer's disease, with emphasis on the past 6 years. The discussion also includes the structure-activity relationship, the structures of the most promising molecules, and their biological activities against Alzheimer's disease. The promising activities revealed by these piperidinebased scaffolds undoubtedly place them at the forefront of discovering prospective drug candidates. Thus, it would be of great interest to researchers working on synthesizing neuroprotective drug candidates.

Topics: Alzheimer Disease; Humans; Neurodegenerative Diseases; Piperidines; Structure-Activity Relationship

Pinus belongs to the family Pinaceae, represented by several species across the globe. Various parts of the plant including needles are rich in biologically active compounds, such as thunbergol, 3-carene, cembrene, α-pinene, quercetin, xanthone. Of all the alkaloids, the piperidine group is one of the important component and holds considerable medicinal importance.. The group of alkaloids was initially identified from the genus Piper through which a large variety of piperidine molecules have been extracted. The planar structure of this heterocyclic nucleus enables acetamide groups to be added at various ring configurations.. Piperidines have gained considerable importance. The broad range of its therapeutic application has paved a way for researchers to implant the nucleus from time to time in diversified pharmacophores and establish new profile.. Biological functions of piperidine metabolites have been mostly examined on a limited scale, and that most of the findings are preliminary. We have tried to present various clinical applications of piperidine alkaloids in this study that researchers have already attempted to demystify with time.. We have also illustrated different types of piperidine structures and their sources in different members of the family Pinaceae with special emphasis on Pinus. Given the importance of the piperidine nucleus, the study will enable the researchers to produce scaffolds of highest therapeutic efficacy.

Topics: Alkaloids; Pinus; Piperidines; Plant Extracts

This personal account focuses on synthesis of polyhydroxylated piperidines, a subset of compounds within the iminosugar family. Cyclisations to form the piperidine ring include reductive amination, substitution via amines, iminium ions and cyclic nitrones, transamidification (N-acyl transfer), addition to alkenes, ring contraction and expansion, photoinduced electron transfer, multicomponent Ugi reaction and ring closing metathesis. Enantiomerically pure piperidines are obtained from chiral pool precursors (e. g. sugars, amino acids, Garner's aldehyde) or asymmetric reactions (e. g. epoxidation, dihydroxylation, aminohydroxylation, aldol, biotransformation). Our laboratory have contributed cascades based on reductive amination from glycosyl azide precursors as well as Huisgen azide-alkene cycloaddition. The latter's combination with allylic azide rearrangement has given substituted piperidines, including those with quaternary centres adjacent to nitrogen.

Topics: Alkenes; Azides; Cycloaddition Reaction; Piperidines

Schizophrenia is a chronic neuropsychiatric disorder that affects nearly 1% of the global population. There are various anti-psychotic drugs available for the treatment of schizophrenia, but they have certain side effects; therefore, there is a need to explore and develop novel potential lead compounds against schizophrenia. The currently available drugs e.g. typical and atypical antipsychotics act on different dopamine and serotonin receptors and as per literature reports, various piperidine and piperazine derivatives have shown promising activity against these receptors. When different heterocyclic groups are attached to basic piperidine and piperazine rings, the antipsychotic activity is greatly potentiated. In this direction, various antipsychotic drugs have been synthesized at the laboratory level, and few are under clinical trial studies, such as Lu AE58054, PF-04802540, ORG25935, DMXB-A, Bitopertin, and ABT-126. In the present review, we include the studies related to the effect of different substituents on piperidine/piperazine derivatives and their anti-psychotic activity. Various series of synthesized compounds by other researchers with piperidine/piperazine nucleus have been reviewed and diagrammatically represented in the form of SAR (structure-activity relationships), which will help the scientists for the development of potential lead compounds.

Topics: Animals; Antipsychotic Agents; Humans; Piperazine; Piperidines; Structure-Activity Relationship

Spirocyclic nitroxyl radicals (SNRs) are stable paramagnetics bearing spiro-junction at a-, b-, or g-carbon atom of the nitroxide fragment, which is part of the heterocyclic system. Despite the fact that the first representatives of SNRs were obtained about 50 years ago, the methodology of their synthesis and their usage in chemistry and biochemical applications have begun to develop rapidly only in the last two decades. Due to the presence of spiro-function in the SNRs molecules, the latter have increased stability to various reducing agents (including biogenic ones), while the structures of the biradicals (SNBRs) comprises a rigid spiro-fused core that fixes mutual position and orientation of nitroxide moieties that favors their use in dynamic nuclear polarization (DNP) experiments. This first review on SNRs will give a glance at various strategies for the synthesis of spiro-substituted, mono-, and bis-nitroxides on the base of six-membered (piperidine, 1,2,3,4-tetrahydroquinoline, 9,9'(10

Topics: Imidazoles; Imidazolidines; Morpholines; Natural Science Disciplines; Nitrogen Oxides; Oxazoles; Piperidines; Pyrrolidines; Reducing Agents

Piperidine is an important pharmacophore, a privileged scaffold and an excellent heterocyclic system in the field of drug discovery which provides numerous opportunities in studying/exploring this moiety as an anticancer agent by acting on various receptors of utmost importance. Cancer is an uncontrolled division of cells that results in the formation of tumour which have the potential to migrate to other parts of the body (metastasis) finally becoming a major threat to human population. Since piperidine displayed great potential in this area it is being further probed to get novel entities for the treatment of cancer. This review throws light on recent biological expansions of piperidine along with structure activity relationships to deliver association between various synthesized newer/novel derivatives and receptor sites.

Topics: Animals; Antineoplastic Agents; Dose-Response Relationship, Drug; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Molecular Structure; Neoplasms; Piperidines; Structure-Activity Relationship

Plants produce a vast variety of specialized metabolites which can be a rich source for lead compounds for the development of new drugs. Alkaloids are one the largest groups of plant specialized metabolites important for natural product based pharmaceuticals. Of these, lysine (Lys)-derived alkaloids exhibit a wide range of pharmacological properties which are beneficial for humans. For instance they have anticancer, anti-Alzheimer's disease, anti-inflammatory, hypocholesterolemic and antiarrhtymic effects. Lys-derived alkaloids are widely distributed throughout the plant kingdom: they can be found in various species from clubmosses to flowering plants. Lys is one of the most essential amino acids for humans and livestock and is synthesized in the plastids of land plants. Lys-derived alkaloids can be divided into four major groups including quinolizidine, lycopodium, piperidine, and indolizidine alkaloids. Despite the importance of these compounds, the biosynthetic pathways of Lys-derived alkaloids are not well understood. With the exception of indolizidine alkaloids, Lys decarboxylase (LDC) is the enzyme involved in the first committed step of the biosynthesis by catalyzing the transformation of L-Lys into cadaverine. Cadaverine is then oxidized by copper amine oxidase (CuAO) and spontaneously cyclized to Δ1-piperideine Schiff base which is a universal intermediate for the production of various Lys-derived alkaloids.. In this review, we briefly summarize the recent understanding about the structures, occurrences, analytical procedures, biosyntheses, and potential health effects and medical applications of Lys-derived alkaloids with emphasis on quinolizidine alkaloids (QAs).

Topics: Alkaloids; Indolizidines; Lycopodium; Lysine; Piperidines; Plants; Quinolizidines

Hepatitis C virus (HCV) infection is a major worldwide epidemic disease. It is estimated that more than 170 million individuals are infected with HCV and with three to four million new cases each year. Many new direct-acting antiviral (DAA) agents that specifically target HCV NS3 protease or NS5B polymerase inhibitors are therefore in development, with a significant effect for the patient and for the market recently. The non-structural 4B (NS4B) protein, is among the least characterized of the HCV proteins. A variety of functions have been recognized for NS4B, such as the ability to induce the membranous web replication platform, RNA binding and NTPase activity. In order to maximize antiviral efficacy and prevent the emergence of resistance, novel NS4B inhibitors have been subjected to pharmacological studies. In this review, we discussed current understanding of the structure and function of NS4B, and novel drug discoveries targeting NS4B as anti-hepatitis C virus such as sulfonamide, piperidine, carboxamide, piperazinone and quinoline derivatives within the last three years.

Topics: Amides; Animals; Antiviral Agents; Drug Discovery; Hepacivirus; Humans; Piperazines; Piperidines; Quinolines; Sulfonamides; Viral Nonstructural Proteins; Virus Replication

2-Piperidineethanol (1) and its corresponding N-protected aldehyde (2) were used for the synthesis of several natural and synthetic compounds. The existence of a stereocenter at position 2 of the piperidine skeleton and the presence of an easily-functionalized group, such as the alcohol, set 1 as a valuable starting material for enantioselective synthesis. Herein, are presented both synthetic and enzymatic methods for the resolution of the racemic 1, as well as an overview of synthesized natural products starting from the enantiopure 1.

Topics: Alkaloids; Biocatalysis; Chemistry Techniques, Synthetic; Ethanol; Kinetics; Piperidines

Plants produce a wide variety of chemical compounds termed secondary metabolites that are not involved in basic metabolism, photosynthesis, or reproduction. These compounds are used as flavors, fragrances, insecticides, dyes, hallucinogens, nutritional supplements, poisons, and pharmaceutical agents. However, in some cases these secondary metabolites found in poisonous plants perturb biological systems. Ingestion of toxins from poisonous plants by grazing livestock often results in large economic losses to the livestock industry. The chemical structures of these compounds are diverse and range from simple, low molecular weight toxins such as oxalate in halogeton to the highly complex norditerpene alkaloids in larkspurs. While the negative effects of plant toxins on people and the impact of plant toxins on livestock producers have been widely publicized, the diversity of these toxins and their potential as new pharmaceutical agents for the treatment of diseases in people and animals has also received widespread interest. Scientists are actively screening plants from all regions of the world for bioactivity and potential pharmaceuticals for the treatment or prevention of many diseases. In this review, we focus the discussion to those plant toxins extensively studied at the USDA Poisonous Plant Research Laboratory that affect the nicotinic acetylcholine receptors including species of Delphinium (Larkspurs), Lupinus (Lupines), Conium (poison hemlock), and Nicotiana (tobaccos).

Topics: Conium; Delphinium; Lupinus; Nicotiana; Nicotinic Agonists; Piperidines; Plants; Receptors, Nicotinic; Toxins, Biological

The exposure of a developing embryo or fetus to alkaloids from plants, plant products, or plant extracts has the potential to cause developmental defects in humans and animals. These defects may have multiple causes, but those induced by piperidine and quinolizidine alkaloids arise from the inhibition of fetal movement and are generally referred to as multiple congenital contracture-type deformities. These skeletal deformities include arthrogyrposis, kyposis, lordosis, scoliosis, and torticollis, associated secondary defects, and cleft palate. Structure-function studies have shown that plant alkaloids with a piperidine ring and a minimum of a three-carbon side-chain α to the piperidine nitrogen are teratogenic. Further studies determined that an unsaturation in the piperidine ring, as occurs in gamma coniceine, or anabaseine, enhances the toxic and teratogenic activity, whereas the N-methyl derivatives are less potent. Enantiomers of the piperidine teratogens, coniine, ammodendrine, and anabasine, also exhibit differences in biological activity, as shown in cell culture studies, suggesting variability in the activity due to the optical rotation at the chiral center of these stereoisomers. In this article, we review the molecular mechanism at the nicotinic pharmacophore and biological activities, as it is currently understood, of a group of piperidine and quinolizidine alkaloid teratogens that impart a series of flexure-type skeletal defects and cleft palate in animals.

Topics: Alkaloids; Animals; Cholinergic Agents; Humans; Piperidines; Pyridines; Quinolizidines; Receptors, Cholinergic; Structure-Activity Relationship; Synaptic Transmission; Teratogens

Alkaloid-containing plants are an intrinsic part of the regular Western diet. The present paper summarizes the occurrence of alkaloids in the food chain, their mode of action and possible adverse effects including a safety assessment. Pyrrolizidine alkaloids are a reason for concern because of their bioactivation to reactive alkylating intermediates. Several quinolizidine alkaloids, β-carboline alkaloids, ergot alkaloids and steroid alkaloids are active without bioactivation and mostly act as neurotoxins. Regulatory agencies are aware of the risks and have taken or are considering appropriate regulatory actions for most alkaloids. These vary from setting limits for the presence of a compound in feed, foods and beverages, trying to define safe upper limits, advising on a strategy aiming at restrictions in use, informing the public to be cautious or taking specific plant varieties from the market. For some alkaloids known to be present in the modern food chain, e.g., piperine, nicotine, theobromine, theophylline and tropane alkaloids risks coming from the human food chain are considered to be low if not negligible. Remarkably, for many alkaloids that are known constituents of the modern food chain and of possible concern, tolerable daily intake values have so far not been defined.

Topics: Alkaloids; Carbolines; Diet; Ergot Alkaloids; Food; Food Chain; Humans; Neurotoxins; Ornithine; Piperidines; Pyrrolizidine Alkaloids; Quinolizidines; Risk Assessment; Tropanes

A review into the aza-Diels-Alder reaction, mainly concentrating on literature examples that form piperidin-4-ones from the reaction of imines and electron rich dienes or enones, either through a Lewis acidic/Brønsted acid approach or through the use of an organocatalyst. This review questions whether the mechanism of the aza-Diels-Alder reaction is step wise as opposed to concerted when using oxygenated dienes.

Topics: Aza Compounds; Catalysis; Oxidation-Reduction; Piperidines; Stereoisomerism; Thermodynamics

Ghrelin is a peptide produced predominantly in the stomach and intestines, and is a natural growth hormone (GH) secretagogue-receptor ligand. It is able to stimulate GH release, but it also exhibits an important role in conditions related to processes regulating nutrition, body composition and growth, and heart, liver, thyroid or kidney dysfunction. Drug discovery efforts initially focused on ghrelin-receptor agonists, known as GH secretagogues, to be used as anabolic agents, but none of them reached the market.. The latest developments in this field are constituted by the discovery of new nonpeptidic compounds endowed with interesting properties: oxindole agonists are able to exert an increase in the fat-free mass, while ghrelin was reported to increase the fat mass gain, and triazole- and 2,4-diaminopyrimidine-based antagonists were shown to be able to reduce food intake, without inhibition of GH secretion stimulated by an agonist to the ghrelin receptor. Other antagonist compounds (quinazolinones) were discovered as antiobesity/antidiabetic agents. Moreover, inverse agonists have been discovered that are able to reduce weight gain.. Taking into account the great number of pathological conditions related to ghrelin, and the discovery of several compounds able to modulate the ghrelin receptor, its importance in the field of medicinal chemistry research is set to increase significantly.

Topics: Azoles; Drug Discovery; Ghrelin; Humans; Piperazine; Piperazines; Piperidines; Receptors, Ghrelin; Spiro Compounds; Structure-Activity Relationship

Optically active alpha,alpha-disubstituted alpha-amino acids belong to an important class of unnatural amino acids. Since the synthesis of such amino acids involves the creation of a quaternary stereocenter, methods for their synthesis have been extensively studied. We have reported that N-t-butoxycarbonyl(Boc)-N-methoxymethyl(MOM)-amino acid derivatives undergo asymmetric alpha-alkylation in up to 93% ee. Original chiral information on an amino acid is preserved in axially chiral enolate intermediates, and thus asymmetric induction is achieved without the aid of external chiral sources (i.e., memory of chirality). Recently, we have reported a new protocol for the asymmetric cyclization of amino acid derivatives, which enables straightforward synthesis of cyclic amino acids with a tetrasubstituted carbon center from the usual alpha-amino acids in up to 98% ee. Here we report the asymmetric construction of highly substituted chiral nitrogen heterocycles via intramolecular conjugate addition of chiral enolates generated from N-Boc-N-alkylylamino acid derivatives. This method is applicable to the asymmetric construction of pyrrolidine, piperidine, tetrahydroisoquinoline, and indoline derivatives with contiguous quaternary and tertiary stereocenters.

Topics: Amino Acids; Heterocyclic Compounds; Indoles; Nitrogen Compounds; Piperidines; Pyrrolidines; Stereoisomerism; Tetrahydroisoquinolines

Topics: Binding Sites; DNA; DNA Damage; DNA-Binding Proteins; DNA-Directed DNA Polymerase; Guanine; Piperidines; Protein Binding; Sequence Analysis, DNA; Sulfuric Acid Esters; Taq Polymerase

Piperidine (Pip) is a normal constituent in mammalian brain, affects synaptic mechanism in the CNS, and influences neural mechanisms governing regulation of emotional behavior and extrapyramidal function. In addition, there are enzyme systems within the brain that synthesize and metabolize Pip, and uptake and storage mechanisms for Pip are found in the nerve endings. Pip is highly concentrated in the pituitary and pineal glands, hippocampus and caudate nucleus among the regions of the brain. Levels of Pip in the brain show physiological variations associated with environmental changes. The levels increase significantly under deep anesthesia. The study on the time relations of the change in brain levels of Pip and the anesthetic activity demonstrates that the level increases prior to the loss of the righting reflex and that the elevated level declines prior to the reappearance of the reflex. Furthermore, Pip levels in the lower brainstem reticular formation show sleep-related changes during REM sleep deprivation and REM sleep rebound that followed. Direct administration of Pip into the hippocampus and amygdala of cats with chronically implanted electrodes and a cannula caused resting and calmness in small doses, and seizure discharge accompanied by hyperemotionality in large doses. Administration into the pontine reticular formation induced REM and NREM sleep. Iontophoretic application produced the excitation and inhibition of single neuron activities in the cerebral cortex, hippocampus, caudate nucleus, cerebellum, and pituitary in anesthetized rats. With no anesthesia, Pip caused the inhibitory action in a higher percentage of the neurons studied, compared with the result obtained under anesthesia. Pip-induced excitation and inhibiton were blocked by tetramethylammonium but little affected by scopolamine. The kinetic study of Pip-induced Cl- current in internally perfused neurons of Aplysia, by using the 'concentration camp' and voltage clamp techniques, revealed that Pip acted on at least two components of nicotinic receptor-Cl- channel complex, and further that Pip could discriminate between the transient and the persistent components of ACh-induced Cl- current. These findings suggest that Pip may have close connections with neuroendocrine as well as neuronal functions, and further, with the mechanisms underlying sleep-consciousness and emotional function. Because of piperidine's multiplex pharmacological activities, the study of piperidine may provide

Topics: Anesthesia; Animals; Brain; Consciousness; Hibernation; Humans; Neurons; Piperidines; Sleep, REM; Tissue Distribution

Topics: Alkaloids; Molecular Structure; Piperidines; Plants; Pyridines; Pyrrolidines

The sigma-1 (σ

Topics: Amnesia; Animals; Cell Survival; Dose-Response Relationship, Drug; Drug Development; Guinea Pigs; Humans; Ligands; Male; Mice; Models, Molecular; Molecular Structure; Piperidines; Rats; Rats, Wistar; Receptors, sigma; Sigma-1 Receptor; Structure-Activity Relationship; Tumor Cells, Cultured

There is continued interest in developing cascade processes for the synthesis of key chiral building blocks and bioactive natural products (or analogues). Here, we report a hybrid bio-organocatalytic cascade for the synthesis of a small panel of 2-substituted piperidines, relying on a transaminase to generate a key reactive intermediate for the complexity building Mannich reaction.

Topics: Piperidines

A series of novel σ

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Humans; Ligands; Lung Neoplasms; Male; Piperidines; Prostatic Neoplasms; Receptors, sigma; Structure-Activity Relationship

Novel fluorescent strigolactone derivatives that contain the piperidine-substituted 1,8-naphthalimide ring system connected through an ether link to a bioactive 3-methyl-furan-2-one unit were synthesized and their spectroscopic properties investigated. The solvatochromic behavior of these piperidine-naphthalimides was monitored in solvents of different polarity using the electronic absorption and fluorescence spectra. These compounds exhibited a strong positive solvatochromism taking into account the change of solvent polarity, and the response mechanism was analyzed by fluorescence lifetime measurements. According to Catalan and [f(n), f(ε), β, α] solvent scales, the dipolarity and polarizability are relevant to describe the solute-solvent interactions. The emission chemosensing activity was discussed in order to determine the water content in organic environments. The emission intensity of these compounds decreased rapidly in dioxane, increasing water level up to 10%. Measuring of quantum yield indicated that the highest values of quantum efficiency were obtained in nonpolar solvents, while in polar solvents these derivatives revealed the lowest quantum yield. The fluorescence decay can be described by a monoexponential model for low water levels, and for higher water contents a biexponential model was valid.

Topics: Fluorescence; Naphthalimides; Piperidines; Solvents; Spectrometry, Fluorescence; Water

Herein, alkenylpiperidine and alkynylpiperidine moieties were introduced into the left wing of DAPYs (diarylpyrimidines) to explore the new site of the NNIBP (non-nucleoside inhibitor binding pocket) protein-solvent interface region via the structure-based drug design strategy. All the synthesized compounds displayed nanomolar to submicromolar activity against WT (wild-type) HIV-1. Among all, compound FT1 (EC

Topics: Anti-HIV Agents; Dose-Response Relationship, Drug; Drug Design; HIV Reverse Transcriptase; HIV-1; Humans; Hydrophobic and Hydrophilic Interactions; Molecular Structure; Piperidines; Pyrimidines; Reverse Transcriptase Inhibitors; Structure-Activity Relationship

Topics: Acetylcholinesterase; Butyrylcholinesterase; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glutathione Transferase; Heterocyclic Compounds; Humans; Magnetic Resonance Spectroscopy; Mass Spectrometry; Molecular Structure; Piperidines; Schiff Bases; Spectrophotometry, Infrared

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Isoxazoles; Models, Molecular; Molecular Structure; Piperidines; Structure-Activity Relationship; Triazoles

Targeting neddylation pathway has been recognized as an attractive anticancer therapeutic strategy, thus discovering potent and selective neddylation inhibitors is highly desirable. Our work reported the discovery of novel cinnamyl piperidine compounds and their antitumor activity in vitro and in vivo. Among these compounds, compound 4g was identified as a novel neddylation inhibitor and decreased the neddylation levels of cullin 1, cullin 3 and cullin 5. Mechanistic studies demonstrated that compound 4g could inhibit the migration ability of gastric cancer cells and induce apoptosis partly mediated by the Nrf2-Keap1 pathway. Furthermore, in vivo anti-tumor studies showed that 4g effectively inhibited tumor growth without obvious toxicity. Collectively, the cinnamyl piperidine derivatives could serve as new lead compounds for developing highly effective neddylation inhibitors for gastric cancer therapy.

Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; Cinnamates; Cullin Proteins; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Piperidines; Stomach Neoplasms; Structure-Activity Relationship; Tumor Cells, Cultured

Topics: Acetic Acid; Amides; Animals; Behavior, Animal; Dose-Response Relationship, Drug; Formaldehyde; Guinea Pigs; Mice; Mice, Inbred ICR; Molecular Dynamics Simulation; Molecular Structure; Neuralgia; Pain Measurement; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Receptors, sigma; Sigma-1 Receptor; Structure-Activity Relationship

An efficient one-step synthesis of 2-acylquinolines using a copper-catalyzed tandem reaction of 2-ethynylanilines with glyoxals in the presence of piperidine has been developed. This new protocol successfully avoids multi-step operation and the use of highly toxic cyanides required in traditional methods, and provides a practical tool for synthetic and pharmaceutical chemists. Various 2-acylquinolines are obtained with perfect regioselectivity in moderate to good yields (up to 86%). The potential synthetic utility of this method is exemplified by a large-scale experiment and synthetic transformation of the products.

Topics: Acetylene; Aniline Compounds; Catalysis; Copper; Cyclization; Glyoxal; Models, Chemical; Piperidines; Quinolines

Manganese lipoxygenase (MnLOX) is an enzyme that converts polyunsaturated fatty acids to alkyl hydroperoxides. In proposed mechanisms for this enzyme, the transfer of a hydrogen atom from a substrate C-H bond to an active-site Mn

Topics: Biomimetics; Catalytic Domain; Coordination Complexes; Fatty Acids, Unsaturated; Hydrogen; Ligands; Lipid Peroxides; Lipoxygenase; Manganese; Molecular Structure; Oxidation-Reduction; Oxygen; Piperidines

6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is a key enzyme in the folate biosynthesis pathway. It catalyzes pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin (HP). HPPK is essential for microorganisms but absent in mammals; therefore, it is an attractive target for developing novel antimicrobial agents. Previously, based on our studies of the structure and mechanism of HPPK, we created first-generation bisubstrate inhibitors by linking 6-hydroxymethylpterin to adenosine through phosphate groups, and developed second-generation inhibitors by replacing the phosphate bridge with a linkage that contains a piperidine moiety. Here, we report third-generation inhibitors designed based on the piperidine-containing inhibitor, mimicking the transition state. We synthesized two such inhibitors, characterized their protein-binding and enzyme inhibition properties, and determined their crystal structures in complex with HPPK, advancing the development of such bisubstrate analog inhibitors.

Topics: Adenosine Triphosphate; Binding Sites; Crystallography, X-Ray; Diphosphotransferases; Dose-Response Relationship, Drug; Enzyme Inhibitors; Escherichia coli; Models, Molecular; Molecular Structure; Piperidines; Pterins; Structure-Activity Relationship

A series of 4-pyridylpiperazine derivatives with varying regulatory region substituents proved to be potent histamine H

Topics: Animals; Anti-Obesity Agents; Body Weight; Dose-Response Relationship, Drug; Female; Histamine H3 Antagonists; Humans; Imidazoles; Ligands; Models, Molecular; Piperazine; Piperidines; Protein Binding; Rats, Wistar; Receptors, Histamine H3; Regulatory Sequences, Nucleic Acid; Structure-Activity Relationship

Taking advantage of the diversity-oriented synthesis strategy with α,β-unsaturated carbonyl compounds, we have successfully established the DNA-compatible transformations for various heterocyclic scaffolds. The ring-closure reactions for pyrrole, pyrrolidine, pyrazole, pyrazoline, isoxazoline, pyridine, piperidine, cyclohexenone, and 5,8-dihydroimidazo[1,2-

Topics: Combinatorial Chemistry Techniques; DNA; Gene Library; Ketones; Molecular Structure; Piperidines

The HBV core protein is a druggable target of interest due to the multiple essential functions in the HBV life cycle to enable chronic HBV infection. The core protein oligomerizes to form the viral capsid, and modulation of the HBV capsid assembly has shown efficacy in clinical trials. Herein is described the identification and hit to lead SAR of a novel series of pyrazolo piperidine HBV capsid assembly modulators.

Topics: Antiviral Agents; Capsid Proteins; Dose-Response Relationship, Drug; Hepatitis B virus; Microbial Sensitivity Tests; Molecular Structure; Piperidines; Pyrazoles; Structure-Activity Relationship

Solid-state photodecarbonylation is an attractive but underutilized methodology to forge hindered C-C bonds in complex molecules. This study discloses the use of this reaction to assemble the vicinal quaternary stereocenter motif present in bis(cyclotryptamine) alkaloids. Our strategy was enabled by experimental and computational investigations of the role of substrate conformation on the success or failure of the solid-state photodecarbonylation reaction. This informed a crystal engineering strategy to optimize the key step of the total synthesis. Ultimately, this endeavor culminated in the successful synthesis of the bis(cyclotryptamine) alkaloid "psychotriadine," which features the elusive piperidinoindoline framework. Psychotriadine, a previously unknown compound, was identified in the extracts of the flower

Topics: Alkaloids; Carbon; Free Radicals; Indoles; Light; Molecular Conformation; Piperidines; Stereoisomerism

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Topics: Animals; Azetidines; Benzamides; Cells, Cultured; Drug Discovery; HEK293 Cells; Humans; NAV1.7 Voltage-Gated Sodium Channel; Piperidines; Rats, Sprague-Dawley; Sulfonamides; Voltage-Gated Sodium Channel Blockers

Phenotypic screening identified a benzothiophene compound with activity against Leishmania donovani, the causative agent of visceral leishmaniasis. Using multiple orthogonal approaches, oxidosqualene cyclase (OSC), a key enzyme of sterol biosynthesis, was identified as the target of this racemic compound and its enantiomers. Whole genome sequencing and screening of a genome-wide overexpression library confirmed that OSC gene amplification is associated with resistance to compound 1. Introduction of an ectopic copy of the OSC gene into wild-type cells reduced susceptibility to these compounds confirming the role of this enzyme in resistance. Biochemical analyses demonstrated the accumulation of the substrate of OSC and depletion of its product in compound (S)-1-treated-promastigotes and cell-free membrane preparations, respectively. Thermal proteome profiling confirmed that compound (S)-1 binds directly to OSC. Finally, modeling and docking studies identified key interactions between compound (S)-1 and the LdOSC active site. Strategies to improve the potency for this promising anti-leishmanial are proposed.

Topics: Antiprotozoal Agents; Crystallography, X-Ray; Enzyme Inhibitors; Intramolecular Transferases; Leishmania donovani; Models, Molecular; Molecular Structure; Parasitic Sensitivity Tests; Piperidines

The de novo synthesis of piperidine nucleosides from our homologating agent 5,6-dihydro-1,4-dithiin is herein reported. The structure and conformation of nucleosides were conceived to faithfully resemble the well-known nucleoside drugs Immucillins H and A in their bioactive conformation. NMR analysis of the synthesized compounds confirmed that they adopt an iminosugar conformation bearing the nucleobases and the hydroxyl groups in the appropriate orientation.

Topics: Adenine; Adenosine; Magnetic Resonance Spectroscopy; Molecular Conformation; Nucleosides; Piperidines; Purine Nucleosides; Pyrimidinones; Pyrrolidines; Structure-Activity Relationship

Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders, characterized by multiple pathological features. Therefore, multi-target drug discovery has been one of the most active fields searching for new effective anti-AD therapies. Herein, a series of hybrid compounds are reported which were designed and developed by combining an aryl-sulfonamide function with a benzyl-piperidine moiety, the pharmacophore of donepezil (a current anti-AD acetylcholinesterase AChE inhibitor drug) or its benzyl-piperazine analogue. The in vitro results indicate that some of these hybrids achieve optimized activity towards two main AD targets, by displaying excellent AChE inhibitory potencies, as well as the capability to prevent amyloid-

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Cell Line, Tumor; Cholinesterase Inhibitors; Donepezil; Humans; Ligands; Piperazines; Piperidines; Structure-Activity Relationship; Sulfonamides

A novel class of HIV-1 protease inhibitors with flexible piperidine as the P2 ligand was designed with the aim of improving extensive interactions with the active subsites. Many inhibitors exhibited good to excellent inhibitory effect on enzymatic activity and viral infectivity. In particular, inhibitor 3a with (R)-piperidine-3-carboxamide as the P2 ligand and 4-methoxybenzenesulfonamide as the P2' ligand showed an enzyme K

Topics: Anti-HIV Agents; Darunavir; Dose-Response Relationship, Drug; Drug Design; Drug Resistance, Viral; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Microbial Sensitivity Tests; Molecular Structure; Piperidines; Structure-Activity Relationship

Plants synthesize many diverse small molecules that affect function of the mammalian central nervous system, making them crucial sources of therapeutics for neurological disorders. A notable portion of neuroactive phytochemicals are lysine-derived alkaloids, but the mechanisms by which plants produce these compounds have remained largely unexplored. To better understand how plants synthesize these metabolites, we focused on biosynthesis of the Lycopodium alkaloids that are produced by club mosses, a clade of plants used traditionally as herbal medicines. Hundreds of Lycopodium alkaloids have been described, including huperzine A (HupA), an acetylcholine esterase inhibitor that has generated interest as a treatment for the symptoms of Alzheimer's disease. Through combined metabolomic profiling and transcriptomics, we have identified a developmentally controlled set of biosynthetic genes, or potential regulon, for the Lycopodium alkaloids. The discovery of this putative regulon facilitated the biosynthetic reconstitution and functional characterization of six enzymes that act in the initiation and conclusion of HupA biosynthesis. This includes a type III polyketide synthase that catalyzes a crucial imine-polyketide condensation, as well as three Fe(II)/2-oxoglutarate-dependent dioxygenase (2OGD) enzymes that catalyze transformations (pyridone ring-forming desaturation, piperidine ring cleavage, and redox-neutral isomerization) within downstream HupA biosynthesis. Our results expand the diversity of known chemical transformations catalyzed by 2OGDs and provide mechanistic insight into the function of noncanonical type III PKS enzymes that generate plant alkaloid scaffolds. These data offer insight into the chemical logic of Lys-derived alkaloid biosynthesis and demonstrate the tightly coordinated coexpression of secondary metabolic genes for the biosynthesis of medicinal alkaloids.

Topics: Alkaloids; Biosynthetic Pathways; Lycopodium; Metabolomics; Mixed Function Oxygenases; Oxidation-Reduction; Piperidines; Regulon; Sesquiterpenes; Transcriptome

A series of benzofuran piperidine derivatives were designed, synthesized and evaluated as multifunctional Aβ antiaggregant to treat Alzheimer's disease (AD). In vitro results revealed that all of them are very good Aβ antiaggregants and some of the compounds are potent acetylcholinesterase (AChE) inhibitors with moderate antioxidant property. Selected compounds were also tested for neuroprotection activity, LDH release, ATP production and inhibitory activity to prevent Aβ peptides binding to the cell membrane. The different modifications introduced in the structure of our lead compound 3 (hAChE IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Benzofurans; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Humans; Models, Molecular; Molecular Structure; Neuroprotective Agents; Piperidines; Protein Aggregates; Protein Aggregation, Pathological; Structure-Activity Relationship

Monoacylglycerol lipase (MAGL) is an enzyme belonging to the endocannabinoid system that mainly metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG). Numerous studies have shown the involvement of this enzyme in various pathological conditions such as pain, cancer progression, Parkinson's and Alzheimer's disease, thus encouraging the development of new MAGL modulators. In this context, we developed new diphenylsulfide-benzoylpiperidine derivatives characterized by a high enzymatic MAGL inhibition activity in the low nanomolar range, a reversible mechanism of action and selectivity. The three most active compounds (15-17) induced an appreciable inhibition of cell viability in a panel of nine cancer cell lines, with IC

Topics: Antineoplastic Agents; Binding Sites; Catalytic Domain; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Humans; Molecular Docking Simulation; Monoacylglycerol Lipases; Piperidines; Recombinant Proteins; Structure-Activity Relationship; Sulfides

Thiopeptide antibiotics are a family of ribosomally synthesized and posttranslationally modified peptide natural products of significant interest in anti-infective agent development. These antibiotics are classified into five subfamilies according to differences in the central 6-membered heterocycle of the thiopeptide framework. The mechanism through which imidazopiperidine, the most heavily functionalized central domain characteristic of a series

Topics: Amino Acid Sequence; Anti-Bacterial Agents; Micromonospora; Mixed Function Oxygenases; Oxidation-Reduction; Peptides; Piperidines; Streptomyces; Thiazoles

Mycobacterium tuberculosis thymidylate kinase (MtTMPK) has emerged as an attractive target for rational drug design. We recently investigated new families of non-nucleoside MtTMPK inhibitors in an effort to diversify MtTMPK inhibitor chemical space. We here report a new series of MtTMPK inhibitors by combining the Topliss scheme with rational drug design approaches, fueled by two co-crystal structures of MtTMPK in complex with developed inhibitors. These efforts furnished the most potent MtTMPK inhibitors in our assay, with two analogues displaying low micromolar MIC values against H37Rv Mtb. Prepared inhibitors address new sub-sites in the MtTMPK nucleotide binding pocket, thereby offering new insights into its druggability. We studied the role of efflux pumps as well as the impact of cell wall permeabilizers for selected compounds to potentially provide an explanation for the lack of correlation between potent enzyme inhibition and whole-cell activity.

Topics: Antitubercular Agents; Dose-Response Relationship, Drug; Enzyme Inhibitors; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Nucleoside-Phosphate Kinase; Piperidines; Structure-Activity Relationship; Thymine

Thirteen epimeric pairs of 5-substituted N-piperonyl-3-phenylpiperidine derivatives were synthesized in order to explore the stereospecific modulation of basicity, lipophilicity, aqueous solubility, and membrane permeation by functional groups in equatorial or axial positions beta to the amine unit. While this comprehensive data set provides enhanced insight into multiple factors that affect basicity and lipophilicity, it fills an important knowledge gap, providing a frame of reference for the property-based design of bioactive compounds. Impacts on amine basicity are very pronounced for the β-equatorial functional groups and parallel basicity-lowering effects known for acyclic amine derivatives. For β-axial functional groups, the basicity-lowering effects are generally decreased, with the nitrile group as the only exception. Basicity and lipophilicity modulations observed for β-axial functional groups are quite diverse and rationalized in terms of intramolecular hydrogen bonding, dipolar interactions, and special solvation effects. Aqueous solubility and (artificial) membrane permeability are discussed with reference to lipophilicity.

Topics: Hydrogen Bonding; Molecular Structure; Piperidines; Solubility

Melanogenesis controls the formation of melanin pigment whose overproduction is related to various hyperpigmentary disorders in humans. Tyrosinase is a type-3 copper enzyme involved in the rate limiting step of melanin synthesis, therefore its inhibition could represent an efficient way for the development of depigmenting agents. In this work, a combination of pharmacophore and docking-based studies has been employed to screen two in-house 3D compound databases containing about 2,000 molecules from natural and synthetic sources. As result we selected two "hit compounds" which proved to inhibit tyrosinase activity showing IC

Topics: Agaricales; Drug Discovery; Drug Evaluation, Preclinical; Enzyme Inhibitors; Molecular Docking Simulation; Molecular Structure; Monophenol Monooxygenase; Piperazine; Piperidines

Multi-target-directed ligands seem to be an interesting approach to the treatment of complex disorders such as Alzheimer's disease. The aim of the present study was to find novel multifunctional compounds in a non-imidazole histamine H

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Benzopyrans; Butyrylcholinesterase; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Electrophorus; Histamine H3 Antagonists; Horses; Humans; Ligands; Molecular Docking Simulation; Molecular Structure; Neuroprotective Agents; Piperidines; Receptors, Histamine H3; Structure-Activity Relationship

Topics: Acetic Acid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dose-Response Relationship, Drug; Formaldehyde; Humans; Hyperalgesia; Inflammation; Molecular Docking Simulation; Molecular Structure; Piperidines; Rats; Rats, Wistar; Structure-Activity Relationship; Triazines; Tryptophan

Dantrolene, the only therapeutic agent for malignant hyperthermia, is known to have not only a muscle relaxant effect, but also a neuroprotective effect and Alzheimer's disease improving effect. Recently, it has been reported that dantrolene has a weak inhibitory effect on acetylcholinesterase (AChE), which is a therapeutic drug target for Alzheimer's disease. Thus, we focused on developing of AChE inhibitors with benzylpiperidine/piperazine moieties that are based on the dantrolene skeleton. Several derivatives showed an inhibitory activity. Among them, ortho-nitro derivative 8c showed the most potent inhibitory activity with the IC

Topics: Acetylcholinesterase; Butyrylcholinesterase; Cholinesterase Inhibitors; Dantrolene; Drug Design; Humans; Inhibitory Concentration 50; Kinetics; Muscle Relaxants, Central; Piperazine; Piperidines; Structure-Activity Relationship

In order to prepare, at low cost, new compounds active against

Topics: Antimalarials; Human Umbilical Vein Endothelial Cells; Humans; Piperidines; Plasmodium falciparum

A series of iodinated ligands for the SPECT imaging of 5-HT

Topics: Animals; Brain Chemistry; CHO Cells; Cricetulus; Dioxanes; Humans; Iodine Radioisotopes; Ligands; Piperidines; Rats; Receptors, Serotonin, 5-HT4; Tomography, Emission-Computed, Single-Photon

Topics: Amides; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Formaldehyde; Guinea Pigs; Injections, Subcutaneous; Mice; Mice, Inbred ICR; Molecular Structure; Neuralgia; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Receptors, sigma; Sciatic Nerve; Sigma-1 Receptor; Structure-Activity Relationship

The piperidine ring is a widespread motif in several natural bioactive alkaloids of both vegetal and marine origin. In the last years, a diversity-oriented synthetic (DOS) approach, aimed at the generation of a library of piperidine-based derivatives, was developed in our research group, employing commercially available 2-piperidine ethanol as a versatile precursor. Here, we report the exploration of another ramification of our DOS approach, that led us to the stereoselective total synthesis of (-)-anaferine, a bis-piperidine alkaloid present in

Topics: Alkaloids; Ethanol; Piperidines; Plant Extracts; Stereoisomerism; Withania

Schizophrenia is a chronic, disabling mental disorder that affects about one percent of world's population. Drugs acting on multiple targets have been demonstrated to provide superior efficacy in schizophrenia than agents acting on single target. In this study, based on FW01, a selective potent 5-HT

Topics: Animals; Antipsychotic Agents; Dose-Response Relationship, Drug; Drug Discovery; HEK293 Cells; Humans; Mice; Mice, Inbred ICR; Models, Molecular; Molecular Structure; Piperidines; Receptor, Serotonin, 5-HT1A; Receptors, Dopamine D2; Serotonin Antagonists; Structure-Activity Relationship

Herein we report on a new series of hydrazidoureidobenzensulfonamides investigated as inhibitors of the cytosolic human (h) hCA I and II isoforms, as well as the transmembrane, tumor-associated enzymes hCA IX and XII. The reported derivatives contain a 4-substituted piperidine fragment in which the hydrazidoureido linker has been involved as spacer between the benzenesulfonamide fragment which binds the zinc ion from the active site, and the tail of the inhibitor. Depending on the substitution pattern at the piperidine ring, low nanomolar inhibitors were detected against hCA II, hCA IX and hCA XII, making the new class of sulfonamides of interest for various pharmacologic applications.

Topics: Antigens, Neoplasm; Benzenesulfonamides; Carbonic Anhydrase II; Carbonic Anhydrase Inhibitors; Carbonic Anhydrase IX; Carbonic Anhydrases; Dose-Response Relationship, Drug; Humans; Hydrazines; Molecular Docking Simulation; Molecular Structure; Piperidines; Structure-Activity Relationship; Sulfonamides

A strategy towards the synthesis of three different target molecules, namely 1,4-dideoxy-1,4-imino-l-xylitol, deacetyl (+)-anisomycin and amino-substituted piperidine iminosugars, molecules of potential biological and medicinal significance, is reported from a common amino-vicinal diol intermediate derived from tri-O-benzyl-d-glucal. Construction of the key pyrrolidine ring present in 1,4-dideoxy-1,4-imino-l-xylitol and (+)-anisomycin was a consequence of thermodynamically driven concomitant intramolecular nucleophilic addition reaction of the amino group to the resultant aldehyde obtained by oxidative cleavage of the amino-vicinal diol. Alternatively, double nucleophilic substitution on an amino-diol, after mesylation, with various amines delivered amino-substituted piperidine iminosugars in good yields.

Topics: Anisomycin; Imino Furanoses; Imino Sugars; Molecular Conformation; Piperidines; Stereoisomerism; Xylitol

Organophosphorus compounds occupy a significant position among the plethora of organic compounds, but a limited number of paramagnetic phosphorus compounds have been reported, including paramagnetic phosphonates. This paper describes the syntheses and further transformations of pyrroline and piperidine nitroxide phosphonates by well-established methods, such as the Pudovik, Arbuzov and Horner-Wadsworth-Emmons (HWE) reactions. The reaction of paramagnetic a-bromoketone produced a vinylphosphonate in the Perkow reaction. Paramagnetic a-hydroxyphosphonates could be subjected to oxidation, elimination and substitution reactions to produce various paramagnetic phosphonates. The synthesized paramagnetic phosphonates proved to be useful synthetic building blocks for carbon-carbon bond-forming reactions in the Horner-Wadsworth-Emmons olefination reactions. The unsaturated compounds achieved could be transformed into various substituted pyrroline nitroxides, proxyl nitroxides and paramagnetic polyaromatics. The Trolox

Topics: Alkenes; Carbon; Molecular Structure; Nitrogen Oxides; Organophosphonates; Piperidines; Pyrroles; Stereoisomerism

The degradation pathways in microorganisms for piperidine, a secondary amine with various applications, are not yet fully understood, especially in non-Mycobacterium species. In this study, we have identified a piperidine-degrading isolate (KU43P) from a soil sample collected in a cultivation field in Osaka, Japan, and characterized its mechanisms of piperidine degradation, thereby furthering current understanding of the process. The genome of isolate KU43P consists of a 5,869,691-bp circular chromosome with 62.67% GC content and with 5,294 predicted protein-coding genes, 77 tRNA genes, and 22 rRNA genes. 16S rRNA gene sequence analysis and average nucleotide identity analysis suggest that the isolate is a novel species of the Pseudomonas putida group in the genus Pseudomonas. The genomic region encoding the piperidine degradation pathway, designated as the pip gene cluster, was identified using transposon mutagenesis and reverse transcription polymerase chain reaction. Deletion analyses of pipA, which encodes a glutamine synthetase (GS)-like protein, and pipBa, which encodes a cytochrome P450 monooxygenase, indicate that pipA and pipBa are involved in piperidine metabolism and suggest that pipA is involved in the first step of the piperidine metabolic pathway. Escherichia coli whole cells overexpressing PipA converted piperidine and glutamate to γ-glutamylpiperidide, and crude cell extract enzyme assays of PipA showed that this reaction requires ATP and Mg

Topics: Amide Synthases; Bacterial Proteins; Biodegradation, Environmental; Cytochrome P-450 Enzyme System; Escherichia coli; Genome, Bacterial; Metabolic Networks and Pathways; Multigene Family; Mutation; Phylogeny; Piperidines; Pseudomonas; Recombinant Proteins; Transcription, Genetic

A series of potent HIV-1 protease inhibitors, containing diverse piperidine analogues as the P2-ligands, 4-substituted phenylsulfonamides as the P2'-ligands and a hydrophobic cyclopropyl group as the P1'-ligand, were designed, synthesized and evaluated in this work. Among these twenty-four target compounds, many of them exhibited excellent activity against HIV-1 protease with half maximal inhibitory concentration (IC50) values below 20 nM. Particularly, compound 22a containing a (R)-piperidine-3-carboxamide as the P2-ligand and a 4-methoxylphenylsulfonamide as the P2'-ligand exhibited the most effective inhibitory activity with an IC50 value of 3.61 nM. More importantly, 22a exhibited activity with inhibition of 42% and 26% against wild-type and Darunavir (DRV)-resistant HIV-1 variants, respectively. Additionally, the molecular docking of 22a with HIV-1 protease provided insight into the ligand-binding properties, which was of great value for further study.

Topics: Crystallography, X-Ray; Darunavir; Drug Design; Enzyme Inhibitors; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Ligands; Molecular Docking Simulation; Molecular Structure; Piperidines; Structure-Activity Relationship; Sulfonamides

Filoviruses, including Ebolavirus (EBOV), Marburgvirus (MARV) and Cuevavirus, cause hemorrhagic fevers in humans with up to 90% mortality rates. In the 2014-2016 West Africa Ebola epidemic, there are 15,261 laboratory confirmed cases and 11,325 total deaths. The lack of effective vaccines and medicines for the prevention and treatment of filovirus infection in humans stresses the urgency to develop antiviral therapeutics against filovirus-associated diseases. Our previous study identified a histamine receptor antagonist compound CP19 as an entry inhibitor against both EBOV and MARV. The preliminary structure-activity relationship (SAR) studies of CP19 showed that its piperidine, coumarin and linker were related with its antiviral activities. In this study, we performed detailed SAR studies on these groups with synthesized CP19 derivatives. We discovered that 1) the piperidine group could be optimized with heterocycles, 2) the substitution groups of C3 and C4 of coumarin should be relatively large hydrophobic groups and 3) the linker part should be least substituted. Based on the SAR analysis, we synthesized compound 32 as a potent entry inhibitor of EBOV and MARV (IC

Topics: Antiviral Agents; Coumarins; Drug Design; Filoviridae; Molecular Targeted Therapy; Piperidines; Structure-Activity Relationship; Viral Envelope Proteins; Virus Internalization

Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) is an attractive therapeutic strategy for targeting cancer metabolism. So far, many potent NAMPT inhibitors have been developed and shown to bind to two unique tunnel-shaped cavities existing adjacent to each active site of a NAMPT homodimer. However, cytotoxicities and resistances to NAMPT inhibitors have become apparent. Therefore, there remains an urgent need to develop effective and safe NAMPT inhibitors. Thus, we designed and synthesized two close structural analogues of NAMPT inhibitors, azaindole-piperidine (

Topics: Binding Sites; Catalytic Domain; Drug Design; Enzyme Inhibitors; Humans; Indoles; Kinetics; Molecular Docking Simulation; Nicotinamide Phosphoribosyltransferase; Piperazine; Piperidines

We report the optimisation of a series of novel amide-piperidine (piperazine) derivatives using the multiple ligand approach with dopamine and serotonin receptors. Of the derivatives, compound 11 exhibited high affinity for the D

Topics: Amides; Animals; Antipsychotic Agents; Dose-Response Relationship, Drug; Ether-A-Go-Go Potassium Channels; Humans; Ligands; Molecular Structure; Piperazine; Piperidines; Rats; Receptors, Dopamine D2; Receptors, Serotonin; Schizophrenia; Structure-Activity Relationship

Several factors have influenced the increasing presence of peptides as an important class of Active Pharmaceutical Ingredients. One is the continued development of synthetic methodologies for peptide synthesis. Herein, we investigated the Fmoc removal step, using the tea-bag strategy. In this regard, three different secondary amines: piperidine, 4-methylpiperidine, and piperazine, were evaluated. As a result of this study, 4-methyl piperidine showed to be an excellent alternative to the usually used piperidine in terms of purity and compliance with green chemistry principles as well.

Topics: Green Chemistry Technology; Peptides; Piperazine; Piperidines; Solid-Phase Synthesis Techniques

α: 7 nicotinic acetylcholine receptors (nAChRs) expressed in the nervous and immune systems have been suggested to play important roles in the control of inflammation. However, the lack of antagonist tools specifically inhibiting α7 nAChR impedes the validation of the channel as therapeutic target. To discover a selective α7 antagonist, we started a pharmacophore-based virtual screening and identified a piperidine-spirooxadiazole derivative T761-0184 that acts as a α7 antagonist. A series of novel piperidine-spirooxadiazole derivatives were subsequently synthesized and evaluated using two-electrode voltage clamp (TEVC) assay in Xenopus oocytes. Lead compounds from two series inhibited α7 with their IC

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Chemistry Techniques, Synthetic; Drug Design; Nicotinic Antagonists; Oxadiazoles; Piperidines; Structure-Activity Relationship; Xenopus laevis

There is currently a lack of efficient reagents to transfect cells with large plasmid DNA, which would be enabling tools for gene editing using CRISPR/Cas9 technology. Herein, we report the discovery of peptide dendrimer Z22 as a non-viral vector for transfecting large CRISPR/Cas9 pDNA into 3D-tumor spheroids with exceptionally high efficiency, low cytotoxicity and low immunogenicity.

Topics: Cell Survival; CRISPR-Cas Systems; Dendrimers; DNA; Gene Editing; Genetic Therapy; HEK293 Cells; HeLa Cells; Heparin; Humans; Peptides; Phosphatidylethanolamines; Piperidines; Spheroids, Cellular; Transfection

The cholinesterase enzymes play a vital role in maintaining balanced levels of the neurotransmitter acetylcholine in the central nervous system. However, the overexpression of these enzymes results in hampered neurotransmission. Both the major forms of cholinesterase enzymes viz. acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) play a crucial role in blocking neurotransmission; therefore, in recent years, a strategy of dual cholinesterase inhibition is being explored. Herein, we developed an energy-optimized e-pharmacophore hypothesis AHHPRR from AChE-donepezil complex and screened a set of 15 scaffolds that were designed imaginarily. The ligand with N-(1-benzylpyridinium) benzamide framework has shown the highest fitness and volume score, which was chosen for synthesis and validation. A series of pyridinium benzamides were synthesized and screened for cholinesterase inhibition that led to the identification of 7b, a naphthalene containing N-(1-benzylpiperidine) benzamide as a potent dual AChE and BChE inhibitor with IC

Topics: Acetylcholinesterase; Benzamides; Blood-Brain Barrier; Butyrylcholinesterase; Cholinesterase Inhibitors; Drug Design; Inhibitory Concentration 50; Molecular Dynamics Simulation; Permeability; Piperidines; Protein Conformation

Dehydroleucodine is a bioactive sesquiterpene lactone. Herein, four dehydroleucodine amino derivatives were synthesized using the amines proline, piperidine, morpholine, and tyramine, and spectroscopic methods and single-crystal X-ray diffraction unambiguously established their structures. The cytotoxic activity of these compounds was evaluated against eight acute myeloid leukemia cell lines, and their toxicity to peripheral blood mononuclear cells was also determined. The proline adduct was the most active compound, it showed anti-leukemic activity, upregulated heme oxygenase 1 (HMOX1) and the primary stress-inducible isoform of the heath shock 70 kDa protein 1 (HSPA1A), and downregulated NFkB1 transcription, it was also found to be about 270 times more water soluble than dehydroleucodine.

Topics: Cell Line, Tumor; Cell Proliferation; Crystallography, X-Ray; Gene Expression Regulation, Leukemic; Heme Oxygenase-1; HSP70 Heat-Shock Proteins; Humans; Lactones; Leukemia, Myeloid, Acute; Leukocytes, Mononuclear; Morpholines; NF-kappa B p50 Subunit; Piperidines; Sesquiterpenes; Tyramine

Topics: Administration, Oral; Amides; Amines; Animals; Chemokine CXCL12; Crystallography, X-Ray; Dogs; Drug Evaluation, Preclinical; Half-Life; Humans; Inhibitory Concentration 50; Mice; Molecular Conformation; Piperidines; Protein Binding; Rats; Receptors, CXCR; Structure-Activity Relationship

A series of propanamide compounds 6a-l was derived by N-substitution reactions, encompassing tosyl, piperidine and 1,3,4-oxadiazole moieties. The intended array of compounds 6a-l was afforded by a series of five steps reaction scheme. 1-Tosylpiperidin-4-carboxylate (1) was synthesized by the reaction of tosyl chloride (a) with ethyl isonipecotate (b) under mild basic conditions. Compound 1 was subjected to nucleophillic substitution by hydrazine to synthesize 1-tosylpiperidin-4-carbohydrazide (2). The compound, 5-(1-tosylpiperidin-4-yl)-1,3,4-oxadiazole-2-thiol (3) was synthesized by intermolecular cyclization of compound 2 by CS2 under strong basic conditions. The target compounds, 6a-l, were finally synthesized from 3 by reacting with different electrophiles, 5a-l, in an aprotic polar solvent with sodium hydride as an activator. The different propanamoyl electrophiles, 5a-l, were synthesized by the reaction of different aromatic and aliphatic amines, 4a-l, with 3-bromopropionyl chloride under mild basic conditions. The structural elucidation was carried out using modern spectroscopic techniques including IR, 1H-NMR and EI-MS. The antibacterial potential of synthesized compounds was assessed against five bacterial strains. Compounds 6a, 6c, 6d, 6e and 6f were found to be potent antibacterial agents.

Topics: Anti-Bacterial Agents; Hydrazines; Microbial Sensitivity Tests; Oxadiazoles; Piperidines; Tosyl Compounds

HDAC8 has been established as one of the vital targets as far as the cancer is concerned. Different compounds having potential HDAC inhibitory activity have been approved by USFDA. However, none of these compounds are selective towards specific HDAC isoform. In this current study, some new hydroxamate derivatives with alkylpiperidine and alkylpiperazine linker moieties have been designed, synthesized and biologically evaluated. All these compounds are effective HDAC8 inhibitors comprising more or less similar cytotoxic potential against different cancer cell lines. It is observed that the piperazine scaffold containing compound is more active than the compound with piperidine scaffold for exerting HDAC8 inhibitory activity. Moreover, the 4-quinolyl cap group is better than the biphenyl group which is better than the benzyl group for producing higher HDAC8 inhibition as well as cytotoxicity. These compounds displayed selective HDAC8 inhibition over HDAC3. Moreover, these compounds showed an increased caspase3/7 activity suggesting their anticancer potential through modulation of apoptotic pathways. Molecular docking study with three potent compounds was performed with both HDAC3 and HDAC8 enzymes to understand the selectivity profile of these compounds. Compound containing 4-quinolyl cap group with alkyl piperazinyl urea linker moiety has been emerged out as the lead molecule that may be further modified to design more effective and selective HDAC8 inhibitors in future.

Topics: A549 Cells; Animals; Antineoplastic Agents; Apoptosis; Cell Line; Cell Line, Tumor; HeLa Cells; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Jurkat Cells; MCF-7 Cells; Melanoma, Experimental; Mice; Molecular Docking Simulation; Piperazine; Piperidines; Receptor, EphB3; Repressor Proteins

(-)-Himeradine A is a complex lycopodium alkaloid with seven rings and ten stereogenic centers that shows anticancer activity against lymphoma L1210 cells. A total synthesis has been developed that builds off prior work on (+)-fastigiatine. A 2,4,6-trisubstitited piperidine ring forms the core of the quinolizidine segment, and was prepared by diastereoselective reduction of a pyridine and classic resolution of an intermediate. The remaining secondary amine was introduced with a catalyst-controlled Overman rearrangement. The piperidine segment was coupled in a B-alkyl Suzuki reaction with a bicyclic bromoenone, which was a key intermediate for the synthesis of (+)-fastigiatine. The final transformation featured a transannular Mannich reaction and cyclization to complete the quinolizidine. Five bonds and four new rings were generated in this one-pot procedure. (-)-Himeradine A was prepared in 17 steps in the longest linear sequence.

Topics: Catalysis; Cyclization; Molecular Structure; Piperidines; Pyridines; Quinolizines; Stereoisomerism

We have synthesized a new series of 1,2,3-triazolo piperazine and piperidine carboxylate derivatives using a simple and one-pot click chemistry with significantly reduced reaction times (~5 min) and enhanced reaction yields (~95-98%). The fourteen novel compounds thus synthesized were tested for ability to target GPR119, a G-protein coupled target receptor that plays critical role in regulation of type-2 diabetes mellitus. Four analogs (3e, 3g, 5e and 5g) demonstrated similar or better EC

Topics: Click Chemistry; Humans; Molecular Structure; Piperazine; Piperidines; Receptors, G-Protein-Coupled; Structure-Activity Relationship

The transient receptor potential ankyrin 1 (TRPA1) channel functions as an irritant sensor and is a therapeutic target for treating pain, itch, and respiratory diseases. As a ligand-gated channel, TRPA1 can be activated by electrophilic compounds such as allyl isothiocyanate (AITC) through covalent modification or activated by noncovalent agonists through ligand binding. However, how covalent modification leads to channel opening and, importantly, how noncovalent binding activates TRPA1 are not well-understood. Here we report a class of piperidine carboxamides (PIPCs) as potent, noncovalent agonists of human TRPA1. Based on their species-specific effects on human and rat channels, we identified residues critical for channel activation; we then generated binding modes for TRPA1-PIPC interactions using structural modeling, molecular docking, and mutational analysis. We show that PIPCs bind to a hydrophobic site located at the interface of the pore helix 1 (PH1) and S5 and S6 transmembrane segments. Interestingly, this binding site overlaps with that of known allosteric modulators, such as A-967079 and propofol. Similar binding sites, involving π-helix rearrangements on S6, have been recently reported for other TRP channels, suggesting an evolutionarily conserved mechanism. Finally, we show that for PIPC analogs, predictions from computational modeling are consistent with experimental structure-activity studies, thereby suggesting strategies for rational drug design.

Topics: Animals; Binding Sites; Calcium Channels; Drug Design; Humans; Isothiocyanates; Ligands; Models, Structural; Molecular Docking Simulation; Mutagenesis; Oximes; Piperidines; Propofol; Protein Domains; Rats; Species Specificity; TRPA1 Cation Channel

Acetylcholinesterase (AChE) catalyzes the conversion of Aβ peptide to its aggregated form and the peripheral anionic site (PAS) of AChE is mainly involved in this phenomenon. Also catalytic active site (CAS) of donepezil stimulates the break-down of acetylcholine (ACh) and depletion of ACh in cholinergic synapses are well established in brains of patients with AD. In this study, a set of compounds bearing phenoxyethyl amines were synthesized and their inhibitory activity toward electric eel AChE (eeAChE) and equine butyrylcholinesterase (eqBuChE) were evaluated. Molecular dynamics (MD) was employed to record the binding interactions of best compounds against human cholinesterases (hAChE and hBuChE) as well as donepezil as reference drug. In vitro results revealed that compound 5c is capable of inhibiting eeAChE activity at IC

Topics: Acetylcholinesterase; Butyrylcholinesterase; Cholinesterase Inhibitors; Drug Design; Enzyme Activation; Humans; Models, Molecular; Molecular Dynamics Simulation; Morpholines; Piperidines

An impaired signaling capacity of the serotonin (5-HT) 5-HT

Topics: Allosteric Regulation; Allosteric Site; Amides; Animals; Azepines; Calcium; CHO Cells; Cricetinae; Cricetulus; Drug Design; Half-Life; Indoles; Locomotion; Molecular Docking Simulation; Piperidines; Protein Isoforms; Protein Structure, Tertiary; Rats; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Agonists; Structure-Activity Relationship

Topics: Acyclic Monoterpenes; Alkenes; Anti-Infective Agents; Apiaceae; Distillation; Escherichia coli; Gas Chromatography-Mass Spectrometry; Hemlock; Microbial Sensitivity Tests; Oils, Volatile; Piperidines; Plant Leaves; Pseudomonas aeruginosa; Sicily

We aimed to identify and develop novel, selective muscarinic M. We developed and utilized a novel M. Using this paradigm, we identified a series of M. We report the discovery of SPP1, a novel, functionally selective, brain penetrant partial orthosteric agonist at M

Topics: Animals; Cells, Cultured; CHO Cells; Cricetulus; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Osteopontin; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M1; Spiro Compounds; Structure-Activity Relationship; Xenopus

Human African Trypanosomiasis (HAT, sleeping sickness) and Malaria both are insect vectored tropical diseases. Only a couple of drugs is able to cure HAT, but all of them are toxic, prone to resistance and require parenteral administration. Malaria is responsible for high morbidity and mortality in humans. It is one of the global killers of children. Wide-spread drug resistance against traditional therapeutics which were once highly effective makes them almost useless. Therefore new drugs against both diseases are urgently needed.. Recently, we reported the synthesis and antiprotozoal activities of a number of new 2- substituted 4-carbamoyl- and 4-aminoquinolines. This study focussed on the synthesis of novel tetrazole derivatives which are linked to the quinoline core via a piperidine ring.. Novel compounds exhibiting a 7-chloroquinoline and a tetrazole ring were prepared via Ugi-azide reaction. Modifications were restricted to the orientation and the substitution of the linker. Compounds were tested for their activities against Trypanosoma brucei rhodesiense (STIB 900). Their antiplasmodial activities were determined against a sensitive (NF54) and a multiresistant strain (K1) of Plasmodium falciparum.. Eighteen tetrazole derivatives were prepared. The results of the biological tests were compared with the activities of drugs in use and structure-activity relationships were discussed. Their antitrypanosomal activities were only moderate. In contrast some of the compounds showed promising activity against both strains of Plasmodium falciparum and good to excellent resistance indices.. The antiplasmodial activities depended on the orientation of the 4-aminopiperidine linker. Compounds with a tertiary amino group in position 4 of the quinoline ring exhibited equal activity against both strains, whereas those with a secondary amino group were mainly active against the sensitive strain.

Topics: Antiprotozoal Agents; Piperidines; Quinolines; Structure-Activity Relationship; Tetrazoles

Novel synthetic opioids include various analogs of fentanyl and emerging non-fentanyl compounds with different chemical structures, such as AH-7921, MT-45 and U-47700. In recent years, these drugs have rapidly emerged on the drug market, and their abuse has been increasing worldwide. The motivations for use of these new compounds include their legal status, ready availability, low cost, users' curiosity or preference for their particular pharmacological properties and the intention to avoid detection. Furthermore, more common drugs like heroin are now increasingly being replaced or cut with fentanyl or new designer opioids; thus, many drug users are unintentionally or unknowingly using synthetic fentanyl analogs. In this scenario, the detection of new psychoactive substances in hair can provide insight into their current diffusion among the population and social characteristics of these synthetic drug users. In this manuscript, we describe a simple, fast, specific and sensitive UHPLC-MS-MS method able to detect 13 synthetic opioids (including fentanyl analogs) and metabolites in hair samples. Furthermore, the method includes the detection of 4-anilino-N-phenethyl-piperidine (4-ANPP), which is considered both a precursor and a metabolite of several fentanyl analogs. The method was applied to 34 real hair samples collected in New York City from subjects who had reported past-year non-medical opioid and/or heroin use. In total, 17 samples tested positive for at least one target analyte, with oxycodone (nine samples) and tramadol (eight samples) being the most common. Among these, the method was able to quantify furanyl-fentanyl and fentanyl in the pg/mg range in two samples. Simultaneously, also 4-ANPP was detected, giving evidence for the first time that this compound can be selected as a marker of fentanyl analogs use via hair testing. In conclusion, this study confirmed the increasing diffusion of new synthetic opioids and "fentalogs" with high potency among non-medical opioid users.

Topics: Adolescent; Adult; Analgesics, Opioid; Benzamides; Biomarkers; Chromatography, Liquid; Designer Drugs; Fentanyl; Furans; Hair; Humans; Illicit Drugs; Oxycodone; Piperidines; Substance Abuse Detection; Tandem Mass Spectrometry; Tramadol; Young Adult

A group of N-benzylpiperidine-3/4-carbohydrazide-hydrazones were designed, synthesized and evaluated for acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) activities, Aβ

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Benzothiazoles; Biphenyl Compounds; Butyrylcholinesterase; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Electrophorus; Horses; Humans; Hydrazones; Models, Molecular; Molecular Structure; Neuroprotective Agents; Picrates; Piperidines; Structure-Activity Relationship; Sulfonic Acids

Poly (ADP-ribose) polymerase-1 (PARP1) is a major member of the PARP superfamily that is involved in DNA damage signalling and other important cellular processes. Here we report the development of a small molecule targeting PARP1 based on the PROTAC strategy. In the MDA-MB-231 cell line, the representative compound 3 can induce significant PARP1 cleavage and programmed cell death.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; DNA Damage; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Humans; Molecular Structure; Piperidines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Proteolysis; Small Molecule Libraries; Structure-Activity Relationship

The phosphoinositide 3-kinase γ (PI3Kγ) has been verified to be a potential drug target for the treatments of various human physical disorders. Although received lots of attention, the development of PI3Kγ-selective inhibitors is still a challenging subject because of its unique protein structural features. Aiming to uncover the interaction mechanism between the selective inhibitors and PI3Kγ, a series of benzothiazole and thiazolopiperidine PI3Kγ isoform-selective inhibitors were studied with an integrated in silico strategy by combining molecular docking, molecular dynamic simulations, binding free energy calculations, and decomposition analysis. Firstly, three molecular docking models, including rigid receptor docking, induced fit docking (IFD), and quantum mechanical-polarized ligand docking, were respectively, built, and the IFD preliminarily predicted the docking poses of all studied inhibitors and roughly analyzed the binding mechanism. Secondly, four binding complexes with representative inhibitors were selected to perform molecular dynamic simulations and free energy calculations. The predicted binding energies were consistent with the experimental bioactivities and different binding patterns between potent and weak inhibitors were uncovered. Finally, through the Molecular Mechanics/Generalized Born Surface Area binding free energy decomposition, residue-inhibitor interactions spectra were obtained and several key residues contributing to favorable binding were highlighted, which provides valuable information for rational PI3Kγ inhibitor design and modification.

Topics: Benzothiazoles; Binding Sites; Catalytic Domain; Class Ib Phosphatidylinositol 3-Kinase; Enzyme Inhibitors; Humans; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Piperidines; Thermodynamics

A series of simple

Topics: Animals; Cells, Cultured; Ceramides; Enzyme Inhibitors; Fibroblasts; Glucosylceramidase; Humans; Hydrolysis; Imino Pyranoses; Imino Sugars; Isomerism; Lysosomes; Melanoma, Experimental; Mice; Molecular Docking Simulation; Molecular Structure; Piperidines; Protein Binding; Pyrrolidines; Structure-Activity Relationship

A P(V)-N activation method based on nucleoside phosphoropiperidate/DCI system has been developed for improved synthesis of diverse UDP-furanoses. The reaction conditions including temperature, amount of activator, and reaction time were optimized to alleviate the degradation of UDP-furanoses to cyclic phosphates. In addition, an efficient and facile phosphoramidite route was employed for the preparation of furanosyl-1-phosphates.

Topics: Arabinose; Imidazoles; Imino Furanoses; Nucleosides; Phosphates; Piperidines; Uridine

The immune system is implicated in the pathology of neurodegenerative disorders. The C-C chemokine receptor 2 (CCR2) is one of the key targets involved in the activation of the immune system. A suitable ligand for CCR2 could be a useful tool to study immune activation in central nervous system (CNS) disorders. Herein, we describe the synthesis, tritium radiolabelling, and preliminary in vitro evaluation in post-mortem human brain tissue of a known potent small molecule antagonist for CCR2. The preparation of a tritium-labelled analogue for the autoradiography (ARG) study gave rise to an intriguing and unexpected side reaction profile through a novel amination of ethanol and methanol in the presence of tritium. After successful preparation of the tritiated radioligand, in vitro ARG measurements on human brain sections revealed nonspecific binding properties of the selected antagonist in the CNS.

Topics: Alcohols; Autoradiography; Chemistry Techniques, Synthetic; Halogenation; Humans; Isotope Labeling; Ligands; Piperidines; Radiochemistry; Receptors, CCR2; Tritium

Retinol-binding protein 4 (RBP4) serves as a transporter for all- trans-retinol (1) in the blood, and it has been proposed to act as an adipokine. Elevated plasma levels of the protein have been linked to diabetes, obesity, cardiovascular diseases, and nonalcoholic fatty liver disease (NAFLD). Recently, adipocyte-specific overexpression of RBP4 was reported to cause hepatic steatosis in mice. We previously identified an orally bioavailable RBP4 antagonist that significantly lowered RBP4 serum levels in Abca4

Topics: Animals; Chemistry Techniques, Synthetic; Disease Models, Animal; Drug Design; Fatty Liver; Male; Mice; Piperidines; Rats; Retinol-Binding Proteins, Plasma; Tissue Distribution

Heterocyclic chemistry is an important field of organic chemistry due to therapeutic potential. The minor modification in the structure of poly-functional compounds has great effect on therapeutic ability. In the presented research work, substituted 1,3,4-oxadiazole derivatives, 8a-p, have been synthesized by the reaction of 1-(4-bromomethylbenzenesulfonyl)-3-methylpiperidine (7) and 5-substituted-1,3,4-oxadiazole-2-thiol (4a-p). The 5-substituted-1,3,4-oxadiazole-2-thiol were synthesized by converting carboxylic acids correspondingly into esters, hydrazides and oxadiazoles. Secondly the electrophile, 1-(4-Bromomethylbenzenesulfonyl)-3-methylpiperidine (7), was prepared by the reaction of 3-methylpiperidine with 4-bromomethylbenzenesulfonyl chloride in the presence of water and Na

Topics: Anti-Bacterial Agents; Drug Evaluation, Preclinical; Enzyme Inhibitors; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; Molecular Structure; Oxadiazoles; Piperidines; Spectrophotometry, Infrared; Sulfonamides; Urease

A series of 3,4-disubstituted piperidine derivatives were obtained based on a conformational restriction strategy and a lead compound,

Topics: Administration, Oral; Animals; Cell Line, Tumor; Drug Discovery; ERG1 Potassium Channel; HCT116 Cells; HEK293 Cells; Human Umbilical Vein Endothelial Cells; Humans; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Mice, Nude; Piperidines; Protein Conformation; Protein Structure, Tertiary; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Xenograft Model Antitumor Assays

Topics: Acetylcysteine; Alkaloids; Benzodioxoles; Chromatography, High Pressure Liquid; Glutathione; Humans; Isomerism; Microsomes, Liver; Piperidines; Polyunsaturated Alkamides; Tandem Mass Spectrometry

A gas chromatographic procedure has been developed for the trace determination of chloroacetyl chloride (CAC) and two of its impurities: methyl chloroacetate (MCA) and chloroacetic acid (CAA). All three compounds are derivatized using piperidine in dichloroethane prior to their analysis via gas chromatography coupled with a flame ionization detection (GC-FID). Recoveries of each compound were assessed in two different pharmaceutical matrices (intermediate and final active pharmaceutical ingredient) and ranged from 75 to 125%. The limit of quantitation has been determined to be 0.10% wt/wt for CAA and 0.03% wt/wt for CAC and MCA. The linearity ranged from 0.03 to 5.00% wt/wt for CAC and MCA and from 0.10 to 5.00% wt/wt for CAA, with correlation coefficients from 0.9995 to 1.0000. Repeatability was evaluated at LOQ and at 5.00% wt/wt and was found to be between 1.4-3.0%.

Topics: Acetates; Chromatography, Gas; Ethylene Dichlorides; Flame Ionization; Limit of Detection; Piperidines

Beginning in the 1950s, a family of potent opioids was synthesized and developed (fentanyl and analogues). They continue to serve as valuable analgesic agents. But the recent spike and notoriety of their abuse has raised alarm, even calls for tighter control. We review the trajectory of these compounds.. To rectify shortcomings of the then available opioid analgesics, an analogue family of compounds was synthesized having a piperidine ring (presumptive principal active moiety in morphine and meperidine). The result was more potent and rapid-acting compounds, including alfentanil, carfentanil, fentanyl, sufentanil and others. These properties, plus availability in formulations for multiple routes of administration, impart broad therapeutic utility. They also unfortunately favour abuse.. The abuse of fentanyl and its analogues (legal and illicit) serves as a case study for the dilemma and difficulties balancing a medical need against psychosocial realities. The fentanyl family provides relief for severe pain, but their very properties also engender abuse.

Topics: Analgesics; Analgesics, Opioid; Fentanyl; Humans; Piperidines; Substance-Related Disorders

Topics: Amino Acid Sequence; Amino Acids; Computer Simulation; Hydrophobic and Hydrophilic Interactions; Ligands; Molecular Structure; Nociceptin Receptor; Piperidines; Protein Binding; Receptors, Opioid; Structure-Activity Relationship

A spirocyclic, sp

Topics: Catalysis; Cyclization; Drug Design; Ethers, Cyclic; Gold; Piperidines; Small Molecule Libraries

The ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) was recently shown to promote mineralization of the aortic valve, hence, its inhibition represents a significant target. A quinazoline-4-piperidine sulfamide compound (QPS1) has been described as a specific and non-competitive inhibitor of NPP1. We report herein the synthesis and in vitro inhibition studies of novel quinazoline-4-piperidine sulfamide analogues using QPS1 as the lead compound. Of the 26 derivatives prepared, four compounds were found to have K

Topics: Amides; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Molecular Structure; Phosphoric Diester Hydrolases; Piperidines; Pyrophosphatases; Quinazolines; Structure-Activity Relationship

Solid-Phase Peptide Synthesis (SPPS) is a rapid and efficient methodology for the chemical synthesis of peptides and small proteins. However, the assembly of peptide sequences classified as "difficult" poses severe synthetic problems in SPPS for the occurrence of extensive aggregation of growing peptide chains which often leads to synthesis failure. In this framework, we have investigated the impact of different synthetic procedures on the yield and final purity of three well-known "difficult peptides" prepared using oxyma as additive for the coupling steps. In particular, we have comparatively investigated the use of piperidine and morpholine/DBU as deprotection reagents, the addition of DIPEA, collidine and N-methylmorpholine as bases to the coupling reagent. Moreover, the effect of different agitation modalities during the acylation reactions has been investigated. Data obtained represent a step forward in optimizing strategies for the synthesis of "difficult peptides".

Topics: Acylation; Amino Acid Sequence; Ethylamines; Morpholines; Peptides; Piperidines; Pregnadienes; Protein Aggregates; Pyridines; Solid-Phase Synthesis Techniques

The design and synthesis of a novel class of 7-azaspiro[3.5]nonane GPR119 agonists are described. In this series, optimization of the right piperidine N-capping group (R

Topics: Alkanes; Animals; Blood Glucose; Cell Line; Diabetes Mellitus, Experimental; Drug Design; Glucose Tolerance Test; Half-Life; Humans; Hypoglycemic Agents; Microsomes, Liver; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Structure-Activity Relationship

In this study, a novel two-photon photothermal therapy (TP-PTT) agent based on an organic-metal microhybrid with surface Plasmon resonance (SPR) enhanced two-photon absorption (TPA) characteristic was designed and synthesized using a fluorescent cyano-carboxylic derivative 2-cyano-3-(9-ethyl-9H-carbazol-3-yl) -acrylic acid (abbreviated as CECZA) and silver nanoparticles through self-assembly process induced by the interfacial coordination interactions between the O/N atom of CECZA and Ag

Topics: Acetates; Acetonitriles; Carbazoles; Cell Survival; Dose-Response Relationship, Drug; Fluorescent Dyes; HeLa Cells; Humans; Metal Nanoparticles; Mitochondria; Photons; Phototherapy; Piperidines; Silver; Surface Plasmon Resonance

Phosphoinositide 3-kinase Delta (PI3Kδ) plays a key role in B-cell signal transduction and inhibition of PI3Kδ was confirmed to have clinical benefit in certain types of activation of B-cell malignancies. Herein, we reported a novel series of 4-pyrrolidineoxy or 4-piperidineamino substituted quinazolines, showing potent PI3Kδ inhibitory activities. Among these compounds, 12d, 14b and 14c demonstrated higher potency against PI3Kδ with the half maximal inhibitory concentration (IC

Topics: Class I Phosphatidylinositol 3-Kinases; Dose-Response Relationship, Drug; Humans; Molecular Structure; Piperidines; Protein Kinase Inhibitors; Pyrrolidines; Quinazolines; Structure-Activity Relationship

There are currently no approved vaccines or small molecule therapeutics available for the prophylaxis or treatment of Middle East Respiratory Syndrome coronavirus (MERS-CoV) infections. MERS-CoV 3CL protease is essential for viral replication; consequently, it is an attractive target that provides a potentially effective means of developing small molecule therapeutics for combatting MERS-CoV. We describe herein the structure-guided design and evaluation of a novel class of inhibitors of MERS-CoV 3CL protease that embody a piperidine moiety as a design element that is well-suited to exploiting favorable subsite binding interactions to attain optimal pharmacological activity and PK properties. The mechanism of action of the compounds and the structural determinants associated with binding were illuminated using X-ray crystallography.

Topics: 3C Viral Proteases; Animals; Antiviral Agents; Cats; Cell Death; Cells, Cultured; Chlorocebus aethiops; Crystallography, X-Ray; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Dose-Response Relationship, Drug; Drug Design; Middle East Respiratory Syndrome Coronavirus; Models, Molecular; Molecular Structure; Piperidines; Structure-Activity Relationship; Vero Cells; Viral Proteins

Epilepsy is a kind of disease with complicated pathogenesis. KCNQ (Kv7) is a voltage dependent potassium channel that is mostly associated with epilepsy and thus becomes an important target in the treatment of epilepsy. In this paper, a series of substituted piperidine derivatives targeting KCNQ were designed and synthesized by using scaffold hopping and active substructure hybridization. Compounds were evaluated by fluorescence-based thallium influx assay, Rb

Topics: Anticonvulsants; Dose-Response Relationship, Drug; Drug Design; Epilepsy; Humans; KCNQ Potassium Channels; Molecular Structure; Piperidines; Structure-Activity Relationship

We previously identified 2-tert-butyl-4-[(3-methoxypropyl)amino]-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]pyrimidine-5-carboxamide 3 as a potent renin inhibitor. Since 3 showed unacceptably low bioavailability (BA) in rats, structural modification, using SBDD and focused on physicochemical properties was conducted to improve its PK profile while maintaining renin inhibitory activity. Conversion of the amino group attached at the 4-position of pyrimidine to methylene group improved PK profile and decreased renin inhibitory activity. New central cores with carbon side chains were explored to improve potency. We had designed a series of 5-membered azoles and fused heterocycles that interacted with the lipophilic S3 pocket. In the course of modification, renin inhibitory activity was enhanced by the formation of an additional hydrogen bonding with the hydroxyl group of Thr77. Consequently, a series of novel benzimidazole derivatives were discovered as potent and orally bioavailable renin inhibitors. Among those, compound 13 exhibited more than five-fold of plasma renin inhibition than aliskiren in cynomolgus monkeys at dose ratio.

Topics: Administration, Oral; Animals; Benzimidazoles; Binding Sites; Biological Availability; Crystallography, X-Ray; Drug Design; Drug Evaluation, Preclinical; Half-Life; Humans; Hydrogen Bonding; Molecular Dynamics Simulation; Piperidines; Protease Inhibitors; Protein Structure, Tertiary; Rats; Renin; Structure-Activity Relationship

Fifteen new piperidine derivatives, pyracyclumines A-J (1-10), including five pairs of enantiomers, (+)-1/(-)-1 to (+)-5/(-)-5, together with three known compounds, agrocybenine (11), 4,6,6-trimethyl-5,6-dihydro-2(1 H)-pyridone (12), and 3,5,5-trimethyl-1,5-dihydro-2 H-pyrrol-2-one (13), were isolated from the roots of Anacyclus pyrethrum. Pyracyclumines A, B, and H (1, 2, and 8) possess a novel 6/5/6/6 dimeric piperidine skeleton, a unique 6/5/6 dimeric piperidine skeleton, and a 1,4,6-triazaindan skeleton, respectively. Pyracyclumine C (3) is based on a rare cyclopentane-piperidine framework. The structures of the isolated compounds were established by analysis of their NMR and HRESIMS data. The racemic pyracyclumines A-E (1-5) were further separated by chiral HPLC to give the enantiomers (+)-1/(-)-1 to (+)-5/(-)-5, for which the absolute configurations were determined by comparison of their experimental and calculated ECD spectra. The plausible biogenetic pathways of these piperidine alkaloids were proposed starting from the basic units of compounds 12 and 13. All of the isolated compounds were tested for their inhibitory effects on menin-mixed lineage leukemia 1 protein-protein interaction.

Topics: Alkaloids; Asteraceae; Chromatography, High Pressure Liquid; Organic Chemicals; Piperidines; Plant Roots; Stereoisomerism

Dihydropyrimidinone derivatives containing piperidine moiety were synthesised in a good yield. All the compounds were confirmed by elemental analysis and spectral data. Anti-ulcer activity of novel dihydropyrimidinone-piperidine hybrids (1-18) was evaluated. Among them, four compounds (3, 8, 11 and 15) were found to be most active in 80% ethanol-induced ulcer experimental animal model. All the potent compounds were further evaluated for anti-ulcer activity by different in vivo anti-ulcer models to study the effect of compounds on anti-secretory and cytoprotective activities. All the active compounds inhibited the formation of gastric ulcers and increased the formation of gastric mucin secretion. Compound 15 was found to be the most potent compound of the series as anti-ulcer agent. Additional experimental studies on lead compound 15 will result in a new class of orally active molecule for anti-ulcer activity.

Topics: Animals; Anti-Ulcer Agents; Crystallography, X-Ray; Disease Models, Animal; Dose-Response Relationship, Drug; Ethanol; Models, Molecular; Molecular Structure; Piperidines; Pyrimidinones; Rats; Rats, Wistar; Stomach Ulcer; Structure-Activity Relationship

Aggregation of amyloid proteins is currently involved in more than 20 serious human diseases that are actually untreated, such as Alzheimer's disease (AD). Despite many efforts made to target the amyloid cascade in AD, finding an aggregation inhibiting compound and especially modulating early oligomerization remains a relevant and challenging strategy. We report herein the first examples of small and non-peptide mimics of acyclic beta-hairpins, showing an ability to delay the fibrillization of amyloid-β (Aβ

Topics: Amyloid beta-Peptides; Dose-Response Relationship, Drug; Humans; Molecular Structure; Piperidines; Protein Aggregates; Small Molecule Libraries; Structure-Activity Relationship

Deregulated RAS activity, often the result of mutation, is implicated in approximately 30% of all human cancers. Despite this statistic, no clinically successful treatment for RAS-driven tumors has yet been developed. One approach for modulating RAS activity is to target and affect the activity of proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1). Here, we report on structure-activity relationships (SAR) in an indole series of compounds. Using structure-based design, we systematically explored substitution patterns on the indole nucleus, the pendant amino acid moiety, and the linker unit that connects these two fragments. Best-in-class compounds activate the nucleotide exchange process at submicromolar concentrations in vitro, increase levels of active RAS-GTP in HeLa cells, and elicit signaling changes in the mitogen-activated protein kinase-extracellular regulated kinase (MAPK-ERK) pathway, resulting in a decrease in pERK1/2

Topics: Drug Design; HeLa Cells; Humans; Indoles; Models, Molecular; Piperidines; Protein Conformation; ras Proteins; Signal Transduction; SOS1 Protein; Structure-Activity Relationship

We have developed versatile methods toward the synthesis of a variety of piperidine/piperazine bridged isosteres of pridopidine. The compounds were assessed against the D2 receptor in agonist and antagonist modes and against the D4 receptor in agonist mode. hERG Binding and the ADME profiles were studied.

Topics: Animals; Bridged Bicyclo Compounds; Crystallography, X-Ray; Dopamine Antagonists; Drug Design; ERG1 Potassium Channel; Humans; Magnetic Resonance Spectroscopy; Mice; Piperazine; Piperidines; Receptors, Dopamine D2; Receptors, Dopamine D4; Structure-Activity Relationship

CCR6 has been implicated in both autoimmune diseases and non-autoimmune diseases. Thus, inhibition of CCR6-dependent cell migration is an attractive strategy for their treatment. An orally available small molecule inhibitor of CCR6 could therefore be a useful biological probe for the pathophysiological studies. Initial SAR study of a hit compound provided potent N-benzenesulfonylpiperidine derivatives that suppressed CCL20-induced Gi signals. By subsequent scaffold morphing of the central ring and further optimization, we identified a novel series of 1,4-trans-1-benzenesulfonyl-4-aminocyclohexanes as potent and selective CCR6 inhibitors with good pharmacokinetic properties. Our compounds showed good correlation between Gi signal inhibitory activity and cell migration inhibitory activity in human CCR6-transfected CHO cells. In addition, representative compound 35 potently inhibited CCR6-dependent cell migration and the increase in ERK phosphorylation in human primary cells. Therefore, the compound could be used effectively as a biological probe against human CCR6.

Topics: Amines; Animals; B-Lymphocytes; Cell Movement; CHO Cells; Cricetulus; Cyclohexanes; Dose-Response Relationship, Drug; Haplorhini; Humans; Molecular Structure; Piperidines; Receptors, CCR6; Small Molecule Libraries; Structure-Activity Relationship

The objective of our study was to develop a transdermal patch of 4-benzylpiperidine and to evaluate its in vitro transdermal permeation profile. Appropriate pressure sensitive adhesives and additives were selected based on solubility and slide crystallization studies. Release liners and backing membranes were selected based on their ability to peel without leaving a residue and their affinity to formulation respectively. Drug-in-adhesive patches developed were investigate for their in vitro drug permeation over 48 h across dermatomed human skin using Franz diffusion cells. Silicone based pressure sensitive adhesive along with colloidal silicon dioxide as viscosity builder, fluoropolymer coated membranes as the release liner and polyester based membranes as backing were chosen to develop a drug in silicone adhesive patch. Polyisobutylene adhesive based patch was developed with drug in polyisobutylene adhesive, along with oleic acid and oleyl alcohol as permeation enhancers, polyester for the release liner and polyethylene as backing. Among the patches developed, polyisobutylene adhesive based patch with higher drug concentration exhibited superior transdermal permeation (1608.5 ± 53.4 µg/cm

Topics: Adhesives; Administration, Cutaneous; Humans; Membranes, Artificial; Piperidines; Polyenes; Polymers; Silicones; Skin; Transdermal Patch

The sigma receptor (σR) family has been considered mysterious for a long time. In fact, the σ2R subtype has been cloned only recently, revealing its identity as TMEM97, a NPC1-binding protein involved in cholesterol biosynthesis and implicated in the pathogenesis of cancer and neurologic disorders. With the aim of developing new chemical entities gifted with σR affinity, herein we report the design and synthesis of new piperidine-based alkylacetamide derivatives with mixed affinity towards both σ1 and σ2R subtypes.

Topics: Cell Line, Tumor; Humans; Ligands; Piperidines; Receptors, sigma

Topics: Administration, Oral; Biological Availability; Chromans; GTP-Binding Proteins; Piperidines

In this article, we report our investigation of a phenomenon by which bridging morpholines across the ring with one-carbon tethers leads to a counterintuitive reduction in lipophilicity. This effect was also found to occur in piperazines and piperidines and lowered the measured log D

Topics: Carbon; Hydrophobic and Hydrophilic Interactions; Models, Molecular; Molecular Structure; Morpholines; Piperazines; Piperidines

A series of novel pyridine-substituted piperidine derivatives were discovered as low nanomolar Ls-AChBP ligands with α7 nAChR partial agonism or antagonism activities. A high-resolution antagonist-bound Ls-AChBP complex was successfully resolved with a classic Loop C opening phenomenon and unique sulfur-π interactions which deviated from our previous docking mode to a large extent. With the knowledge of the co-complex, 27 novel piperidine derivatives were designed and synthesized. The structure-activity relationships (SARs) of the aromatic and pyridine regions were well established and binding modes were illustrated with the help of molecular docking which indicated that interactions with Trp 143 and the "water bridge" are essential for the high binding affinities. Halogen bonding as well as the space around 5'- or 6'- position of the pyridine ring was also proposed to influence the binding conformation of the compounds. Notably, two enantiomers of compound 2 showed opposite functions toward α7 nAChR and compound (S)-2 showed sub-nanomolar affinity (K

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Carrier Proteins; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Discovery; Humans; Ligands; Lymnaea; Models, Molecular; Molecular Structure; Nicotinic Agonists; Piperidines; Structure-Activity Relationship

8-Oxo-7,8-dihydro-2'-deoxyguanosine(8-oxodGuo) is a common primary product of cellular oxidative DNA damage. 8-OxodGuo is more readily oxidized than 2'-deoxyguanosine (dG); a two-electron oxidation generates a highly reactive intermediate (OG

Topics: 8-Hydroxy-2'-Deoxyguanosine; Deoxyguanosine; DNA; DNA Damage; Ethylamines; Ferricyanides; Histones; Kinetics; Nucleosomes; Oxidation-Reduction; Piperidines

Leishmaniasis is one of the most important neglected tropical diseases (NTDs) that are especially common among low-income populations in developing regions of Africa, Asia, and the Americas. Many natural products, particularly alkaloids, have been reported to have inhibitory activity against arginase, the key enzyme in the pathology caused by Leishmania sp. In this way, piperidine alkaloids (-)-cassine (1), (-)-spectaline (2), (-)-3-O-acetylcassine (3), and (-)-3-O-acetylspectaline (4) were isolated from Senna spectabilis flowers. These compounds (1/2 and 3/4) initially present as homologous mixtures were separated by high performance liquid chromatography and evaluated against the promastigote phase of Leishmania amazonensis. In addition, molecular docking simulations were implemented in order to probe the binding modes of the ligands 1-4 to the amino acids in the active site of L. amazonensis arginase. Alkaloid 2 (IC

Topics: Alkaloids; Antiprotozoal Agents; Dose-Response Relationship, Drug; Leishmania; Leishmaniasis; Molecular Docking Simulation; Molecular Structure; Parasitic Sensitivity Tests; Piperidines; Senna Plant; Structure-Activity Relationship

A Pt(II)-terpyridine compound, bearing two piperidine substituents at positions 2 and 2' of the terpyridine ligand (1), is highly cytotoxic and shows a mechanism of action distinct from cisplatin. 1 has been incorporated within the ferritin nanocage (AFt).. Spectroscopic and crystallographic data of the Pt(II)-AFt nanocomposite have been collected and in vitro anticancer activity has been explored using cancer cells.. Pt(II)-containing fragments bind His49, His114 and His132. Pt(II)-AFt nanocomposite is less cytotoxic than 1, but it is more toxic than cisplatin at high concentrations. The Pt(II)-AFt nanocomposite triggers necrosis in cancer cells, as free 1 does.. Pt(II)-AFt nanocomposites are promising vehicles to deliver Pt-based drugs to cancer cells.

Topics: Amino Acid Sequence; Amino Acids; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Cisplatin; Drug Carriers; Drug Design; Drug Liberation; Ferritins; Humans; Models, Molecular; Molecular Structure; Nanocomposites; Particle Size; Piperidines; Protein Binding; Signal Transduction; Structure-Activity Relationship; Surface Properties

Mycobacterium tuberculosis, Vibrio cholerae, and pathogenic Escherichia coli are global concerns for public health. The emergence of multi-drug resistant (MDR) strains of these pathogens is creating additional challenges in controlling infections caused by these deadly bacteria. Recently, we reported that Acetate kinase (AcK) could be a broad-spectrum novel target in several bacteria including these pathogens.. Here, using in silico and in vitro approaches we show that (i) AcK is an essential protein in pathogenic bacteria; (ii) natural compounds Chlorogenic acid and Pinoresinol from Piper betel and Piperidine derivative compound 6-oxopiperidine-3-carboxylic acid inhibit the growth of pathogenic E. coli and M. tuberculosis by targeting AcK with equal or higher efficacy than the currently used antibiotics; (iii) molecular modeling and docking studies show interactions between inhibitors and AcK that correlate with the experimental results; (iv) these compounds are highly effective even on MDR strains of these pathogens; (v) further, the compounds may also target bacterial two-component system proteins that help bacteria in expressing the genes related to drug resistance and virulence; and (vi) finally, all the tested compounds are predicted to have drug-like properties.. Suggesting that, these Piper betel derived compounds may be further tested for developing a novel class of broad-spectrum drugs against various common and MDR pathogens.

Topics: Acetate Kinase; Anti-Bacterial Agents; Bacterial Proteins; Carboxylic Acids; Chlorogenic Acid; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Enzyme Inhibitors; Escherichia coli; Furans; Lignans; Microbial Sensitivity Tests; Molecular Docking Simulation; Molecular Structure; Mycobacterium tuberculosis; Piper betle; Piperidines; Structure-Activity Relationship

With the aim to discover a gastric antisecretory agent more potent than the existing proton pump inhibitors, novel 3,4-dihydro-1H-spiro(naphthalene-2,2'-piperidin)-1-one derivatives, which could occupy two important lipophilic pockets (described as LP-1 and LP-2) of H

Topics: Administration, Intravenous; Animals; Area Under Curve; Binding Sites; Drug Evaluation, Preclinical; Gastric Acid; Gastric Mucosa; H(+)-K(+)-Exchanging ATPase; Half-Life; Histamine; Inhibitory Concentration 50; Molecular Docking Simulation; Naphthalenes; Piperidines; Potassium; Proton Pump Inhibitors; Rats; ROC Curve; Spiro Compounds; Structure-Activity Relationship

In solid-phase peptide synthesis, the nominal batch size is calculated using the starting resin substitution and the mass of the starting resin. The starting resin substitution constitutes the basis for the calculation of a whole set of important process parameters, such as the number of amino acid derivative equivalents. For Fmoc-substituted resins, substitution determination is often performed by suspending the Fmoc-protected starting resin in 20% (v/v) piperidine in DMF to generate the dibenzofulvene-piperidine adduct that is quantified by ultraviolet-visible spectroscopy. The spectrometric measurement is performed at the maximum absorption wavelength of the dibenzofulvene-piperidine adduct, that is, at 301.0 nm. The recorded absorption value, the resin weight and the volume are entered into an equation derived from Lambert-Beer's law, together with the substance-specific molar absorption coefficient at 301.0 nm, in order to calculate the nominal substitution. To our knowledge, molar absorption coefficients between 7100 l mol

Topics: Composite Resins; Peptide Fragments; Peptides; Piperidines; Solid-Phase Synthesis Techniques

Polymeric nanoreactors (NRs) have distinct advantages to improve chemical reaction efficiency, but the in vivo applications are limited by lack of tissue-specificity. Herein, novel glucose oxidase (GOD)-loaded therapeutic vesicular NRs (theraNR) are constructed based on a diblock copolymer containing poly(ethylene glycol) (PEG) and copolymerized phenylboronic ester or piperidine-functionalized methacrylate (P(PBEM-co-PEM)). Upon systemic injection, theraNR are inactive in normal tissues. At a tumor site, theraNR are specifically activated by the tumor acidity via improved permeability of the membranes. Hydrogen peroxide (H

Topics: Antineoplastic Agents; Antioxidants; Boronic Acids; Cell Death; Cell Membrane Permeability; Drug Carriers; Esters; Glucose Oxidase; Glutathione; Humans; Hydrogen Peroxide; Hydrogen-Ion Concentration; Indolequinones; Methacrylates; Microscopy, Electron, Transmission; Nanostructures; Neoplasms; Piperidines; Polyethylene Glycols; Proof of Concept Study

Herein we describe the discovery and characterization of a novel, piperidine-based inhibitor of cholesteryl ester transfer protein (CETP) with a core structure distinct from other reported CETP inhibitors. A versatile synthesis starting from 4-methoxypyridine enabled an efficient exploration of the SAR, giving a lead molecule with potent CETP inhibition in human plasma. The subsequent optimization focused on improvement of pharmacokinetics and mitigation of off-target liabilities, such as CYP inhibition, whose improvement correlated with increased lipophilic efficiency. The effort led to the identification of an achiral, carboxylic acid-bearing compound 16 (TAP311) with excellent pharmacokinetics in rats and robust efficacy in hamsters. Compared to anacetrapib, the compound showed substantially reduced lipophilicity, had only modest distribution into adipose tissue, and retained potency in hypertriglyceridemic plasma in vitro and in vivo. Furthermore, in contrast to torcetrapib, the compound did not increase aldosterone secretion in human adrenocortical carcinoma cells nor in chronically cannulated rats. On the basis of its preclinical efficacy and safety profile, the compound was advanced into clinical trials.

Topics: Aged; Animals; Chick Embryo; Cholesterol Ester Transfer Proteins; Humans; Hypertriglyceridemia; Male; Mesocricetus; Piperidines; Rats; Structure-Activity Relationship

Grewia nervosa is a herbal plant used in traditional medicine for different purposes. Bioassay-guided chemical fractionation of G. nervosa roots resulted in an identification of two known and one new compound, namely microgrewiapine A, homomicrogrewiapine, and N-methylmicrocosamine, respectively. Their structures were determined using combination of LC/HR-MS,

Topics: Alkaloids; alpha-Glucosidases; Binding Sites; Chromatography, High Pressure Liquid; Glycoside Hydrolase Inhibitors; Grewia; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Mass Spectrometry; Molecular Conformation; Molecular Docking Simulation; Piperidines; Plant Extracts; Plant Roots; Protein Structure, Tertiary

A dual synthetic strategy to afford 2-substituted trihydroxypiperidines is disclosed. The procedure involved Grignard addition either to a carbohydrate-derived aldehyde or to a nitrone derived thereof, and took advantage of an efficient ring-closure reductive amination strategy in the final cyclization step. An opposite diastereofacial preference was demonstrated in the nucleophilic attack to the two electrophiles, which would finally produce the same piperidine diastereoisomer as the major product. However, use of a suitable Lewis acid in the Grignard addition to the nitrone allowed reversing the selectivity, giving access to 2-substituted piperidines with the opposite configuration at C-2.

Topics: Aldehydes; Amination; Nitrogen Oxides; Organometallic Compounds; Oxidation-Reduction; Piperidines; Stereoisomerism

The farnesoid X receptor (FXR) is a nuclear receptor that acts as a master regulator of bile acid metabolism and signaling. Activation of FXR inhibits bile acid synthesis and increases bile acid conjugation, transport, and excretion, thereby protecting the liver from the harmful effects of bile accumulation, leading to considerable interest in FXR as a therapeutic target for the treatment of cholestasis and nonalcoholic steatohepatitis. We identified a novel series of highly potent non-bile acid FXR agonists that introduce a bicyclic nortropine-substituted benzothiazole carboxylic acid moiety onto a trisubstituted isoxazole scaffold. Herein, we report the discovery of 1 (tropifexor, LJN452), a novel and highly potent agonist of FXR. Potent in vivo activity was demonstrated in rodent PD models by measuring the induction of FXR target genes in various tissues. Tropifexor has advanced into phase 2 human clinical trials in patients with NASH and PBC.

Topics: Administration, Oral; Animals; Benzothiazoles; Biological Availability; Cholestasis; Dogs; Drug Evaluation, Preclinical; Fibroblast Growth Factors; Gene Expression Regulation; Humans; Isoxazoles; Male; Microsomes, Liver; Non-alcoholic Fatty Liver Disease; Piperidines; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Structure-Activity Relationship; Triglycerides

Four novel compounds-two phenylpropionamides, one piperidine, and one phenolic derivatives-were isolated and identified from the fruit of a medicinal plant,

Topics: Ailanthus; Amides; Flavonoids; Fruit; Phenols; Piperidines; Plant Extracts

The piperidine fragment in ceritinib was replaced with diverse aliphatic amines to improve inherent resistance issues of ceritinib. While most of the prepared compounds exhibit as similar in vitro activities as ceritinib, compound 10 shows encouraging activities against wild-type ALK as well as crizotinib-resistant mutants including extremely resistant G1202R mutant with an IC

Topics: Amines; Anaplastic Lymphoma Kinase; Animals; Crizotinib; Drug Resistance, Neoplasm; Heterografts; Humans; Mice; Mutation; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Rosbin (Thieno [2, 3-c] piperidine-3-carboxamide-2-[(3-methoxy-naphtha-lene-2-carbonyl)-amino]-6-(benzyl)-, hydrochloride), a synthetic piperidinothieno derivative compound obtained from chemical genetics screenings, significantly suppresses the viability of non-small cell lung cancer A549 cells with an IC50 of 2.05 ± 0.31 µM. It only decreases growth of non-tumour MRC-5 cells at the doses higher than 10 µM. Rosbin induces apoptosis in a dose-dependent manner by reducing the mitochondrial membrane potential (MMP) and increasing activities of caspases-3/7 and caspase-9 in A549 cells, without affecting the activity of caspase-8. Further studies showed that reactive oxygen species (ROS) induced apoptosis of A549 in the presence of rosbin as apoptosis was inhibited by N-acetyl cysteine (NAC). These results suggest that rosbin is a novel apoptosis inducer, and ROS played a significant role in the A549 apoptosis induced by rosbin.

Topics: A549 Cells; Acetylcysteine; Antineoplastic Agents; Apoptosis; Caspase 3; Caspase 7; Caspase 9; Flow Cytometry; Humans; Membrane Potential, Mitochondrial; Mitochondria; Piperidines; Reactive Oxygen Species; Thiophenes

A series of novel piperazine or piperidine-containing non-covalent peptidyl derivatives possessing a neopentyl-asparagine residue were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were screened for their 20S proteasome chymotrypsin-like inhibitory activities, and 15 ones displayed more potent activities than carfilzomib with IC

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Stability; Humans; Mice; Molecular Docking Simulation; Peptides; Piperazines; Piperidines; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Conformation

In a series of partially fluorinated N-propyl- and N-butylpiperidine derivatives, three compounds were found to exhibit unexpected instability under mild biophysical assay conditions. These compounds carry a single terminal fluorine in the δ-position of an N-butyl group as a common structural feature. An adjacent fluorine substituent at the γ-position significantly slows down the reactivity. All other compounds, having either no or more than one fluorine substituent at the δ-position are chemically inert under all assay conditions. The reactivity of the labile compounds is traced to an intramolecular ring-closing fluorine substitution reaction by the moderately basic piperidine unit, leading to a spiro-pyrrolidinium salt. The chemical lability of δ-monofluorinated or γ,δ-difluorinated N-butylpiperidine derivatives even under very mild biophysical assay conditions constitutes a caveat to the molecular design of partially fluorinated alkylamines.

Topics: Drug Stability; Fluorine; Kinetics; Magnetic Resonance Spectroscopy; Piperidines; Spectrometry, Mass, Electrospray Ionization; Water

The dopamine hypothesis states that decreased dopaminergic neurotransmission reduces schizophrenia symptoms. Neurokinin-3 receptor (NK3) antagonists reduce dopamine release and have shown positive effects in pre-clinical and clinical trials. We employed 2D and 3D-QSAR analysis on a series of 40 non-peptide NK3 antagonists. Multivariate statistical analysis, PCA and HCA, were performed to rational training/test set splitting and PLS regression was employed to construct all QSAR models. We constructed one highly predictive CoMFA model (q(2)= 0.810 and r(2)= 0.929) and acceptable HQSAR and CoMSIA models (HQSAR q(2)= 0.644 and r(2)= 0.910; CoMSIA q(2)= 0.691, r(2)= 0.911). The three different techniques provided convergent physicochemical results. All models indicate cyclopropane, piperidine and di-chloro-phenyl ring attached to cyclopropane ring and also the amide group attached to the piperidine ring could play an important role in ligand-receptor interactions. These findings may contribute to develop potential NK3 receptor antagonists for schizophrenia.

Topics: Cyclopropanes; Humans; Piperidines; Quantitative Structure-Activity Relationship; Receptors, Neurokinin-3; Schizophrenia

Piperidine, piperazine and morpholine as archetypes for secondary heterocyclic amines, a structural unit that is often present in pharmaceuticals (e.g., ritalin, cetirizine, timolol, ciprofloxacin) were investigated in their reaction with ozone. In principle the investigated compounds can be degraded with ozone in a reasonable time, based on their high reaction rate constants with respect to ozone (1.9 × 10(4)-2.4 × 10(5) M(-1) s(-1)). However, transformation is insufficient (13-16%), most likely due to a chain reaction, which decomposes ozone. This conclusion is based on OH scavenging experiments, leading to increased compound transformation (18-27%). The investigated target compounds are similar in their kinetic and stoichiometric characteristics. However, the mechanistic considerations based on product formation indicate various reaction pathways. Piperidine reacts with ozone via a nonradical addition reaction to N-hydroxypiperidine (yield: 92% with and 94% without scavenging, with respect to compound transformation). However, piperazine degradation with ozone does not lead to N-hydroxypiperazine. In the morpholine/ozone reaction, N-hydroxymorpholine was identified. Additional oxidation pathways in all cases involved the formation of OH with high yields. One important pathway of piperazine and morpholine by ozonation could be the formation of C-centered radicals after ozone or OH radical attack. Subsequently, O2 addition forms unstable peroxyl radicals, which in one pathway loose superoxide radicals by generating a carbon-centered cation. Subsequent hydrolysis of the carbon-centered cation leads to formaldehyde, whereby ozonation of the N-hydroxy products can proceed in the same way and in addition give rise to hydroxylamine. A second pathway of the short-lived peroxyl radicals could be a dimerization to form short-lived tetraoxides, which cleave by forming hydrogen peroxide. All three products have been found.

Topics: Kinetics; Morpholines; Ozone; Pharmaceutical Preparations; Piperazine; Piperazines; Piperidines; Waste Disposal, Fluid; Water Pollutants, Chemical

Calcitonin gene-related peptide (CGRP) is a potent neuropeptide implicated in the pathophysiology of migraine. In the course of seeking CGRP antagonists with improved oral bioavailability, metabolic stability, and pharmacokinetic properties, lower molecular weight, structurally simpler piperidine and piperazine analogs of BMS-694153 were prepared. Several were found to have nM binding affinity in vitro. The synthesis and SAR of these substituted piperidine and piperazine CGRP antagonists are discussed.

Topics: Calcitonin Gene-Related Peptide; Cell Line, Tumor; Cell Membrane Permeability; Humans; Indazoles; Inhibitory Concentration 50; Piperazine; Piperazines; Piperidines; Quinazolinones; Structure-Activity Relationship

Ultrasound-assisted synthesis of benzimidazo[2,1-b]quinazolin-1(1H)-ones was achieved via piperidine-catalyzed three-component reaction of 2-aminobenzimidazoles, an aromatic aldehyde, and 1,3-dione in aqueous isopropanol. This mechanism was first suspected following our identification of unusual reaction intermediates in a one-pot reaction. An unprecedented coupling reaction, it involved a nucleophilic attack by 2-aminobenzimidazole on in situ generated Michael adduct, followed by electrocyclic ring formation reaction. In contrast to the commonly accepted mechanism, that the direct reaction of 2-amino benzimidazole with a Knoevenagel adduct cannot deliver target compounds.

Topics: Benzimidazoles; Catalysis; Combinatorial Chemistry Techniques; Crystallography, X-Ray; Models, Molecular; Piperidines; Quinazolinones; Sonication

An iron-porphyrin-based metal organic framework PCN-222(Fe) is investigated upon postsynthetic reduction with piperidine. Fe K-edge X-ray absorption and Kβ mainline emission spectroscopy measurements reveal the local coordination geometry, oxidation, and spin state changes experienced by the Fe sites upon reaction with this axially coordinating reducing agent. Analysis and fitting of these data confirm the binding pattern predicted by a space-filling model of the structurally constrained pore environments. These results are further supported by UV-vis diffuse reflectance, IR, and resonance Raman spectroscopy data.

Topics: Heme; Iron; Models, Molecular; Organometallic Compounds; Oxidation-Reduction; Piperidines; Spectrometry, X-Ray Emission; Spectrophotometry, Infrared; Spectrophotometry, Ultraviolet; Spectrum Analysis, Raman

A series of novel piperidine, piperazine, morpholine and thiomorpholine appended dibenzo[b,d]thiophene-1,2,3-triazoles were designed and synthesized utilizing azide-alkyne click chemistry in the penultimate step. The required azide building block 6a-e was synthesized from commercial dibenzo[b,d]thiophene in good yields following five step reaction sequence. All the new analogues 8a-f, 9a-f, 10a-f, 11a-f &12a-f were characterized by their NMR and mass spectral analysis. Screening all thirty new compounds for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv, resulted 8a, 8f and 11e as potent analogues with MIC 0.78μg/mL, 0.78μg/mL & 1.56μg/mL, respectively, and has shown lower cytotoxicity. Interestingly, all six piperazine appended dibenzo[b,d]thiophene-1,2,3-triazoles 11a-f exhibited Mtb inhibition activity with MIC 1.56-12.5μg/mL. To some extent, the data observed here indicated Mycobacterium tuberculosis inhibition among the appendages is in the order, piperazine>thiomorpholine>morpholine.

Topics: Antitubercular Agents; Cell Survival; Click Chemistry; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Molecular Structure; Morpholines; Mycobacterium tuberculosis; Piperazine; Piperazines; Piperidines; Structure-Activity Relationship; Thiophenes; Triazoles

We searched for a strong and selective nonprostanoid IP agonist bearing piperidine and benzanilide moieties. Through optimization of substituents on the benzanilide moiety, the crucial part of the agonist, 43 (2-((1-(2-(N-(4-tolyl)benzo[d][1,3]dioxole-5-carboxamido)ethyl)piperidin-4-yl)oxy)acetic acid monohydrate monohydrochloride) was discovered and exhibited strong platelet aggregation inhibition (IC50=21nM) and 100-fold selectivity for IP receptor over other PG receptors. The systemic exposure level and bioavailability after oral administration of 43 were also good in dog.

Topics: Animals; Dogs; Dose-Response Relationship, Drug; Humans; Molecular Structure; Piperidines; Platelet Aggregation; Platelet Aggregation Inhibitors; Receptors, Epoprostenol; Structure-Activity Relationship

In this study, 3,4,5-trisubstituted piperidines were synthesized enantioselectively, and their antioxidant activity was evaluated. The 3,4,5-trisubstituted piperidines containing TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) and a spatially proximal hydroxy group showed good antioxidant activity. Some of these compounds showed IC50 values in a nanomolar range, comparable to that of TEMPO. Probably the TEMPO generated from the homolysis of the CON bond of 3,4,5-trisubstituted piperidines functions as a radical-scavenging entity, and the hydroxy group of piperidines has a synergistic effect to the antioxidant activity.

Topics: Antioxidants; Dose-Response Relationship, Drug; Molecular Structure; Piperidines; Stereoisomerism; Structure-Activity Relationship

A divergent, new, and highly stereoselective synthesis of cis-2,6-disubstituted piperidine natural products including isosolenopsins, deoxocassine, and spectaline was achieved from chiral aziridine decorated with appropriate alkyl chains for isosolenopsins or alkynyl groups for deoxocassine and spectaline at C2. The characteristic feature of this synthesis is one-pot sequential reactions under atmospheric hydrogen including the reduction of alkyne (for deoxocassine and spectaline), reductive ring-opening of aziridine, debenzylation, and intramolecular reductive amination in high yields. The prerequisite aziridines were elaborated from commercially available (2S)-hydroxymethylaziridine through oxidation, Wittig olefination, and the Grignard reaction for isosolenopsins or substrate-controlled lithium alkynylate addition for deoxocassine and spectaline.

Topics: Alkaloids; Aziridines; Chemistry Techniques, Synthetic; Ketones; Piperidines; Stereoisomerism

The generation of homogeneously glycosylated proteins is essential for defining glycoform-specific activity and improving protein-based therapeutics. We present a novel glycodendron prosthetic which can be site-selectively appended to recombinant proteins to create 'N-glycosylated' glycoprotein mimics. Using computational modeling, we designed the dendrimer scaffold and protein attachment point to resemble the native N-glycan architecture. Three piperidine-melamine glycodendrimers were synthesized via a chemoenzymatic route and attached to human growth hormone and the F

Topics: Dendrimers; Humans; Molecular Structure; Piperidines; Polysaccharides; Proteins; Triazines

The synthesis of a new library of 5-arylidenethiazolidinone compounds using an efficient three component reaction with thiazolidine-2,4-dione, piperidine and appropriate aldehydes is reported. This reaction is excellently high yielding, tolerant towards a variety of aldehydes and provides access to these compounds in a single step (in comparison to low yielding multistep syntheses reported in the literature). Once the reaction is complete, the desired product precipitates out of the reaction mixture and is isolated by filtration and purified by washing and recrystallization. These compounds revealed anti-proliferative activities against human breast cancer cells (MCF7 and MDA). Phenotypic profiling established the most active compound 17i (EC50 = 4.52 μM) as an apoptotic agent. A novel chemical proteomics approach identified β-actin-like protein 2, γ-enolase and macrophage migration inhibitory factor (MMIF) as putative cellular binding partners of 17i.

Topics: Apoptosis; Chemistry Techniques, Synthetic; Humans; Indicators and Reagents; MCF-7 Cells; Models, Molecular; Molecular Conformation; Piperidines; Thiazolidines

The Oxa-Pictet-Spengler reaction of methyl 3-hydroxy-4-phenylbutanoate (8) was explored to obtain novel σ receptor ligands. 1-Acyl protected piperidone ketals 10 and 11 reacted with phenylethanol 8 to yield spirocyclic compounds. Aliphatic aldehyde acetals 19 provided 1,3-disubstituted 2-benzopyrans 20 with high cis-diastereoselectivity. The intramolecular Oxa-Pictet-Spengler reaction of 24 led to the tricyclic compound 25. The spirocyclic compounds 18 show high σ1 affinity (Ki 20-26nM) and σ1/σ2 selectivity (>9-fold), when a large substituent (n-octyl, benzyl, phenylpropyl) is attached to the piperidine N-atom. Opening of the piperidine ring to yield aminoethyl (22, 23) or aminomethyl derivatives (21) resulted in reduced σ1 affinity and σ1/σ2 selectivity.

Topics: Animals; Benzopyrans; Guinea Pigs; Ligands; Piperidines; Rats; Receptors, sigma; Spiro Compounds

Site selectivity, differentiating instances of the same functional group type on one substrate, represents a forward-looking theme within chemistry: reduced dependence on protection/deprotection protocols for increased overall yield and step-efficiency. Despite these potential benefits and the expanded tactical advantages afforded to synthetic design, site selectivity remains elusive and especially so for ketone-based substrates. Herein, site-selective intermolecular mono-aldolization has been demonstrated for an array of prochiral 4-keto-substituted cyclohexanones with concomitant regio-, diastereo-, and enantiocontrol. Importantly, the aldol products allow rapid access to molecularly complex ketolactones or keto-1,3-diols, respectively containing three and four stereogenic centers. The reaction conditions are of immediate practical value and general enough to be applicable to other reaction types. These findings are applied in the first enantioselective, formal, synthesis of a leading Alzheimer's research drug, a γ-secretase modulator (GSM), in the highest known yield.

Topics: Aldehydes; Alzheimer Disease; Amyloid Precursor Protein Secretases; Chemistry Techniques, Synthetic; Drug Discovery; Humans; Ketones; Piperidines; Stereoisomerism

We report the design and synthesis of a series of non-nucleoside MtbTMPK inhibitors (1-14) based on the gram-positive bacterial TMPK inhibitor hit compound 1. A practical synthesis was developed to access these analogues. Several compounds show promising MtbTMPK inhibitory potency and allow the establishment of a structure-activity relationship, which is helpful for further optimization.

Topics: Antitubercular Agents; Dose-Response Relationship, Drug; Humans; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Mycobacterium tuberculosis; Nucleoside-Phosphate Kinase; Piperidines; Protein Kinase Inhibitors; Structure-Activity Relationship

Despite a number of intriguing utilities associated with thioamide-containing peptides and proteins in the context of biophysics, pharmacology and chemical biology, it has hitherto remained as one of the underexplored territories of peptidomimetics. The synthesis of long mono to multiply substituted endothioamide peptides is invariably accompanied with severe epimerization, oxoamide formation and various other undesired side reactions, resulting in messy product profiles. This has completely restrained their use as novel chemical tools for biological studies. During the chain elongation of an N-terminally located thioamide peptide using the Fmoc/t-Bu chemistry, it becomes vulnerable to the repetitive basic treatments as required for such chemistry. The incompatibility of thioamide moiety with bases as well as strong coupling reagents leads to epimerization as well as other side reactions due to its nucleophilicity, resulting in the loss of the stereochemical identity of the thioamidated amino acid residue. An easy-to-implement and efficient protocol to synthesize long (>10-mer) endothioamide peptides, significantly suppressing epimerization and other side reactions using 10% piperidine/dimethylformamide for 1 min, is reported herein. The novelty of the protocol is shown through the efficient synthesis of a number of 10-12-mer mono to multiply thioamide-substituted peptides with broad substrate scopes. The utility of the protocol in the context of protein engineering and chemical protein synthesis is also shown through the synthesis of a thioamide version of the 16-mer peptide from the B1 domain of protein G. Such a protocol to synthesize long endothioamide peptides would open up avenues toward engineering and accessing novel thiopeptide and thioprotein-based chemical tools, the synthesis of which had been a serious hurdle thus far. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

Topics: Amino Acid Sequence; Bacterial Proteins; Dimethylformamide; Fluorenes; Models, Molecular; Peptides; Peptidomimetics; Piperidines; Protein Domains; Protein Engineering; Protein Structure, Secondary; Solid-Phase Synthesis Techniques; Stereoisomerism; Thioamides

Piperidine and indolizidine are two basic units of alkaloids that are frequently observed in natural and synthetic compounds. Their biosynthesis in natural products is highly conserved and mostly derived from the incorporation of lysine cyclization products. Through in vitro reconstitution, we herein identified a novel pathway involving a group of polyketide-derived indolizidines, which comprises the processes of tandem two-electron thioester reduction, transamination, and imine reduction to convert acyl carrier protein (ACP)-tethered polyketide chains into the piperidine moieties of their indolizidine scaffolds. The enzymes that catalyze the imine reduction are distinct from previous known imine reductases, which have a fold of acyl-CoA dehydrogenase but do not require flavin for reduction. Our results not only provide a new way for the biosynthesis of the basic units of alkaloids but also show a novel class of imine reductases that may benefit the fields of biocatalysis and biomanufacturing.

Topics: Acyl Carrier Protein; Acyl-CoA Dehydrogenases; Biosynthetic Pathways; Imines; Indolizidines; Piperidines; Polyketides; Streptomyces

A concise asymmetric synthesis of an 11β-HSD-1 inhibitor has been achieved using inexpensive starting materials with excellent step-economy at low catalyst loadings. The catalytic enantioselective total synthesis of 1 was accomplished in 7 steps and 38% overall yield aided by the development of an innovative, sequential strategy involving Pd-catalyzed pyridinium C-H arylation and Ir-catalyzed asymmetric hydrogenation of the resulting fused tricyclic indenopyridinium salt highlighted by the use of a unique P,N-ligand (MeO-BoQPhos) with 1000 ppm of [Ir(COD)Cl]

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Catalysis; Enzyme Inhibitors; Humans; Hydrogenation; Iridium; Molecular Conformation; Palladium; Piperidines; Stereoisomerism

MMV007564 is a novel antimalarial benzimidazolyl piperidine chemotype identified in cellular screens. To identify the genetic determinant of MMV007564 resistance, parasites were cultured in the presence of the compound to generate resistant lines. Whole genome sequencing revealed distinct mutations in the gene named Plasmodium falciparum cyclic amine resistance locus (pfcarl), encoding a conserved protein of unknown function. Mutations in pfcarl are strongly associated with resistance to a structurally unrelated class of compounds, the imidazolopiperazines, including KAF156, currently in clinical trials. Our data demonstrate that pfcarl mutations confer resistance to two distinct compound classes, benzimidazolyl piperidines and imidazolopiperazines. However, MMV007564 and the imidazolopiperazines, KAF156 and GNF179, have different timings of action in the asexual blood stage and different potencies against the liver and sexual blood stages. These data suggest that pfcarl is a multidrug-resistance gene rather than a common target for benzimidazolyl piperidines and imidazolopiperazines.

Topics: Antimalarials; Drug Resistance; Humans; Life Cycle Stages; Malaria, Falciparum; Mutation; Piperidines; Plasmodium falciparum; Protozoan Proteins

A simple and efficient method for the synthesis of highly diverse pyrano[2,3-c]pyridazines was achieved by a one pot multicomponent reaction using piperidine as the organocatalyst. The synthesis of a series of heterocyclic derivatives with varying functionality (e.g. thiazine, tetrazole and pyrimidine) incorporating the pyrano[2,3-c]pyridazine moiety were achieved via reaction of 2a-e with different reagents. The structures of the synthesized derivatives were elucidated by FTIR, MS, (1)H and (13)C NMR spectroscopy. A number of the newly synthesized targeted compounds 2b-e, 3a-c and 4a-c were evaluated for their in vitro antibacterial activity and were compared with chloramphenicol and nystatin as broad spectrum reference standard antibiotics. Tests were carried out against Staphylococcus aureus (MTCC3160) and Enterococcusi fecalis as Gram-positive bacteria, and Escherichia coli (MTCC1652) and Klebsiella pneumonia as Gram-negative bacteria. Antifungal potential against Candida albicans, and Aspergillus albicans strains were also evaluated. The results revealed that compounds 3a and 3c showed strong significant activity relative to the reference against these bacterial and fungal strains.

Topics: Anti-Bacterial Agents; Antifungal Agents; Aspergillus; Candida albicans; Catalysis; Chloramphenicol; Enterococcus faecalis; Escherichia coli; Klebsiella pneumoniae; Microbial Sensitivity Tests; Nystatin; Piperidines; Pyridazines; Pyrimidines; Staphylococcus aureus; Structure-Activity Relationship; Tetrazoles; Thiazines

Depleted uranium (DU) has a chemical toxicity that is independent of its radioactivity. The purpose of this study was to explore the photoactivation of uranyl ion by ultraviolet (UV) radiation as a chemical mechanism of uranium genotoxicity. The ability of UVB (302 nm) and UVA (368 nm) radiation to photoactivate uranyl ion to produce single strand breaks was measured in pBR322 plasmid DNA, and the presence of adducts and apurinic/apyrimidinic sites that could be converted to single strand breaks by heat and piperidine was analyzed. Results showed that DNA lesions in plasmid DNA exposed to UVB- or UVA-activated DU were only slightly heat reactive, but were piperidine sensitive. The cytotoxicity of UVB-activated uranyl ion was measured in repair-proficient and repair-deficient Chinese hamster ovary cells and human keratinocyte HaCaT cells. The cytotoxicity of co-exposures of uranyl ion and UVB radiation was dependent on the order of exposure and was greater than co-exposures of arsenite and UVB radiation. Uranyl ion and UVB radiation were synergistically cytotoxic in cells, and cells exposed to photoactivated DU required different DNA repair pathways than cells exposed to non-photoactivated DU. This study contributes to our understanding of the DNA lesions formed by DU, as well as their repair. Results suggest that excitation of uranyl ion by UV radiation can provide a pathway for uranyl ion to be chemically genotoxic in populations with dermal exposures to uranium and UV radiation, which would make skin an overlooked target organ for uranium exposures.

Topics: Animals; Cell Line; Cell Survival; CHO Cells; Cocarcinogenesis; Cricetulus; DNA; DNA Adducts; DNA Breaks, Single-Stranded; DNA Repair; Hot Temperature; Humans; Indicators and Reagents; Keratinocytes; Mutagens; Organometallic Compounds; Photochemical Processes; Piperidines; Plasmids; Ultraviolet Rays

The solid charge-transfer (CT) molecular complexes formed in the reaction of the electron donor 4-methylpiperidine (4MP) with the σ-electron acceptor iodine and π-acceptors 7,7,8,8-tetracyanoquinodimethane (TCNQ), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and 2,4,4,6-tetrabromo-2,5-cyclohexadienone (TBCHD) have been investigated spectrophotometrically in chloroform at 25 °C. These were characterized through electronic and infrared spectra as well as elemental and thermal analysis. The obtained results showed that the formed solid CT-complexes have the formulas [(4MP) I](+)I(-)3, [(4MP)(DDQ)2] and [(4MP)(TBCHD)] and with TCNQ the adduct [TCMPQDM] is obtained through N-substitution reaction in full agreement with the known reaction stoichiometries in solution as well as the elemental measurements. The formation constant KCT, molar extinction coefficient εCT, free energy change ΔG(0), CT energy ECT and the ionization potential Ip have been calculated for the CT-complexes [(4MP) I](+)I(-)3, [(4MP)(DDQ)2] and [(4MP)(TBCHD)].

Topics: Absorption, Physicochemical; Benzoquinones; Electrons; Nitriles; Piperidines; Solvents; Spectrophotometry, Infrared; Thermodynamics; Titrimetry

The aim of this study was to estimate the effective absorbed radiation dose to human organs following promising in-vivo results of intravenous administration of 4-benzyl-1-(3-[125I]-iodobenzylsulfonyl)piperidine (4-B-[125I]-IBSP) using normal biodistribution data obtained from rats.. Five rats were killed at exact time intervals and the percentage of injected dose per gram of each organ was measured by direct counting from rat data. The medical internal radiation dose formulation was applied to extrapolate from rats to humans and to project the absorbed radiation dose for various human organs.. The dose estimation shows that the organs that received the highest absorbed dose were the brain, bone surface, and red marrow (10.51, 0.69, and 0.08 μGy/MBq, respectively). Our prediction shows that a 185 MBq injection of 4-B-[125I]-IBSP into humans might result in an estimated absorbed dose of 49.39 μGy for the whole body. The highest effective absorbed dose for 4-B-[125I]-IBSP was in the brain (19.4 μSv) and the organs that received the next highest doses were the bone surface, red marrow, muscle, and thyroid, with magnitudes of 15.27, 1.81, 0.15, and 0.10 μSv, respectively.. The results of this study suggest that 4-B-[125I]-IBSP is a suitable and safe candidate in clinical studies and in lung malignancies.

Topics: Animals; Female; Humans; Piperidines; Radiation Dosage; Rats; Sulfonamides; Tissue Distribution

The tumor microenvironment represents a burden that hampers the proper activation of immune cells, including the dendritic cells (DCs). It is, therefore, desired that the important characteristics of a given anticancer drug candidate be seen as consisting not solely of its antitumor properties, but that it also lacks potential side effects that could additionally constrain the development and function of immune cells associated with tumor immunity. We have previously identified compounds with a N-amidinopiperidine scaffold that selectively induce apoptosis in Burkitt's lymphoma cells through proteasome inhibition. Here, we demonstrate that SPI-15 affected neither the viability of DCs nor their differentiation. In addition, the compound had no significant effect on their cytokine secretion or allostimulatory capacity. Moreover, DC functionality in the context of tumor microenvironment was also unaffected, as demonstrated by experiments performed on DCs differentiated in Ramos-conditioned media in the presence or absence of SPI-15. The cytokine profile and functional assays revealed that SPI-15 rescues DC differentiation from the immunosuppressive environment produced by Ramos cells; this was seen by their reacquired ability to induce IFN-γ-secretion from naïve CD4(+)CD45RA(+) T cells and the consequently induced Th1-effector differentiation. Herein, we present novel characteristics of an N-amidinopiperidine-based protease inhibitor whose anticancer properties are not associated with the immunosuppression of DCs. We propose future studies toward the design of structurally similar compounds with the aim of developing potent anticancer drugs with minimal negative effects on crucial factors involved in tumor immunity.

Topics: Amidines; Antineoplastic Agents; Apoptosis; Blotting, Western; Burkitt Lymphoma; Cell Differentiation; Cell Proliferation; Cells, Cultured; Cytokines; Dendritic Cells; Flow Cytometry; Humans; Lymphocyte Activation; Piperidines; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Th1 Cells; Tumor Microenvironment

Potent compounds do not necessarily make the best drugs in the market. Consequently, with the aim to describe tools that may be fundamental for refining the screening of candidates for animal and preclinical studies and further development, molecules of different structural classes synthesized within the frame of a broad screening platform were evaluated for their trypanocidal activities, cytotoxicities against murine macrophages J774.1 and selectivity indices, as well as for their ligand efficiencies and structural chemical properties. To advance into their modes of action, we also describe the morphological and ultrastructural changes exerted by selected members of each compound class on the parasite Trypanosoma brucei. Our data suggest that the potential organelles targeted are either the flagellar pocket (compound 77, N-Arylpyridinium salt; 15, amino acid derivative with piperazine moieties), the endoplasmic reticulum membrane systems (37, bisquaternary bisnaphthalimide; 77, N-Arylpyridinium salt; 68, piperidine derivative), or mitochondria and kinetoplasts (88, N-Arylpyridinium salt; 68, piperidine derivative). Amino acid derivatives with fumaric acid and piperazine moieties (4, 15) weakly inhibiting cysteine proteases seem to preferentially target acidic compartments. Our results suggest that ligand efficiency indices may be helpful to learn about the relationship between potency and chemical characteristics of the compounds. Interestingly, the correlations found between the physico-chemical parameters of the selected compounds and those of commercial molecules that target specific organelles indicate that our rationale might be helpful to drive compound design toward high activities and acceptable pharmacokinetic properties for all compound families.

Topics: Animals; Cell Line; Cysteine Proteases; Fumarates; Hydrogen-Ion Concentration; Macrophages; Mice; Mitochondria; Organelles; Piperazine; Piperazines; Piperidines; Trypanocidal Agents; Trypanosoma brucei brucei

A newly developed P,N-bidentate ligand enables enantioselective intramolecular cyclopropanation by a reactive α-oxo gold carbene intermediate generated in situ. The ligand design is based on our previously proposed structure (with a well-organized triscoordinated gold center) of the carbene intermediate in the presence of a P,N-bidentate ligand. A C2-symmetric piperidine ring was incorporated in the ligand as the nitrogen-containing moiety. A range of racemic transformations of α-oxo gold carbene intermediates have been developed recently, and this new class of chiral ligands could enable their modification for asymmetric synthesis, as demonstrated in this study.

Topics: Catalysis; Crystallography, X-Ray; Cyclopropanes; Gold; Ligands; Methane; Molecular Conformation; Nitrogen; Oxidation-Reduction; Phosphorus; Piperidines; Stereoisomerism

In this work, we will report a combined experimental and theoretical study on molecular and vibrational structure of 4-bromo-1-(ethoxycarbonyl)piperidine-4-carboxylic acid (BEPA). BEPA has been characterized by FT-IR, FT-Raman, (1)H NMR, (13)C NMR and UV spectroscopy. The FT-IR and FT-Raman spectra of BEPA were recorded in the solid phase. The optimized geometry was calculated by B3LYP and M06-2X methods using 6-311G(d,p) basis set. The FT-IR and FT-Raman spectra of BEPA were calculated at the same level and were interpreted in terms of Potential Energy Distribution (PED) analysis. The scaled theoretical wavenumber showed very good agreement with the experimental values. The (1)H and (l3)C nuclear magnetic resonance (NMR) chemical shifts of the molecule were calculated by the Gauge-Independent Atomic Orbital (GIAO) method. Stability of the molecule arising from hyperconjugative interactions and charge delocalization has been analyzed using Natural Bond Orbital (NBO) analysis. Density plots over the highest occupied molecular orbitals (HOMO) and lowest unoccupied molecular orbitals (LUMO) energy surface directly identifies the donor and acceptor atoms in the molecule. It also provides information about the charge transfer within the molecule. To obtain chemical reactivity of the molecule, the molecular electrostatic potential (MEP) surface map is plotted over the optimized geometry of the molecule.

Topics: Carboxylic Acids; Halogenation; Magnetic Resonance Spectroscopy; Models, Molecular; Piperidines; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis, Raman; Static Electricity

Type 2 diabetes (T2D) is a lifestyle disease affecting millions of people worldwide. Various therapies are available for the management of T2D and dipeptidyl peptidase-IV (DPP-IV) inhibition has emerged as a promising therapy for the treatment of type 2 diabetes (T2D). Here we report design, synthesis and in vitro efficacy of sulfonamide derivatives of pyrrolidine and piperidine as anti-diabetic agents. Amongst all the compounds synthesized in this series, 9a, is the most potent (IC50 = 41.17 nM).

Topics: Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Design; Humans; Hypoglycemic Agents; Molecular Docking Simulation; Molecular Structure; Piperidines; Pyrrolidines; Structure-Activity Relationship; Sulfonamides

Rodent selectivity data of piperidine-4-yl-1H-indoles, a series of CC chemokine receptor-3 (CCR3) antagonists, are presented and discussed as part of an overall optimization effort within this lead compound class. Although attachment of an acidic moiety to the 1-position of the indole led to an overall balanced in vitro profile, in particular reducing inhibition of the hERG channel, potency on the rat and mouse receptor worsened. These findings could be rationalized in the context of a CCR3 homology model.

Topics: Animals; Humans; Indoles; Mice; Models, Molecular; Piperidines; Protein Structure, Secondary; Protein Structure, Tertiary; Rats; Receptors, CCR3; Species Specificity

An organocatalyzed asymmetric tandem reaction of cyclic N-sulfonylimines and α,β-unsaturated aldehydes was developed. These substrates follow an alternative reaction pathway to that of reactions involving saturated aldehydes, affording similar piperidine derivatives.

Topics: Aldehydes; Catalysis; Imines; Models, Molecular; Molecular Conformation; Piperidines; Solvents; Sulfones

A novel class of potent cannabinoid receptor 2 (CB2) agonists based on a (S)-piperidine scaffold was identified using ligand-based pharmacophore models. Optimization of solubility and metabolic stability led to the identification of several potent CB2 agonists (e.g., 30) that displayed selectivity over cannabinoid receptor 1 (CB1) and acceptable drug like properties. In rats, compound 30 demonstrated a favorable pharmacokinetic profile and efficacy in a Streptozotocin-induced diabetic neuropathy model, with full reversal of mechanical hyperalgesia.

Topics: Animals; Diabetic Neuropathies; Half-Life; Humans; Ligands; Male; Microsomes, Liver; Pain; Pipecolic Acids; Piperidines; Protein Binding; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Solubility; Structure-Activity Relationship; Thiazines

Highly selective orexin receptor antagonists (SORAs) of the orexin 2 receptor (OX2R) have become attractive targets both as potential therapeutics for insomnia as well as biological tools to help further elucidate the underlying pharmacology of the orexin signaling pathway. Herein, we describe the discovery of a novel piperidine ether 2-SORA class identified by systematic lead optimization beginning with filorexant, a dual orexin receptor antagonist (DORA) that recently completed Phase 2 clinical trials. Changes to the ether linkage and pendant heterocycle of filorexant were found to impart significant selectivity for OX2R, culminating in lead compound PE-6. PE-6 displays sub-nanomolar binding affinity and functional potency on OX2R while maintaining >1600-fold binding selectivity and >200-fold functional selectivity versus the orexin 1 receptor (OX1R). PE-6 bears a clean off-target profile, a good overall preclinical pharmacokinetic (PK) profile, and reduces wakefulness with increased NREM and REM sleep when evaluated in vivo in a rat sleep study. Importantly, subtle structural changes to the piperidine ether class impart dramatic changes in receptor selectivity. To this end, our laboratories have identified multiple piperidine ether 2-SORAs, 1-SORAs, and DORAs, providing access to a number of important biological tool compounds from a single structural class.

Topics: Animals; Dogs; Drug Evaluation, Preclinical; Ethers; Half-Life; Humans; Orexin Receptor Antagonists; Orexin Receptors; Piperidines; Protein Binding; Pyrimidines; Rats; Sleep; Structure-Activity Relationship

Anaplastic lymphoma kinase (ALK) has gained increased attention as an attractive therapeutic target for the treatment of various cancers, especially non-small-cell lung cancer (NSCLC). Recently, piperidine carboxamides were reported as Type I1/2 inhibitors of ALK, which occupy both the ATP binding site and the back ATP hydrophobic cavity in DFG-in conformation. Due to the dynamic behavior of ALK in the binding of Type I1/2 inhibitors, the accurate predictions of the binding structures and relative binding potencies of these inhibitors are quite challenging. In this study, different modeling techniques, including molecular docking, ensemble docking based on multiple receptor conformations, molecular dynamics simulations and free energy calculations, were utilized to explore the binding mechanisms of piperidine carboxamides. Our predictions show that the conventional docking protocols are not sufficient to predict the relative binding potencies of the studied inhibitors with high accuracy, but incorporating protein flexibility before or after docking is quite effective to improve the prediction accuracy. Notably, the binding free energies predicted by MM/GBSA or MM/PBSA based on the MD simulations for the docked poses give the highest correlation with the experimental data, highlighting the importance of the inclusion of receptor flexibility for the accurate predictions of the binding potencies for Type I1/2 inhibitors of ALK. Furthermore, the comprehensive analysis of several pairs of representative inhibitors demonstrates the importance of hydrophobic interactions in improving the binding affinities of the inhibitors with the hot-spot residues surrounding the binding pocket. This work is expected to provide valuable clues for further rational design of novel and potent Type I1/2 ALK inhibitors.

Topics: Amides; Anaplastic Lymphoma Kinase; Binding Sites; Entropy; Hydrophobic and Hydrophilic Interactions; Molecular Docking Simulation; Piperidines; Protein Binding; Protein Kinase Inhibitors; Protein Structure, Tertiary; Receptor Protein-Tyrosine Kinases; Structure-Activity Relationship

The diastereoselective synthesis and biological activity of piperidine-3,4-diol and piperidine-3-ol-derived pyrrolotriazine inhibitors of anaplastic lymphoma kinase (ALK) are described. Although piperidine-3,4-diol and piperidine-3-ol derivatives showed comparable in vitro ALK activity, the latter subset of inhibitors demonstrated improved physiochemical and pharmacokinetic properties. Furthermore, the stereochemistry of the C3 and C4 centers had a marked impact on the in vivo inhibition of ALK autophosphorylation. Thus, trans-4-aryl-piperidine-3-ols (22) were more potent than the cis diastereomers (20).

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Cell Line, Tumor; Crystallography, X-Ray; Humans; Lymphoma, Large-Cell, Anaplastic; Mice, SCID; Models, Molecular; Piperidines; Protein Kinase Inhibitors; Pyrroles; Rats, Sprague-Dawley; Receptor Protein-Tyrosine Kinases; Triazines

The metalation of 4,4-dimethyloxazoline using TMPZnCl·LiCl provides a stable 2-zincated oxazolinyl reagent which readily undergoes palladium-catalyzed Negishi cross-couplings allowing a new access to 2-aryloxazolines. Cu-mediated acylation and allylation reactions also proceed in good yields.

Topics: Catalysis; Organometallic Compounds; Oxazoles; Piperidines; Zinc

A direct approach to the synthesis of polyhydroxylated piperidine and pyrrolidine peptidomimetics is described. The presented strategy is based on one-pot reduction of sugar-derived lactams with Schwartz's reagent followed by a multicomponent Ugi-Joullié reaction.

Topics: Carbohydrates; Lactams; Peptidomimetics; Piperidines; Pyrrolidines; Stereoisomerism

The synthesis and SAR of 4-methoxy-3-(piperidin-4-yl) benzamides identified after a high-throughput screen of the MLPCN library is reported. SAR was explored around the 3-piperidine substituent as well as the amide functionality of the reported compounds. Starting from the initial lead compounds, 1-7, iterative medicinal chemistry efforts led to the identification of ML352 (10m). ML352 represents a potent and selective inhibitor of CHT based on a drug-like scaffold.

Topics: Animals; Benzamides; Half-Life; HEK293 Cells; Humans; Membrane Transport Proteins; Piperidines; Protein Binding; Rats; Structure-Activity Relationship; Symporters; Tissue Distribution

The nucleobase guanine in DNA (dG) and RNA (rG) has the lowest standard reduction potential of the bases, rendering it a major site of oxidative damage in these polymers. Mapping the sites at which oxidation occurs in an oligomer via chemical reagents utilizes hot piperidine for cleaving oxidized DNA and aniline (pH 4.5) for cleaving oxidized RNA. In the present studies, a series of time-dependent cleavages of DNA and RNA strands containing various guanine lesions were examined to determine the strand scission rate constants. The guanine base lesions 8-oxo-7,8-dihydroguanine (OG), spiroiminodihydantoin (Sp), 5-guanidinohydantoin (Gh), 2,2,4-triamino-2H-oxazol-5-one (Z), and 5-carboxamido-5-formamido-2-iminohydantoin (2Ih) were evaluated in piperidine-treated DNA and aniline-treated RNA. These data identified wide variability in the chemical lability of the lesions studied in both DNA and RNA. Further, the rate constants for cleaving lesions in RNA were generally found to be significantly smaller than for lesions in DNA. The OG nucleotides were poorly cleaved in DNA and RNA; Sp nucleotides were slowly cleaved in DNA and did not cleave significantly in RNA; Gh and Z nucleotides cleaved in both DNA and RNA at intermediate rates; and 2Ih oligonucleotides cleaved relatively quickly in both DNA and RNA. The data are compared and contrasted with respect to future experimental design.

Topics: Aniline Compounds; DNA; DNA Cleavage; Guanine; Kinetics; Molecular Structure; Oxidation-Reduction; Piperidines; RNA; RNA Cleavage; Time Factors

A novel series of piperidin-4-yl-aminopyrimidine derivatives were designed fusing the pharmacophore templates of etravirine-VRX-480773 hybrids our group previously described and piperidine-linked aminopyrimidines. Most compounds displayed significantly improved activity against wild-type HIV-1 with EC50 values in single-digit nanomolar concentrations compared to etravirine-VRX-480773 hybrids. Selected compounds were also evaluated for activity against reverse transcriptase, and had lower IC50 values than that of nevirapine. The improved potency observed in this in vitro model of HIV RNA replication partly validates the mechanism by which this class of allosteric pyrimidine derivatives inhibits reverse transcriptase, and represents a remarkable step forward in the development of AIDS therapeutics.

Topics: Anti-HIV Agents; Cells, Cultured; Drug Discovery; HIV Reverse Transcriptase; Humans; Molecular Structure; Nitriles; Piperidines; Pyridazines; Pyrimidines; Reverse Transcriptase Inhibitors; Structure-Activity Relationship

Synthetic routes to six 3-D scaffolds containing piperazine, pyrrolidine and piperidine cores have been developed. The synthetic methodology focused on the use of N-Boc α-lithiation-trapping chemistry. Notably, suitably protected and/or functionalised medicinal chemistry building blocks were synthesised via concise, connective methodology. This represents a rare example of lead-oriented synthesis. A virtual library of 190 compounds was then enumerated from the six scaffolds. Of these, 92 compounds (48%) fit the lead-like criteria of: (i) -1⩽AlogP⩽3; (ii) 14⩽number of heavy atoms⩽26; (iii) total polar surface area⩾50Å(2). The 3-D shapes of the 190 compounds were analysed using a triangular plot of normalised principal moments of inertia (PMI). From this, 46 compounds were identified which had lead-like properties and possessed 3-D shapes in under-represented areas of pharmaceutical space. Thus, the PMI analysis of the 190 member virtual library showed that whilst scaffolds which may appear on paper to be 3-D in shape, only 24% of the compounds actually had 3-D structures in the more interesting areas of 3-D drug space.

Topics: Combinatorial Chemistry Techniques; Drug Discovery; Heterocyclic Compounds; Lithium; Molecular Structure; Organometallic Compounds; Piperazine; Piperazines; Piperidines; Pyrrolidines; Small Molecule Libraries

Chloramphenicol (CAP) was an old antimicrobial agent. However, the use of CAP is limited because of its harmful side effects, such as leukemia. The molecular mechanism through which CAP has been strongly correlated with leukemogenesis is still unclear. To elucidate the mechanism of genotoxicity, we examined DNA damage by CAP and its metabolites, nitroso-CAP (CAP-NO), N-hydroxy-CAP (CAP-NHOH), using isolated DNA. CAP-NHOH have the ability of DNA damage including 8-oxo-7,8-dihydro-2'-deoxyguanosine formation in the presence of Cu(II), which was greatly enhanced by the addition of an endogenous reductant NADH. CAP-NO caused DNA damage in the presence of Cu(II), only when reduced by NADH. NADH can non-enzymatically reduce the nitroso form to hydronitroxide radicals, resulting in enhanced generation of reactive oxygen species followed by DNA damage through the redox cycle. Furthermore, we also studied the site specificity of base lesions in DNA treated with piperidine or formamidopyrimidine-DNA glycosylase, using (32)P-5'-end-labeled DNA fragments obtained from the human tumor suppressor gene. CAP metabolites preferentially caused double base lesion, the G and C of the ACG sequence complementary to codon 273 of the p53 gene, in the presence of NADH and Cu(II). Therefore, we conclude that oxidative double base lesion may play a role in carcinogenicity of CAP.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Anti-Bacterial Agents; Cattle; Chloramphenicol; Deoxyguanosine; DNA; DNA Damage; DNA-Formamidopyrimidine Glycosylase; Free Radicals; Genes, p53; Humans; Hydroxides; Hydroxylamines; Leukemia; Oxygen; Piperidines; Reactive Oxygen Species; Spectrophotometry, Ultraviolet; Thymus Gland

A conventional and microwave assisted efficient synthesis of diphenyl substituted pyrazole using PEG 600 as green solvent has been described. A relatively shorter reaction time with excellent yield of the piperidine mediated protocol has been attracted economically attractive and eco-friendly. All newly synthesized compounds were characterized by standard spectroscopic techniques viz., UV-visible, FT-IR, (1)H-NMR and Mass spectra. The anti-microbial activities of compounds have also been tested using Minimum Inhibitory Concentration (MIC) method with two different microorganisms Staphylococcus aureus (MTCC3381) and Escherichia coli (MTCC739). The results of the antimicrobial activity revealed that the diphenyl substituted pyrazole derivatives have nice inhibiting nature against both types of bacteria of present investigation than corresponding chalcones. Since, the work has been focused on green chemical approach towards the synthesis, this protocol may be recommended for eco-friendly applications.

Topics: Anti-Bacterial Agents; Biphenyl Compounds; Chalcones; Escherichia coli; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; Microwaves; Piperidines; Polyethylene Glycols; Pyrazoles; Solvents; Spectroscopy, Fourier Transform Infrared; Staphylococcus aureus

A simple and stereoselective synthesis of 3-methylthalidomide, a configurationally stable thalidomide analog, is presented. Herein we describe the synthesis of (R)-3-methylthalidomide starting from (S)-alanine by piperidin-2-one ring assembly approach in high yield and enantiomeric purity without using a chiral auxiliary or reagent. Starting from (R)-alanine, the corresponding (S)-3-methylthalidomide can be prepared using the same methodology.

Topics: Chemistry Techniques, Synthetic; Hydrogen-Ion Concentration; Piperidines; Piperidones; Stereoisomerism; Thalidomide

A novel series of ester and carbamate derivatives was synthesized and evaluated its activities against Leishmania amazonensis. All compounds exhibited weaker leishmanicidal activity than amphotericin B. However, results indicated that substituents on the aryl-acyl subunit are important for modulation of the leishmanicidal effect. The nitro derivative showed the highest activity of the series with an IC50 = 17.24 μM, and comparable potency to the 3,4-benzodioxole ester and n-hexyl carbamate derivatives. All compounds showed low toxicity against human cells. These results revealed interesting novel piperine-like molecular pattern for exploitation in search and development of effective and low toxic antileishmanial drug candidates.

Topics: Antiprotozoal Agents; Benzodioxoles; Drug Discovery; Humans; Inhibitory Concentration 50; Leishmania; Molecular Structure; Piperidines

With the increasing concerns about chemical pollution and sustainability of resources, among the significant challenges facing synthetic chemists are the development and application of elegant and efficient methods that enable the concise synthesis of natural products, drugs, and related compounds in a step-, atom- and redox-economic manner. One of the most effective ways to reach this goal is to implement reaction cascades that allow multiple bond-forming events to occur in a single vessel. This Account documents our progress on the rational design and strategic application of asymmetric catalytic cascade reactions in constructing diverse scaffolds and synthesizing complex chiral molecules. Our research is aimed at developing robust cascade reactions for the systematic synthesis of a range of interesting molecules that contain structural motifs prevalent in natural products, pharmaceuticals, and biological probes. The strategies employed to achieve this goal can be classified into three categories: bifunctional base/Brønsted acid catalysis, covalent aminocatalysis/N-heterocyclic carbene catalysis, and asymmetric organocatalytic relay cascades. By the use of rationally designed substrates with properly reactive sites, chiral oxindole, chroman, tetrahydroquinoline, tetrahydrothiophene, and cyclohexane scaffolds were successfully assembled under bifunctional base/Brønsted acid catalysis from simple and readily available substances such as imines and nitroolefins. We found that some of these reactions are highly efficient since catalyst loadings as low as 1 mol % can promote the multistep sequences affording complex architectures with high stereoselectivities and yields. Furthermore, one of the bifunctional base/Brønsted acid-catalyzed cascade reactions for the synthesis of chiral cyclohexanes has been used as a key step in the construction of the tetracyclic core of lycorine-type alkaloids and the formal synthesis of α-lycorane. Guided by the principles of covalent aminocatalysis and N-heterocyclic carbene catalysis, we synthesized chiral piperidine, indole, and cyclobutane derivatives. The synthesis of chiral cyclobutanes and pyrroloindolones showed unprecedented reactivity of substrates and catalysts. The development of the strategy of asymmetric organocatalytic relay cascades has provided a useful tool for the controlled synthesis of specific diastereomers in complex molecules. This Account gives a panoramic view and the logic of our research on the desi

Topics: Biological Products; Catalysis; Cyclobutanes; Indoles; Molecular Conformation; Piperidines; Stereoisomerism

A series of high affinity second-generation thiazolopiperidine inhibitors of PI3Kγ were designed based on some general observations around lipid kinase structure. Optimization of the alkylimidazole group led to inhibitors with higher levels of PI3Kγ selectivity. Additional insights into PI3K isoform selectivity related to sequence differences in a known distal hydrophobic pocket are also described.

Topics: Cell Line; Drug Discovery; Enzyme Inhibitors; Humans; Hydrophobic and Hydrophilic Interactions; Isoenzymes; Models, Molecular; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Protein Conformation; Substrate Specificity

Clopidogrel is a prodrug anticoagulant with active metabolites that irreversibly inhibit the platelet surface GPCR P2Y12 and thus inhibit platelet activation. However, gaining an understanding of patient response has been limited due to imprecise understanding of metabolite activity and stereochemistry, and a lack of acceptable analytes for quantifying in vivo metabolite formation. Methods for the production of all bioactive metabolites of clopidogrel, their stereochemical assignment, and the development of stable analytes via three conceptually orthogonal routes are disclosed.

Topics: Biological Phenomena; Clopidogrel; Humans; Microsomes, Liver; Piperidines; Platelet Aggregation Inhibitors; Prodrugs; Stereoisomerism; Ticlopidine

Insect repellents are known since many decades ago and constitute a major tool for personal protection against the biting of mosquitoes. Despite their wide use, the understanding of why and how repellents repel is relatively recent. In particular, the question about to what extent insects other than mosquitoes are repulsed by repellents remains open. We developed a series of bioassays aimed to test the performance of well established as well as potential repellent molecules on the Chagas disease vector Rhodnius prolixus. Besides testing their ability to prevent biting, we tested the way in which they act, i.e., by obstructing the detection of attractive odours or by themselves. By using three different experimental protocols (host-biting, open-loop orientation to odours and heat-triggered proboscis extension response) we show that DEET repels bugs both in the presence and in the absence of host-associated odours but only at the highest quantities tested. Piperidine was effective with or without a host and icaridine only repelled in the absence of a living host. Three other molecules recently proposed as potential repellents due to their affinity to the Ir40a(+) receptor (which is also activated by DEET) did not evoke significant repellency. Our work provides novel experimental tools and sheds light on the mechanism behind repellency in haematophagous bugs.

Topics: Animals; Behavior, Animal; Chagas Disease; DEET; Disease Vectors; Feeding Behavior; Humans; Insect Repellents; Nymph; Odorants; Piperidines; Rhodnius; Smell

A series of 4-benzylpiperidine carboxamides were designed and synthesized, and tested for their dual (serotonin and norepinephrine) reuptake inhibition. The synthesis of 4-benzylpiperidine carboxamides involved two main steps: amidation and substitution. Derivatives with 3 carbon linker displayed better activity than with 2 carbon linker. 4-Biphenyl- and 2-naphthyl-substituted derivatives 7e and 7j showed greater dual reuptake inhibition than standard drug venlafaxine HCl.

Topics: Amides; Drug Design; HEK293 Cells; Humans; Norepinephrine Plasma Membrane Transport Proteins; Piperidines; Protein Binding; Selective Serotonin Reuptake Inhibitors; Serotonin and Noradrenaline Reuptake Inhibitors; Serotonin Plasma Membrane Transport Proteins; Structure-Activity Relationship

The design and discovery of JDTic as a potent and selective kappa opioid receptor antagonist used the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine pharmacophore as the lead structure. In order to determine if the 3-methyl or 4-methyl groups were necessary in JDTic and JDTic analogs for antagonistic activity, compounds 4a-c, and 4d-f which have either the 3-methyl or both the 3- and 4-methyl groups removed, respectively, from JDTic and analogs were synthesized and evaluated for their in vitro opioid receptor antagonist activities using a [(35)S]GTPγS binding assay. Other ADME properties were also assessed for selected compounds. These studies demonstrated that neither the 3-methyl or 3,4-dimethyl groups present in JDTic and analogs are required to produce potent and selective κ opioid receptor antagonists.

Topics: Animals; Cell Membrane Permeability; Dogs; Drug Design; Drug Evaluation, Preclinical; Half-Life; Madin Darby Canine Kidney Cells; Narcotic Antagonists; Piperidines; Protein Binding; Receptors, Opioid, kappa; Tetrahydroisoquinolines

A novel class of NaV1.7 inhibitors has been identified by high-throughput screening followed by structure activity relationship studies. Among this series of compounds, piperidine 9o showed potent human and mouse NaV1.7 inhibitory activities with fair subtype selectivity over NaV1.5. Compound 9o successfully demonstrated analgesic efficacy in mice comparable to that of the currently used drug, mexiletine, but with an expanded central nervous system safety margin.

Topics: Animals; Drug Discovery; Humans; Inhibitory Concentration 50; Mexiletine; Mice; Molecular Structure; NAV1.7 Voltage-Gated Sodium Channel; Piperidines; Voltage-Gated Sodium Channel Blockers

The geometries of 1-naphthol-(piperidine)n (1-NpOH-(Pip)n) (n = 0-3) clusters have been calculated by using density functional theory (DFT) and time-dependent density functional theory (TD-DFT) methods to investigate excited-state proton transfer (ESPT) in the low-lying singlet excited states, La and Lb. For the n = 1 cluster, no PT structure was found in Lb and La as well as the ground state, S0. For n = 2, optically accessible Lb from S0 shows the PT structure. We therefore concluded that the threshold size of ESPT is n = 2, which is consistent with previous experimental results. ESPT in 1-NpOH-(Pip)n is simply triggered by optical excitation to Lb. It is essentially different from the 1-NpOH-(NH3)n cluster in which an internal conversion process is required to promote ESPT. From the calculated structures, the importance of the solvation of the π-ring is strongly suggested rather than the proton affinity in ESPT.

Topics: Hydrogen Bonding; Models, Molecular; Naphthols; Piperidines; Protons; Quantum Theory

Three series of 4,6-dimethoxy-, 4,6-dipiperidino- and 4,6-dimorpholino-1,3,5-triazin-2-yl) amino acid derivatives were synthesized and characterized. A preliminary study for their monoamine oxidase inhibitory activity showed that compounds 7, 18, and 25 had MAO-A inhibition activity comparable to that of the standard clorgyline, with apparently more selective inhibitory activity toward MAO-A than MAO-B and no significant acute toxicity.

Topics: Amino Acids; Clorgyline; Monoamine Oxidase Inhibitors; Morpholines; Piperidines; Quantitative Structure-Activity Relationship; Triazines

Wild-type and variant forms of transthyretin (TTR), a normal plasma protein, are amyloidogenic and can be deposited in the tissues as amyloid fibrils causing acquired and hereditary systemic TTR amyloidosis, a debilitating and usually fatal disease. Reduction in the abundance of amyloid fibril precursor proteins arrests amyloid deposition and halts disease progression in all forms of amyloidosis including TTR type. Our previous demonstration that circulating serum amyloid P component (SAP) is efficiently depleted by administration of a specific small molecule ligand compound, that non-covalently crosslinks pairs of SAP molecules, suggested that TTR may be also amenable to this approach. We first confirmed that chemically crosslinked human TTR is rapidly cleared from the circulation in mice. In order to crosslink pairs of TTR molecules, promote their accelerated clearance and thus therapeutically deplete plasma TTR, we prepared a range of bivalent specific ligands for the thyroxine binding sites of TTR. Non-covalently bound human TTR-ligand complexes were formed that were stable in vitro and in vivo, but they were not cleared from the plasma of mice in vivo more rapidly than native uncomplexed TTR. Therapeutic depletion of circulating TTR will require additional mechanisms.

Topics: Animals; Binding Sites; Cross-Linking Reagents; Humans; Ligands; Mice; Mice, Inbred C57BL; Models, Molecular; Piperidines; Prealbumin; Protein Structure, Quaternary; Thyroxine

The reactions of hypochlorous acid (HOCl) with ammonia, (di)methylamine, and heterocyclic amines have been studied computationally using double-hybrid DFT methods (B2PLYP-D and BK-PLYP) and a G3B3 composite scheme. In the gas phase the calculated energy barriers for N- and/or C-hydroxylation are ca. 100 kJ mol(-1) lower than the barrier for N-chlorination of amines. In the model solvent, however, the latter process becomes kinetically more favored. The explicit solvent effects are crucial for determination of the reaction mechanism. The N-chlorination is extremely susceptible to the presence of explicit water molecules, while no beneficial solvation effect has been found for the N- or C-hydroxylation of amines. The origin of the observed solvent effects arises from differential solvation of the respective transition states for chlorine- and oxygen-transfers, respectively. The nature of solvation of the transition state structures has been explored in more detail by classical molecular dynamics (MD) simulation. In agreement with the quantum mechanical approach, the most stable structural motif, which includes the amine, HOCl, and two reactive waters, has been identified during the MD simulation. The inclusion of 5 or 6 explicit water molecules is required to reproduce the experimental barriers for HOCl-induced formation of N-chloramines in an aqueous environment.

Topics: Amines; Chlorine; Hydroxylation; Hypochlorous Acid; Molecular Docking Simulation; Molecular Structure; Morpholines; Piperidines

The aim of this study was to synthesize and evaluate diazapentacyclic analogs for their acetylcholinesterase (AChE) inhibitory activity. The pentacyclic analogs were synthesized by one-pot three-component domino reactions in a microwave synthesizer. Most of the compounds exhibited moderate to good AChE inhibitory activity, compound 5i showed potent inhibitory activity with IC50 1.12 ± 0.01 µM and this may provide a new lead for developing potential inhibitors for Alzheimer's disease.

Topics: Acetylcholinesterase; Aza Compounds; Cholinesterase Inhibitors; Cyclopentanes; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Models, Molecular; Molecular Structure; Piperidines; Structure-Activity Relationship

Novel, potent non-imidazole histamine H3 receptor antagonists have been prepared and in vitro tested as H3 -receptor antagonists (the electrically evoked contraction of the guinea-pig jejunum). The present compounds contain a 4-hydroxypiperidine core, which behaves as a conformationally restricted version of the 3-amino-1-propanol moiety common to the many previously described non-imidazole H3 ligands. Detailed structure-activity studies revealed that 1-(2-benzofuranylmethyl)- 5c (pA2 = 8.47 ± 0.05) and 1-(3-benzofuranylmethyl)-4-[5-(N-methyl-N-propyl)pentyloxy]piperidine 5d (pA2 = 8.15 ± 0.07) exhibit high potency for the H3 histamine receptor. In addition, the potency of selected 1-[(N-substituted-N-methyl)-3-propyloxy]-5-(N-methyl-N-propyl)pentanediamines as antagonist of the H3 histamine receptor was also evaluated. Replacement of the 4-hydroxypiperidine of the leads 7 and 5c by a highly flexible 3-(methylamino)propyloxy chain yields compounds 6a (pA2 = 8.02) and 6b (pA2 = 6.23) with higher and lower potency than their piperidine analogues (7, pA2 = 7.79; 5c, pA2 = 8.47), respectively. The histaminergic H1 antagonism of selected compounds 5c, 5d and 6a has been established on the isolated guinea-pig ileum by conventional methods; the pA2 values have compared with the potency of pyrilamine. None of them showed any H1 -antagonistic activity (pA2 < 4; for pyrilamine pA2 = 8.5).

Topics: Amines; Animals; Guinea Pigs; Histamine Antagonists; Jejunum; Male; Muscle Contraction; Piperidines; Receptors, Histamine H3; ROC Curve; Structure-Activity Relationship

The spectroscopic characteristics of the solid charge-transfer molecular complexes (CT) formed in the reaction of the electron donor 4-(aminomethyl) piperidine (4AMP) with the σ-acceptor iodine and the π-acceptors 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), 2,4,4,6-tetrabromo-2,5-cyclohexadienone (TBCHD) and 7,7,8,8-tetracyanoquinodimethane (TCNQ) have been studied in chloroform at 25°C. These were investigated through electronic, infrared spectra and thermal analysis as well as elemental analysis. The results show that the formed solid CT-complexes have the formulas [(4AMP)I](+)I3(-), [(4AMP)(DDQ)2] and [(4AMP)(TBCHD)] while in the case of 4AMP-TCNQ reaction, a short-lived CT complex is formed followed by rapid N-substitution by TCNQ forming the final reaction product 7,7,8-tricyano-8-aminomethylpiperidinylquinodimethane [TCAMPQDM] in full agreement with the known reaction stoichiometries in solution as well as the elemental measurements and the thermal analysis confirmed the structure of the obtained compounds. The formation constant kCT, molar extinction coefficient εCT, free energy change ΔG(0) and CT energy ECT have been calculated for the CT-complexes [(4AMP)I](+)I3(-), [(4AMP)(DDQ)2] and [(4AMP)(TBCHD)].

Topics: Amines; Benzoquinones; Cyclohexenes; Electrons; Iodine; Methylation; Nitriles; Piperidines; Spectrophotometry; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Thermodynamics

Giardia intestinalis is the most frequent protozoan agent of intestinal diseases worldwide. Though commonly regarded as an anaerobic pathogen, it preferentially colonizes the fairly oxygen-rich mucosa of the proximal small intestine. Therefore, when testing new potential antigiardial drugs, O2 should be taken into account, since it also reduces the efficacy of metronidazole, the gold standard drug against giardiasis. In this study, 46 novel chalcones were synthesized by microwave-assisted Claisen-Schmidt condensation, purified, characterized by high-resolution mass spectrometry, (1)H and (13)C nuclear magnetic resonance, and infrared spectroscopy, and tested for their toxicity against G. intestinalis under standard anaerobic conditions. As a novel approach, compounds showing antigiardial activity under anaerobiosis were also assayed under microaerobic conditions, and their selectivity against parasitic cells was assessed in a counterscreen on human epithelial colorectal adenocarcinoma cells. Among the tested compounds, three [30(a), 31(e), and 33] were more effective in the presence of O2 than under anaerobic conditions and killed the parasite 2 to 4 times more efficiently than metronidazole under anaerobiosis. Two of them [30(a) and 31(e)] proved to be selective against parasitic cells, thus representing potential candidates for the design of novel antigiardial drugs. This study highlights the importance of testing new potential antigiardial agents not only under anaerobic conditions but also at low, more physiological O2 concentrations.

Topics: Antiprotozoal Agents; Caco-2 Cells; Cell Survival; Chalcones; Giardia lamblia; Humans; Piperazine; Piperazines; Piperidines

A series of novel N-arylmethyl substituted piperidine-linked aniline derivatives were designed, synthesized and evaluated for their anti-HIV activity in MT-4 cells. All the new compounds showed moderate to potent activities against wild-type (wt) HIV-1 with an EC₅₀ range from 0.022 to 2.1 μM. Among them, compound 5a6 (EC₅₀=0.022 ± 0.0091 μM, SI >10,770) was confirmed to be the most potent and selective inhibitor, which proved more potent than DDI and DLV in a cell-based assay against wt HIV-1, and more efficient than NVP in an RT (reverse transcriptase) assay. Besides, it is worth noting that compound 7a1 retained moderate inhibitory activity (EC₅₀=4.8 ± 0.95 μM) against the HIV-1 double RT mutant strain (K103N/Y181C). The preliminary structure-activity relationship was discussed and rationalized by molecular simulation.

Topics: Aniline Compounds; Anti-HIV Agents; Drug Design; HIV-1; Humans; Models, Molecular; Piperidines; Structure-Activity Relationship

Phosphonium and uronium salt-based reagents enable efficient and effective coupling reactions and are indispensable in peptide chemistry, especially in machine-assisted SPPS. However, after the activating and coupling steps with these reagents in the presence of tertiary amines, Fmoc derivatives of Cys are known to be considerably racemized during their incorporation. To avoid this side reaction, a coupling method mediated by phosphonium/uronium reagents with a weaker base, such as 2,4,6-trimethylpyridine, than the ordinarily used DIEA or that by carbodiimide has been recommended. However, these methods are appreciably inferior to the standard protocol applied for SPPS, that is, a 1 min preactivation procedure of coupling with phosphonium or uronium reagents/DIEA in DMF, in terms of coupling efficiency, and also the former method cannot reduce racemization of Cys(Trt) to an acceptable level (<1.0%) even when the preactivation procedure is omitted. Here, the 4,4'-dimethoxydiphenylmethyl and 4-methoxybenzyloxymethyl groups were demonstrated to be acid-labile S-protecting groups that can suppress racemization of Cys to an acceptable level (<1.0%) when the respective Fmoc derivatives are incorporated via the standard SPPS protocol of phosphonium or uronium reagents with the aid of DIEA in DMF. Furthermore, these protecting groups significantly reduced the rate of racemization compared to the Trt group even in the case of microwave-assisted SPPS performed at a high temperature.

Topics: Amino Acid Sequence; Amino Acids; Dimethylformamide; Fluorenes; Microwaves; Organophosphorus Compounds; Peptides; Piperidines; Solid-Phase Synthesis Techniques; Solvents; Stereoisomerism; Triazoles

A facile synthesis of piperidine alkene-alkaloids including natural (+)-Caulophyllumine B in high yields has been developed by Heck cross-coupling reaction catalyzed by simple in situ formed palladium-N-heterocyclic carbenes (Pd-NHCs). Formation of Pd(0) nanoparticles has been noticed during the reaction course. The synthesized piperidine alkene-alkaloids were evaluated for in vitro anti-cancer activity against a panel of human tumor cell lines of lung, breast and ovarian. Several of these piperidine alkene-alkaloids were found to possess highest growth inhibition activity than the standard drug cisplatin and support the concept to modulate drug receptor interaction.

Topics: Alkaloids; Alkenes; Antineoplastic Agents; Catalysis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Heterocyclic Compounds; Humans; MCF-7 Cells; Methane; Molecular Conformation; Organometallic Compounds; Palladium; Piperidines; Structure-Activity Relationship

A few bicyclic hybrid sugar molecules comprising of oxa-aza, oxa-oxa, and oxa-carbasugar fused skeletons were designed and synthesized from C-2 acetoxyglucal involving Ferrier rearrangement, Grignard addition, and ring-closing metathesis as key steps. The inhibitory activities of the synthesized molecules were tested against commercially available enzymes, which revealed the sugar-piperidine and sugar-pyran hybrids as potent and selective inhibitors.

Topics: Aza Compounds; Carbasugars; Enzyme Inhibitors; Glycoside Hydrolases; Oxides; Piperidines; Pyrans

This Letter describes the development and SAR of a novel series of GlyT1 inhibitors derived from a scaffold hopping approach that provided a robust intellectual property position, in lieu of a traditional, expensive HTS campaign. Members within this new [3.1.0]-based series displayed excellent GlyT1 potency, selectivity, free fraction, CNS penetration and efficacy in a preclinical model of schizophrenia (prepulse inhibition).

Topics: Bridged Bicyclo Compounds; Dose-Response Relationship, Drug; Glycine Plasma Membrane Transport Proteins; Humans; Molecular Structure; Piperidines; Structure-Activity Relationship

This Letter describes the development and SAR of a novel series of GlyT1 inhibitors derived from a scaffold hopping approach, in lieu of an HTS campaign, which provided intellectual property position. Members within this new [3.3.0]-based series displayed excellent GlyT1 potency, selectivity, free fraction, and modest CNS penetration. Moreover, enantioselective GlyT1 inhibition was observed, within this novel series and a number of other piperidine bioisosteric cores.

Topics: Dose-Response Relationship, Drug; Glycine Plasma Membrane Transport Proteins; Humans; Molecular Structure; Piperidines; Structure-Activity Relationship; Sulfonamides

New tetrahydropyridinyl and piperidinyl ethylamine derivatives were designed with hypothetical mapping on pharmacophore model generated from ligand-based virtual screening. The designed compounds were synthesized, and their inhibitory activities on T-type calcium channel were assayed using FDSS and patch-clamp assay. Among them, compounds 7b and 10b showed potent T-type calcium current blocking activity against Ca(v)3.1 (α(1G)) and Ca(v)3.2 (α(1H)) channel simultaneously. With hERG and pharmacokinetics studies, compounds 7b and 10b were evaluated for the antinociceptive effect on rat model of neuropathic pain. They were significantly effective in decreasing the pain responses to mechanical and cold allodynia induced by spinal nerve ligation. These results suggest that modulation of α(1G) and α(1H) subtype T-type calcium channels may provide a promising approach for the treatment of neuropathic pain.

Topics: Analgesics; Animals; Calcium Channel Blockers; Calcium Channels, T-Type; Drug Evaluation, Preclinical; Humans; Magnetic Resonance Spectroscopy; Neuralgia; Piperidines; Pyridines; Rats

Minimalist secondary structure mimics are typically made to resemble one interface in a protein-protein interaction (PPI), and thus perturb it. We recently proposed suitable chemotypes can be matched with interface regions directly, without regard for secondary structures. Here we describe a modular synthesis of a new chemotype 1, simulation of its solution-state conformational ensemble, and correlation of that with ideal secondary structures and real interface regions in PPIs. Scaffold 1 presents amino acid side-chains that are quite separated from each other, in orientations that closely resemble ideal sheet or helical structures, similar non-ideal structures at PPI interfaces, and regions of other PPI interfaces where the mimic conformation does not resemble any secondary structure. 68 different PPIs where conformations of 1 matched well were identified. A new method is also presented to determine the relevance of a minimalist mimic crystal structure to its solution conformations. Thus DLD-1 faf crystallized in a conformation that is estimated to be 0.91 kcal mol(-1) above the minimum energy solution state.

Topics: Amino Acids; Models, Molecular; Molecular Conformation; Piperidines; Protein Binding; Protein Structure, Secondary

The crystal structures of cis-dichlorido(ethylamine-κN)(piperidine-κN)platinum(II), [PtCl2(C2H7N)(C5H11N)], (I), cis-dichlorido(3-methoxyaniline-κN)(piperidine-κN)platinum(II), [PtCl2(C5H11N)(C7H9NO)], (II), and cis-dichlorido(piperidine-κN)(quinoline-κN)platinum(II), [PtCl2(C5H11N)(C9H7N)], (III), have been determined at 100 K in order to verify the influence of the nonpiperidine ligand on the geometry and crystal packing. The crystal packing is characterized by N-H...Cl hydrogen bonding, resulting in the formation of chains of molecules connected in a head-to-tail fashion. Hydrogen-bonding interactions play a major role in the packing of (I), where the chains further aggregate into planes, but less so in the case of (II) and (III), where π-π stacking interactions are of greater importance.

Topics: Amines; Crystallography, X-Ray; Hydrogen Bonding; Ligands; Organoplatinum Compounds; Piperidines

The first example of C alkylation of 1,2-dihydropyridines with alkyl triflates and Michael acceptors was developed to introduce quaternary carbon centers with high regio- and diastereoselectivity. Hydride or carbon nucleophile addition to the resultant iminium ion also proceeded with high diastereoselectivity. Carbon nucleophile addition results in an unprecedented level of substitution to provide piperidine rings with adjacent tetrasubstituted carbon atoms.

Topics: Alkylation; Catalysis; Dihydropyridines; Molecular Structure; Piperidines; Stereoisomerism

A novel tandem imination-isocyanate-mediated annulation was explored. Ionic liquid-immobilized 2-aminobenzimidazoles react sequentially with aldehydes and isocyanates to give highly functionalized benzimidazole-embedded triazines. The second-stage transformation revealed that the formation of triazinone functionality is entirely regioselective to allow rapid assembly of biologically interesting tricyclic skeletons. In conjunction with the application of microwave irradiation and IL support, this method provides an efficient route to access substituted benzoimidazotriazines.

Topics: Benzimidazoles; Catalysis; Imines; Ionic Liquids; Isocyanates; Microwaves; Models, Molecular; Piperidines; Triazines

The nociceptin opioid receptor (NOP) and its endogenous peptide ligand nociceptin/orphanin FQ have been shown to modulate the pharmacological effects of the classical opioid receptor system. Suppression of opioid-induced reward associated with mu-opioid receptor (MOP)-mediated analgesia, without decreasing anti-nociceptive efficacy, can potentially be achieved with NOP agonists having bifunctional agonist activity at MOP, to afford 'non-addicting' analgesics. In Part II of this series, we describe a continuing structure-activity relationship (SAR) study of the NOP-selective piperidin-4-yl-1,3-dihydroindol-2-one scaffold, to obtain bifunctional activity at MOP, and a suitable ratio of NOP/MOP agonist activity that produces a non-addicting analgesic profile. The SAR reported here is focused on the influence of various piperidine nitrogen aromatic substituents on the ratio of binding affinity and intrinsic activity at both the NOP and MOP receptors.

Topics: Analgesics; Animals; Ligands; Mice; Models, Animal; Nociceptin Receptor; Pain; Piperidines; Protein Binding; Receptors, Opioid; Receptors, Opioid, mu; Structure-Activity Relationship

We developed an asymmetric organocatalytic synthesis of 4,6-bis(1H-indole-3-yl)-piperidine-2-carboxylates using 10 mol% of a chiral phosphoric acid. The products, which are novel bisindole-piperidine-amino acid hybrids, can be obtained in one step from 3-vinyl indoles with imino esters in dichloromethane at room temperature after 1 h of reaction time. A variety of these compounds could be synthesized in up to 70% yield and 99% ee, and they were experimentally and computationally analyzed regarding their relative and absolute stereochemistry.

Topics: Amino Acids; Catalysis; Chemistry, Organic; Circular Dichroism; Imines; Indole Alkaloids; Phosphoric Acids; Piperidines; Thiourea

Loperamide is a piperidine butyramide mu-opiate receptor agonist and currently employed to treat diarrhea. Because a single past report of tritiating loperamide was limited to only a very low specific activity product without technical details or extensive analysis, the synthesis of [N-methyl-(3)H]loperamide at high specific activity is now described in detail. An imine precursor was alkylated with [(3)H]methyl iodide to obtain a quaternary intermediate, which was then reacted with 4-(4-chlorophenyl)-4-hydroxypiperidine to afford the desired product [N-methyl-(3)H]loperamide, characterized by thin layer chromatography (TLC), HPLC, MS, UV, and proton-decoupled tritium NMR.

Topics: Chemistry Techniques, Synthetic; Loperamide; Piperidines; Radiochemistry; Tritium

A new 3,5-disubstituted pyridine with two porphyrin moieties was prepared through an efficient synthetic approach involving 2-formyl-5,10,15,20-tetraphenylporphyrin (1), piperidine, and catalytic amounts of [La(OTf)3]. 3,5-Bis(5,10,15,20-tetraphenylporphyrin-2-ylmethyl)pyridine (2) was fully characterized and its sensing ability towards Zn(2+), Cu(2+), Hg(2+), Cd(2+), and Ag(+) was evaluated in solution by absorption and fluorescence spectroscopy and in gas phase by using matrix-assisted laser desorption/ionization (MALDI)-TOF mass spectrometry. Strong changes in the ground and excited state were detected in the case of the soft metal ions Zn(2+), Cd(2+), Hg(2+), and Cu(2+). A three-metal-per-ligand molar ratio was obtained in all cases and a significant ratiometric behavior was observed in the presence of Zn(2+) with the appearance of a new band at 608 nm, which can be assigned to a metal-to-ligand charge transfer. The system was able to quantify 79 ppb of Zn(2+) and the theoretical calculations are in accordance with the stoichiometry observed in solution. The gas-phase sensorial ability of compound 2 towards all metal ions was confirmed by using MALDI-TOF MS and in solid state by using polymeric films of polymethylmethacrylate (PMMA) doped with ligand 2. The results showed that compound 2 can be analytically used to develop new colorimetric molecular devices that are able to discriminate between Hg(2+) and Zn(2+) in solid phase. The crystal structure of Zn(II) complex of 3,5-bisporphyrinylpyridine was unequivocally elucidated by using single-crystal X-ray diffraction studies.

Topics: Crystallography, X-Ray; Fluorescent Dyes; Gases; Ions; Molecular Conformation; Piperidines; Polymethyl Methacrylate; Porphyrins; Spectrometry, Fluorescence; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Zinc

Simultaneously with warming climate, other climatic and environmental factors are also changing. Here, we investigated for the first time the effects of elevated temperature, increased ultraviolet-B (UVB) radiation, fertilization and all combinations of these on the growth, secondary chemistry and needle structure of 1-year-old Norway spruce (Picea abies (L.) Karst.) seedlings in an outdoor experiment. After one growing season, elevated temperature increased root : shoot ratio and concentrations of needle piperidine alkaloids, while concentrations of needle catechins and acetophenones and bark flavonoids decreased compared with ambient temperature seedlings. UVB-radiation increased concentrations of bark condensed tannins, while fertilization increased total biomass and concentrations of needle catechins. In addition to the main effects, concentrations of some individual phenolic compounds showed UV × temperature or UV × temperature × fertilization interactions, and fertilization modified temperature response on root : shoot ratio. All the treatments described here affected the defence chemistry profiles of the seedlings, which may imply some changes in plant-herbivore interactions in connection with changing climate. The interactions between treatments indicate a need for further experiments involving several simultaneously affecting environmental changes.

Topics: Abies; Alkaloids; Chromatography, High Pressure Liquid; Fertilizers; Finland; Gas Chromatography-Mass Spectrometry; Phenols; Piperidines; Plant Leaves; Temperature; Ultraviolet Rays

The dopaminergic stabilizers pridopidine [4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine] and ordopidine [1-ethyl-4-(2-fluoro-3-(methylsulfonyl)phenyl)piperidine] inhibit psychostimulant-induced hyperactivity, and stimulate behaviour in states of hypoactivity. While both compounds act as dopamine D2 receptor antagonists in vitro, albeit with low affinity, their specific state-dependent behavioural effect profile is not shared by D2 receptor antagonists in general. To further understand the neuropharmacological effects of pridopidine and ordopidine, and how they differ from other dopaminergic compounds in vivo, we assessed the expression of activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc), an immediate early gene marker associated with synaptic activation, in the frontal cortex and striatum. Furthermore, monoamine neurochemistry and locomotor activity were assessed. The effects of pridopidine and ordopidine were compared to reference dopamine D1 and D2 receptor agonists and antagonists, as well as the partial dopamine D2 agonist aripiprazole. Pridopidine and ordopidine induced significant increases in cortical Arc expression, reaching 2.2- and 1.7-fold levels relative to control, respectively. In contrast, none of the reference dopamine D1 and D2 compounds tested increased cortical Arc expression. In the striatum, significant increases in Arc expression were seen with both pridopidine and ordopidine as well as the dopamine D2 receptor antagonists, remoxipride and haloperidol. Interestingly, striatal Arc expression correlated strongly and positively with striatal 3,4-dihydroxyphenylacetic acid, suggesting that antagonism of dopamine D2 receptors increases Arc expression in the striatum. In conclusion, the concurrent increase in cortical and striatal Arc expression induced by pridopidine and ordopidine appears unique for the dopaminergic stabilizers, as it was not shared by the reference compounds tested. The increase in cortical Arc expression is hypothesized to reflect enhanced N-methyl-D-aspartic acid receptor-mediated signalling in the frontal cortex, which could contribute to the state-dependent locomotor effects of pridopidine and ordopidine.

Topics: 3,4-Dihydroxyphenylacetic Acid; Analysis of Variance; Animals; Apoptosis Regulatory Proteins; Cerebral Cortex; Chromatography, High Pressure Liquid; Corpus Striatum; Dopamine; Dopamine Agents; Electrochemical Techniques; Gene Expression Regulation; Male; Motor Activity; Muscle Proteins; Piperidines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Statistics as Topic

A practical and highly stereoselective approach to access 2,6-disubstituted piperidines using an amidine auxiliary is reported. Following the diastereoselective addition of Grignard reagents at the 2-position of an activated pyridinium salt, the amidine group directs a regioselective metalation at the 6-position, enabling further functionalization. A subsequent electrophilic quench or a Negishi cross-coupling could be performed, resulting in 2,6-disubstituted dihydropyridines. These were reduced to the saturated piperidine rings with high diastereoselectivity.

Topics: Amidines; Dihydropyridines; Molecular Structure; Piperidines; Stereoisomerism

A method based on silica gel chromatography and GC-MS/GC-FID analyses was developed for the quantitation of alkaloidal compounds in imported fire ants, Solenopsis richteri, S. invicta, and their hybrid found in the southern United States. The cis and trans alkaloids from fire ant body extracts were successfully separated by silica gel chromatography, identified by GC-MS, and quantitated by GC-FID. Piperideine compounds were eluted together with the cis and trans piperidines, but were well-resolved on a nonpolar GC column. Eight pairs of piperidine isomers and 12 piperideines were quantitated. The ratios of trans alkaloids to corresponding cis isomers ranged from 87 to 378:1 in S. invicta and were significantly higher than in S. richteri and hybrid ants. The results were discussed in relation to the evolution of fire ant venom alkaloids and their role as host location cues for parasitic Pseudacteon phorid flies.

Topics: Alkaloids; Animals; Ants; Chromatography, Gas; Isomerism; Molecular Structure; Piperidines; Venoms

Conjugated cyclic trienes without nonbenzenoid aromatic characteristic were successfully employed as fine-tunable dipolarophiles in the Cu(I)-catalyzed asymmetric azomethine ylide-involved 1,3-dipolar [3 + 6] cycloaddition for the first time, affording a variety of bridged heterocycles bearing piperidine moiety in good yield with exclusive regioselectivity and excellent stereoselectivity. 2-Acyl group is the key factor that determines the annulation preferentially through [3 + 6]-pathway, while 2-ester group modulates the annulation through [3 + 2]-pathway.

Topics: Azo Compounds; Catalysis; Cyclization; Cycloheptanes; Heterocyclic Compounds; Molecular Conformation; Organometallic Compounds; Piperidines; Thiosemicarbazones

The cerium(IV) ammonium nitrate (CAN)-catalyzed, three-component reaction between primary amines, β-dicarbonyl compounds, and α,β-unsaturated aldehydes in ethanol heated to reflux, constitutes a general, one-pot synthesis of 1,4-dihydropyridines. Their reduction with sodium triacetoxyborohydride furnished piperidine derivatives bearing up to five substituents with full diastereoselectivity in a hitherto inaccessible stereochemical arrangement. The reaction proceeded with no significant loss of enantiomeric purity under mild reduction conditions that are compatible with several functional groups that are normally sensitive to reduction. Octahydroquinolin-5-one derivatives, which were prepared by a modified version of the initial multicomponent reaction, were not suitable substrates for the sodium triacetoxyborohydride mediated reduction, but they were transformed into the corresponding decahydroquinolines, including a precursor of the amphibian alkaloid pumiliotoxin C, by catalytic hydrogenation under a variety of conditions.

Topics: Amines; Cerium; Molecular Structure; Nitrates; Piperidines; Stereoisomerism

Extensive evidence implicates GluN2B-containing NMDA receptors (GluN2B-NMDARs) in excitotoxic-insult-induced neurodegeneration and amyloid β (Aβ)-induced synaptic dysfunction. Therefore, inhibiting GluN2B-NMDARs would appear to be a potential therapeutic strategy to provide neuroprotection and improve cognitive function in Alzheimer's disease (AD). However, there are no reports of long-term in vivo treatment of AD mouse models with GluN2B antagonists. We used piperidine18 (Pip18), a potent and selective GluN2B-NMDAR antagonist with favorable pharmacokinetic properties, for long-term dosing in AD mouse models. Reduced freezing behavior in Tg2576 mice during fear conditioning was partially reversed after subchronic (17 d) Pip18 treatment. However, analysis of freezing behavior in different contexts indicated that this increased freezing likely involves elevated anxiety or excessive memory generalization in both nontransgenic (NTG) and Tg2576 mice. In PS2APP mice chronically fed with medicated food containing Pip18 for 4 months, spatial learning and memory deficits were not rescued, plaque-associated spine loss was not affected, and synaptic function was not altered. At the same time, altered open field activity consistent with increased anxiety and degraded performance in an active avoidance task were observed in NTG after chronic treatment. These results indicate that long-term treatment with a GluN2B-NMDAR antagonist does not provide a disease-modifying benefit and could cause cognitive liabilities rather than symptomatic benefit in AD mouse models. Therefore, these results challenge the expectation of the therapeutic potential for GluN2B-NMDAR antagonists in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Attention Deficit and Disruptive Behavior Disorders; Behavior, Animal; Disease Models, Animal; Female; HEK293 Cells; Humans; In Vitro Techniques; Male; Maze Learning; Membrane Potentials; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Piperidines; Synapses

Herein we report a novel class of 1,4-disubstituted piperidines as potential anticancer agents. One-step and efficient synthesis of a structurally diverse library of piperidine-based analogs with five points of diversity has been developed using the Ugi four-component reaction. A structure-activity relationship (SAR) study showed that the presence of a benzyl or a Boc group at the N-1 position together with two or three aromatic groups at the C-4 position of the piperidine ring are important for optimal cytostatic properties. Compounds 20, 22, 27 and 29 were found to be the most potent with a 50% inhibitory concentration (IC50) ranging between 3 and 9.5 μM in the cancer cell lines evaluated. The NCI60 screen confirmed this 50% cytostatic concentration range for compound 20, irrespective of the nature of the tumor cell lines evaluated. The NCI COMPARE algorithm did not show any significant correlation between the growth inhibition profile of compound 20 with the NCI database compound profiles suggesting a potential novel mechanism of action.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Design; Humans; Mice; Piperidines; Structure-Activity Relationship

Ligands incorporating a tetraazamacrocycle receptor, a 'click'-derived triazole and a 1,8-naphthalimide fluorophore have proven utility as probes for metal ions. Three new cyclam-based molecular probes are reported, in which a piperidinyl group has been introduced at the 4-position of the naphthalimide fluorophore. These compounds have been synthesized using the copper(I)-catalyzed azide-alkyne Huisgen cycloaddition and their photophysical properties studied in detail. The alkylamino group induces the expected red-shift in absorption and emission spectra relative to the simple naphthalimide derivatives and gives rise to extended fluorescence lifetimes in aqueous buffer. The photophysical properties of these systems are shown to be highly solvent-dependent. Screening the fluorescence responses of the new conjugates to a wide variety of metal ions reveals significant and selective fluorescence quenching in the presence of copper(II), yet no fluorescence enhancement with zinc(II) as observed previously for the simple naphthalimide derivatives. Reasons for this different behaviour are proposed. Cytotoxicity testing shows that these new cyclam-triazole-dye conjugates display little or no toxicity against either DLD-1 colon carcinoma cells or MDA-MB-231 breast carcinoma cells, suggesting a potential role for these and related systems in biological sensing applications.

Topics: Biosensing Techniques; Cell Line, Tumor; Copper; Female; Fluorescent Dyes; Heterocyclic Compounds; Humans; Piperidines

We previously identified two small-molecule CD4 mimetics--NBD-556 and NBD-557--and synthesized a series of NBD compounds that resulted in improved neutralization activity in a single-cycle HIV-1 infectivity assay. For the current investigation, we selected several of the most active compounds and assessed their antiviral activity on a panel of 53 reference HIV-1 Env pseudoviruses representing diverse clades of clinical isolates. The selected compounds inhibited tested clades with low-micromolar potencies. Mechanism studies indicated that they act as CD4 agonists, a potentially unfavorable therapeutic trait, in that they can bind to the gp120 envelope glycoprotein and initiate a similar physiological response as CD4. However, one of the compounds, NBD-09027, exhibited reduced agonist properties, in both functional and biophysical studies. To understand the binding mode of these inhibitors, we first generated HIV-1-resistant mutants, assessed their behavior with NBD compounds, and determined the X-ray structures of two inhibitors, NBD-09027 and NBD-10007, in complex with the HIV-1 gp120 core at ∼2-Å resolution. Both studies confirmed that the NBD compounds bind similarly to NBD-556 and NBD-557 by inserting their hydrophobic groups into the Phe43 cavity of gp120. The basic nitrogen of the piperidine ring is located in close proximity to D368 of gp120 but it does not form any H-bond or salt bridge, a likely explanation for their nonoptimal antagonist properties. The results reveal the structural and biological character of the NBD series of CD4 mimetics and identify ways to reduce their agonist properties and convert them to antagonists.

Topics: Anti-HIV Agents; CD4 Antigens; Cell Line, Tumor; Crystallography, X-Ray; HeLa Cells; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; Oxalates; Piperidines; Protein Binding

A series of novel 2,4-diaminopyrimidines containing piperidine and piperazine moieties were synthesized via an efficient one-pot methodology. The bioassay tests demonstrated that compounds 27 and 28 displayed much stronger antitumor activities against four human cancer cell lines (HepG2, A549, MDA-MB-231 and MCF-7) than positive control fluorouracil. Particularly, compound 28 showed a two-fold improvement compared to fluorouracil in inhibiting MDA-MB-231 and A549 cell proliferation with IC50 values of 7.46 and 12.78 μM, respectively. Further flow-activated cell sorting analysis revealed that the most promising compound 28 displayed a significant effect on G2/M cell-cycle arrest in a dose-dependent manner in MDA-MB-231 cells.

Topics: Antineoplastic Agents; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Hep G2 Cells; Humans; MCF-7 Cells; Molecular Structure; Piperazine; Piperazines; Piperidines; Pyrimidines; Structure-Activity Relationship

Bacterial DNA gyrase is a well-established and clinically validated target to develop novel antibacterial. Our effort was designated to search for synthetically better compounds with possibility of hit to lead development. With this as objective, a series of 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one derivatives were designed by molecular hybridization strategy and synthesized following nine step reaction to yield activity in low nanomolar range and commendable antibacterial activities. Compound 1-(4-fluorophenyl)-3-(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)urea (35) emerged as the most promising inhibitor with an IC50 of 78 nM against Mycobacterium tuberculosis DNA gyrase enzyme, with MTB MIC of 0.62 μM, and not cytotoxic at 50 μM in eukaryotic cell line.

Topics: Anti-Bacterial Agents; DNA Gyrase; Drug Design; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nitrogen; Piperidines; Protein Structure, Tertiary; Structure-Activity Relationship; Topoisomerase II Inhibitors

A functional high throughput screen identified a novel chemotype for the positive allosteric modulation (PAM) of the muscarinic acetylcholine receptor (mAChR) subtype 5 (M5). Application of rapid analog, iterative parallel synthesis efficiently optimized M5 potency to arrive at the most potent M5 PAMs prepared to date and provided tool compound 8n (ML380) demonstrating modest CNS penetration (human M5 EC50 = 190 nM, rat M5 EC50 = 610 nM, brain to plasma ratio (Kp) of 0.36).

Topics: Allosteric Regulation; Animals; Central Nervous System; Drug Discovery; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Humans; Indazoles; Male; Piperidines; Rats; Receptor, Muscarinic M5; Substrate Specificity; Sulfonamides

γ-Butyrobetaine hydroxylase (BBOX) is a 2-oxoglutarate dependent oxygenase that catalyzes the final hydroxylation step in the biosynthesis of carnitine. BBOX was shown to catalyze the oxidative desymmetrization of achiral N,N-dialkyl piperidine-4-carboxylates to give products with two or three stereogenic centers.

Topics: Biocatalysis; Carboxylic Acids; Carnitine; Catalytic Domain; gamma-Butyrobetaine Dioxygenase; Oxidation-Reduction; Piperidines; Stereoisomerism

A series of piperidine-based derivatives were identified as novel and potent inhibitors of the influenza virus through structural modification of a compound that was selected from a high-throughput screen. Various analogues were synthesized and confirmed as inhibitors. The structure–activity relationship (SAR) studies suggested that the ether linkage between the quinoline and piperidine is critical for the inhibitory activity. The optimized compound tert-butyl 4-(quinolin-4-yloxy)piperidine-1-carboxylate 11e had an excellent inhibitory activity against influenza virus infection from a variety of influenza virus strains, with EC50 values as low as 0.05 μM. The selectivity index value (SI = MLD50/EC50) of 11e is over 160000 based on cytotoxicity, measured by MTT assays of three cell lines. We carried out a time-of-addition experiment to delineate the mechanism of inhibition. The result indicates that 11e interferes with the early to middle stage of influenza virus replication.

Topics: Animals; Antiviral Agents; Dogs; Drug Discovery; HEK293 Cells; HeLa Cells; Humans; Madin Darby Canine Kidney Cells; Microbial Sensitivity Tests; Molecular Structure; Orthomyxoviridae; Piperidines; Structure-Activity Relationship

Accumulation of lipofuscin in the retina is associated with pathogenesis of atrophic age-related macular degeneration and Stargardt disease. Lipofuscin bisretinoids (exemplified by N-retinylidene-N-retinylethanolamine) seem to mediate lipofuscin toxicity. Synthesis of lipofuscin bisretinoids depends on the influx of retinol from serum to the retina. Compounds antagonizing the retinol-dependent interaction of retinol-binding protein 4 (RBP4) with transthyretin in the serum would reduce serum RBP4 and retinol and inhibit bisretinoid formation. We recently showed that A1120 (3), a potent carboxylic acid based RBP4 antagonist, can significantly reduce lipofuscin bisretinoid formation in the retinas of Abca4(-/-) mice. As part of the NIH Blueprint Neurotherapeutics Network project we undertook the in vitro exploration to identify novel conformationally flexible and constrained RBP4 antagonists with improved potency and metabolic stability. We also demonstrate that upon acute and chronic dosing in rats, 43, a potent cyclopentyl fused pyrrolidine antagonist, reduced circulating plasma RBP4 protein levels by approximately 60%.

Topics: Animals; Atrophy; Chemistry Techniques, Synthetic; Drug Design; Ligands; Macular Degeneration; Male; Mice; Molecular Docking Simulation; Piperidines; Prealbumin; Protein Conformation; Rats; Retinol-Binding Proteins, Plasma; Stargardt Disease; Structure-Activity Relationship

Mycobacterium tuberculosis (MTB) consumes nitrate as the alternate mechanism of respiration in the absence of oxygen, thus increasing its survival and virulence during latent stage of tuberculosis infection. NarL is a nitrate/nitrite response transcriptional regulatory protein of two-component signal transduction system which regulates nitrate reductase and formate dehydrogenase for MTB adaptation to anaerobic condition. Phosphorylation by sensor kinase (NarX) is the primary mechanism behind the activation of NarL although many response regulators get activated by small molecule phospho-donors in the absence of sensor kinase. Virtual screening was performed using Autodock suite for the compounds from ZINC database against NarL and potential inhibitors was identified to inhibit the activation of NarL by affecting its phosphorylation. Molecular dynamics simulation studies predicted the stability of 1-{1-[(3-nitrophenyl) methyl] piperidin-2-yl} ethan-1-amine in the active site of NarL over 10 ns simulation. Phosphorylation of NarL by small molecule phospho-donors is also investigated in the present study. Here we suggest that nitro benzene - amine piperidine moiety can be an effective lead candidate for developing novel anti-tuberculosis drugs.

Topics: Antitubercular Agents; Bacterial Proteins; Catalytic Domain; DNA-Binding Proteins; Formate Dehydrogenases; Humans; Molecular Docking Simulation; Mycobacterium tuberculosis; Nitrate Reductases; Nitrates; Nitrites; Nitrobenzenes; Nitrogen; Phosphorylation; Piperidines; Protein Kinases; Sequence Homology, Amino Acid; Signal Transduction; Transcription Factors; Tuberculosis

The key hydrolytic enzymes of the endocannabinoid system, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), are potential targets for various therapeutic applications. In this paper, we present more extensively the results of our previous work on piperazine and piperidine carboxamides and carbamates as FAAH and MAGL inhibitors. The best compounds of these series function as potent and selective MAGL/FAAH inhibitors or as dual FAAH/MAGL inhibitors at nanomolar concentrations. This study revealed that MAGL inhibitors should comprise leaving-groups with a conjugate acid pKa of 8-10, while diverse leaving groups are tolerated for FAAH inhibitors.

Topics: Amides; Amidohydrolases; Carbamates; Dose-Response Relationship, Drug; Enzyme Inhibitors; HEK293 Cells; Humans; Models, Molecular; Molecular Structure; Monoacylglycerol Lipases; Piperazine; Piperazines; Piperidines; Structure-Activity Relationship

An efficient and practical strategy for the synthesis of (3R,4s,5S)-4-(2-hydroxyethyl) piperidine-3,4,5-triol and its N-alkyl derivatives 8a-f, starting from the D-glucose, is reported. The chiral pool methodology involves preparation of the C-3-allyl-α-D-ribofuranodialdose 10, which was converted to the C-5-amino derivative 11 by reductive amination. The presence of C-3-allyl group gives an easy access to the requisite hydroxyethyl substituted compound 13. Intramolecular reductive aminocyclization of C-5 amino group with C-1 aldehyde provided the γ-hydroxyethyl substituted piperidine iminosugar 8a that was N-alkylated to get N-alkyl derivatives 8b-f. Iminosugars 8a-f were screened against glycosidase enzymes. Amongst synthetic N-alkylated iminosugars, 8b and 8c were found to be α-galactosidase inhibitors while 8d and 8e were selective and moderate α-mannosidase inhibitors. In addition, immunomodulatory activity of compounds 8a-f was examined. These results were substantiated by molecular docking studies using AUTODOCK 4.2 programme.

Topics: Alkylation; alpha-Galactosidase; Binding Sites; Cell Proliferation; Cell Survival; Cells, Cultured; Enzyme Inhibitors; Humans; Imino Sugars; Immunosuppressive Agents; Jurkat Cells; Leukocytes, Mononuclear; Molecular Docking Simulation; Piperidines; Protein Structure, Tertiary

Stable nitroxide radical bearing organic polymer materials are attracting much attention for their application as next generation energy storage materials. A greater understanding of the inherent charge transfer mechanisms in such systems will ultimately be paramount to further advancements in the understanding of both intrafilm and interfacial ion- and electron-transfer reactions. This work is focused on advancing the fundamental understanding of these dynamic charge transfer properties by exploiting the fact that these species are efficient fluorescence quenchers. We systematically incorporated fluorescent perylene dyes into solutions containing the 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) radical and controlled their interaction by binding the TEMPO moiety into macromolecules with varying morphologies (e.g., chain length, density of radical pendant groups). In the case of the model compound, 4-oxo-TEMPO, quenching of the perylene excited state was found to be dominated by a dynamic (collisional) process, with a contribution from an apparent static process that is described by an ∼2 nm quenching sphere of action. When we incorporated the TEMPO unit into a macromolecule, the quenching behavior was altered significantly. The results can be described by using two models: (A) a collisional quenching process that becomes less efficient, presumably due to a reduction in the diffusion constant of the quenching entity, with a quenching sphere of action similar to 4-oxo-TEMPO or (B) a collisional quenching process that becomes more efficient as the radius of interaction grows larger with increasing oligomer length. This is the first study that definitively illustrates that fluorophore quenching by a polymer system cannot be explained using merely a classical Stern-Volmer approach but rather necessitates a more complex model.

Topics: Cyclic N-Oxides; Fluorescent Dyes; Molecular Conformation; Molecular Dynamics Simulation; Nitrogen Oxides; Perylene; Piperidines; Polymers; Spectrometry, Fluorescence

We demonstrated synthetically that the eight-membered heterocycles 2,6,9-triazabicyclo[3.3.1]nonanes and 1,5-diazacyclooctanes are the initial and exclusive products of the reaction, through an imino [4+4] cycloaddition, of biologically relevant amines with acrolein. The stabilities of the aminoacetals within the eight-membered heterocycles determined whether the product was subsequently transformed gradually into the 3-formyl-3,4-dehydropiperidine (FDP), which is widely used as an oxidative stress marker. The reactivity profiles discovered in this study suggested that some of the imino [4+4] cycloaddition products are reactive intermediates of FDP and contribute to the mechanisms underlying the oxidative stress response to acrolein.

Topics: Acrolein; Amines; Cycloaddition Reaction; Imines; Norepinephrine; Oxidative Stress; Piperidines; Sphingosine

A series of seventeen morpholin/piperidin-1-yl-carbamodithioate (3-19) were synthesized as topical vaginal microbicidal spermicides. The synthesized compounds were evaluated for their anti-Trichomonas activity against MTZ susceptible and resistant strains along with their spermicidal and antifungal potential. All the synthesized compounds were assessed for their safety through cytotoxic assay against human cervical cell line (HeLa) and compatibility with vaginal flora, Lactobacillus. The study identified eleven dually active compounds with apparent safety. The plausible mode of action of these compounds was through sulfhydryl binding, confirmed via reduction in available free thiols on human sperm. The most promising compound 9 significantly inhibited (P<0.001) thiol-sensitive sperm hexokinase. The stability of compound 9 in simulated vaginal fluid (SVF) was performed via HPLC-PDA method, which supported its utility for vaginal administration.

Topics: Antifungal Agents; Cell Survival; Drug Design; Female; HeLa Cells; Hexokinase; Humans; Lactobacillus; Male; Microbial Sensitivity Tests; Morpholines; Piperidines; Spermatocidal Agents; Spermatozoa; Structure-Activity Relationship; Sulfhydryl Compounds; Thiocarbamates; Trichomonas vaginalis

This Letter describes the on-going SAR efforts based on two scaffolds, a PLD1-biased piperidinyl benzimidazolone and a PLD2-biased piperidinyl triazaspirone, with the goal of enhancing PLD inhibitory potency and isoform selectivity. Here, we found that addition of an α-methyl moiety within the PLD2-biased piperidinyl triazaspirone scaffold abolished PLD2 preference, while the incorporation of substituents onto the piperidine moiety of the PLD1-biased piperidinyl benzimidazolone, or replacement with a bioisosteric [3.3.0] core, generally retained PLD1 preference, but at diminished significance. The SAR uncovered within these two allosteric PLD inhibitor series further highlights the inherent challenges of developing isoform selective PLD inhibitors.

Topics: Animals; Benzimidazoles; Enzyme Inhibitors; HEK293 Cells; Humans; Kinetics; Microsomes; Phospholipase D; Piperidines; Protein Binding; Rats; Structure-Activity Relationship

We report herein the synthesis of a series of 7-[3-alkoxyimino-4-(methyl)aminopiperidin-1-yl]quinolone/naphthyridone derivatives. In vitro antibacterial activity of these derivatives was evaluated against representative strains, and compared with ciprofloxacin (CPFX), levofloxacin (LVFX) and gemifloxacin (GMFX). The results reveal that all of the target compounds 19a-c and 20 have considerable Gram-positive activity, although they are generally less active than the reference drugs against the Gram-negative strains with some exceptions. Especially, novel compounds 19a2, 19a4 and 19a5 were found to show strong antibacterial activity (MICs: <0.008-0.5μg/mL) against all of the tested 15 Gram-positive strains including MRSA, LVFX- and GMFX-resistant MRSE, and CPFX-, LVFX- and GMFX-resistant MSSA.

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Gram-Negative Bacteria; Gram-Positive Bacteria; Microbial Sensitivity Tests; Piperidines; Quinolones; Structure-Activity Relationship

Conformationally constrained spirocycles (17-23) and (31-36) were synthesised. In vitro data revealed that these compounds are CCR1 antagonists with sub-nanomolar potency. In a functional assay 22, 23 and 36 inhibited CCR1 mediated chemotaxis with an IC50 value of 2, 2.6 and 68nM, respectively.

Topics: Animals; Caco-2 Cells; Cell Line; Chemotaxis; Humans; Microsomes, Liver; Piperidines; Protein Binding; Rats; Receptors, CCR1; Spiro Compounds

Synthesis and structure-activity relationship of a series of substituted piperidinyl glycine 2-cyano-4,5-methano pyrroline DPP-IV inhibitors are described. Improvement of the inhibitory activity and chemical stability of this series of compounds was respectively achieved by the introduction of bulky groups at the 4-position and 1-position of the piperidinyl glycine, leading to a series of potent and stable DPP-IV inhibitors.

Topics: Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hydrogen-Ion Concentration; Piperidines; Protein Binding; Pyrrolidines; Structure-Activity Relationship; Temperature

The long chain Mannich bases, especially with the piperidine and morpholine groups, display very promising antimicrobial activity. In order to extend our knowledge on their impact on biological systems, we examined the interactions of the 5-pentadecyl-2-((piperidin-1-yl)methyl)phenol (PPDP) with model lipid membrane by means of differential scanning calorimetry (DSC) and fluorescence measurements. The small unilamellar vesicles of dipalmitoylophosphatidylcholine (DPPC) with different piperidine Mannich base concentration were investigated as a function of the increase of temperature. The phase separation accompanied by the rise of the transition enthalpy of both subcomponents, the increase of the function of the GP values of Laurdan versus the wavelength of excitation in the gel phase of PPDP/DPPC systems, and no remarkable differences in the fluorescence anisotropy of PPDP molecules in lipid environment for different mixtures of PPDP/DPPC was observed. Additionally, it was shown that PPDP itself interdigitated in solid state.

Topics: 1,2-Dipalmitoylphosphatidylcholine; Calorimetry, Differential Scanning; Liposomes; Mannich Bases; Phase Transition; Piperidines; Spectrometry, Fluorescence

On the basis of an initial molecular modeling study suggesting the favorable binding of the "privileged" fragment 8-hydroxyquinoline with HIV-1 integrase (IN) at the IN-lens epithelium-derived growth factor/p75 (LEDGF/p75) interface , we developed a set of modified 8-hydroxyquinoline fragments demonstrating micromolar IC50 values for inhibition of the IN-LEDGF/p75 interaction, but significant cytotoxicity was associated with these initial compounds. Diverse modifications at the C5 and C7 carbons of the 8-hydroxyquinoline core improved potency, but reduction of diversity to only modifications at the C5 position ultimately yielded potent inhibitors with low cytotoxicity. Two of these particular compounds, 5-((p-tolylamino)methyl)quinolin-8-ol and 5-(((3,4-dimethylphenyl)amino)methyl)quinolin-8-ol, inhibited viral replication in MT-4 cells with low micromolar EC50. This is the first study providing evidence for 8-hydroxyquinolines as novel inhibitors of the IN-LEDGF/p75 interaction. Our lead compounds are druglike, have low molecular weights, and are amenable to various substitutions suitable for enhancing their potency and selectivity.

Topics: Anti-HIV Agents; Cell Line; Drug Discovery; HIV Integrase; HIV-1; Humans; Inhibitory Concentration 50; Intercellular Signaling Peptides and Proteins; Models, Molecular; Oxyquinoline; Piperazine; Piperazines; Piperidines; Protein Binding; Protein Conformation; Structure-Activity Relationship

2,6-Disubstituted pyridazinone 4 was identified by HTS as a novel acetylcholinesterase (AChE) inhibitor. Under SAR development, compound 17e stood out as displaying high AChE inhibitory activity and AChE/butyrylcholinesterase (BuChE) selectivity in vitro. Docking studies revealed that 17e might interact with the catalytic active site (CAS) and the peripheral anionic site (PAS) simultaneously. Based on this novel binding information, 6-ortho-tolylamino and N-ethyl-N-isopropylacetamide substituted piperidine were disclosed as new PAS and CAS binders.

Topics: Acetylcholinesterase; Alzheimer Disease; Binding, Competitive; Biocatalysis; Butyrylcholinesterase; Catalytic Domain; Cholinesterase Inhibitors; Drug Discovery; Humans; Models, Molecular; Molecular Structure; Piperidines; Protein Binding; Protein Structure, Tertiary; Pyridazines; Structure-Activity Relationship

R adamantly beats S: 11β-HSD1 is a target for treating metabolic syndrome. The R isomer 5 was selected as a starting point for optimization and SAR studies. Inhibitor 8 w emerged after several rounds of optimization, showing cross-species inhibition of human and mouse 11β-HSD1. It also displays a good DMPK profile in vitro, and was advanced to PK/PD evaluations in vivo. The results confirmed its dose-dependent activity in mice.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Amides; Animals; Binding Sites; Drug Design; Enzyme Inhibitors; Half-Life; Humans; Isomerism; Mice; Molecular Docking Simulation; Piperidines; Protein Structure, Tertiary; Structure-Activity Relationship

Monoacylglycerol lipase (MAGL) terminates the signaling function of the endocannabinoid, 2-arachidonoylglycerol (2-AG). During 2-AG hydrolysis, MAGL liberates arachidonic acid, feeding the principal substrate for the neuroinflammatory prostaglandins. In cancer cells, MAGL redirects lipid stores toward protumorigenic signaling lipids. Thus MAGL inhibitors may have great therapeutic potential. Although potent and increasingly selective MAGL inhibitors have been described, their number is still limited. Here, we have characterized piperazine and piperidine triazole ureas that combine the high potency attributable to the triazole leaving group together with the bulky aromatic benzodioxolyl moiety required for selectivity, culminating in compound JJKK-048 that potently (IC50 < 0.4 nM) inhibited human and rodent MAGL. JJKK-048 displayed low cross-reactivity with other endocannabinoid targets. Activity-based protein profiling of mouse brain and human melanoma cell proteomes suggested high specificity also among the metabolic serine hydrolases.

Topics: Animals; Benzodioxoles; Enzyme Inhibitors; HEK293 Cells; Humans; Mice; Monoacylglycerol Lipases; Piperazine; Piperazines; Piperidines; Rats; Substrate Specificity; Triazoles; Urea

A growing number of the elements identified in intracellular signaling events that affect cell growth and transformation are proteins that physically interact with each other via domains or specifically recognized amino acid sequences. Some of these intracellular protein-protein interactions are attractive targets for anticancer targeted therapy, but progress in this field has been compromised by the paucity of compounds with suitable biological profiles and pharmacological properties. This Letter covers salient achievements in the identification and development of inhibitors of the p53-hdm2 protein-protein interaction, and highlights different screening techniques and structure-based design approaches that may be brought to bear on the discovery and development of inhibitors of other therapeutically relevant intracellular protein-protein interactions.

Topics: Binding Sites; Drug Design; HCT116 Cells; Humans; Imidazolines; Molecular Docking Simulation; Piperidines; Protein Binding; Protein Interaction Domains and Motifs; Proto-Oncogene Proteins c-mdm2; Structure-Activity Relationship; Tumor Suppressor Protein p53

A series of novel hybrid spiro heterocycles comprising pyrrolizine, spiroxindole and piperidine moieties was synthesized chemo-, regio- and stereoselectively in good yields from 1,3-dipolar cycloaddition reaction of a series of 1-acryloyl-3,5-bisarylmethylidenepiperidin-4-ones with azomethine ylides generated in situ from 5-choloroisatin and l-proline in methanol. These cycloadducts displayed significant cholinesterase inhibitory activity. Among the compounds screened, 8g and 8e, showed maximum inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinestrase (BChE) with IC50 values of 3.33 and 3.13μM, respectively.

Topics: Butyrylcholinesterase; Cholinesterase Inhibitors; Cholinesterases; Cyclization; Dose-Response Relationship, Drug; Indoles; Models, Molecular; Molecular Structure; Oxindoles; Piperidines; Pyrroles; Spiro Compounds; Stereoisomerism; Structure-Activity Relationship

The nociceptin receptor (NOP) and its endogenous agonist, nociceptin/orphanin FQ (N/OFQ), members of the opioid receptor and peptide families respectively, modulate the pharmacological effects of classical opioids, particularly opioid-induced reward and nociception. We hypothesized that compounds containing both NOP and opioid receptor activity in a single molecule may have useful pharmacological profiles as non-addicting analgesics or as drug abuse medications. We report here our forays into the structure-activity relationships for discovering 'bifunctional' NOP-mu opioid receptor (MOP) ligands, starting from our NOP-selective scaffolds. This initial SAR suggests pharmacophoric elements that may be modified to modulate/increase opioid affinity, while maintaining high affinity for the NOP receptor, to result in potent bifunctional small-molecule NOP/MOP ligands.

Topics: Drug Design; Nociceptin Receptor; Piperidines; Protein Binding; Receptors, Opioid; Receptors, Opioid, mu; Structure-Activity Relationship

The manipulation of traditionally unreactive functional groups is of paramount importance in modern chemical synthesis. We have developed an iron-dipyrrinato catalyst that leverages the reactivity of iron-borne metal-ligand multiple bonds to promote the direct amination of aliphatic C-H bonds. Exposure of organic azides to the iron dipyrrinato catalyst furnishes saturated, cyclic amine products (N-heterocycles) bearing complex core-substitution patterns. This study highlights the development of C-H bond functionalization chemistry for the formation of saturated, cyclic amine products and should find broad application in the context of both pharmaceuticals and natural product synthesis.

Topics: Amination; Amines; Azetidines; Azides; Catalysis; Chemical Phenomena; Cyclization; Heterocyclic Compounds; Iron; Ligands; Molecular Structure; Piperidines; Pyrrolidines

In our continued efforts to discover more active and less toxic HIV-1 non-nucleoside reverse transcriptase inhibitors, we recently designed a novel series of piperidine-linked pyridine analogues on the basis of diarylpyrimidine derivatives, among which two drugs-etravirine and rilpivirine-are approved for use by the US FDA. The title compounds were evaluated for activity against wild-type and resistant mutant strains of HIV-1 as well as HIV-2 in MT-4 cells. The highly potent compound BD-c1 (EC50 =10 nM, CC50 ≥146 μM, SI≥14 126) displays lower cytotoxicity and higher selectivity than etravirine (EC50 =2.2 nM, CC50 =28 μM, SI=12 884) against wild-type HIV-1. Compound BD-e2 (EC50 =5.1 nM) shows greater antiviral efficacy against wild-type HIV-1 than do the four reference drugs nevirapine, delavirdine, efavirenz, and zidovudine. Many compounds were also found to be active against the frequently observed drug-resistant double mutant (K103N+Y181C) HIV-1 strain. Herein we report the design, synthesis, anti-HIV evaluation, preliminary structure-activity relationships, and molecular simulations of novel piperidine-linked pyridine analogues.

Topics: Anti-HIV Agents; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Discovery; HIV Reverse Transcriptase; HIV-1; Humans; Microbial Sensitivity Tests; Models, Molecular; Molecular Dynamics Simulation; Molecular Structure; Piperidines; Pyridines; Reverse Transcriptase Inhibitors; Structure-Activity Relationship

This study presents the synthesis and biological evaluation of a new series of arylalkyl/arylalkylsulfonyl piperazine and piperidine-based derivatives as sigma receptor ligands. It was found that a number of halogen substituted sulfonamides display relatively high and low affinities to σ1 and σ2 receptors, respectively. The σ1 affinities and subtype selectivities of four piperidine derivatives were also found to be generally comparable to those of piperazine analogues. Compared to σ1-Rs compounds with n = 0 and 2, those with n = 1 proved to have optimal length of carbon chain by exhibiting higher affinities. Within this series, the 4-benzyl-1-(3-iodobenzylsulfonyl)piperidine sigma ligand was identified with 96-fold σ1/σ2 selectivity ratio (Kiσ1 = 0.96 ± 0.05 nM and Kiσ2 = 91.8 ± 8.1 nM).

Topics: Animals; Binding Sites; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Guinea Pigs; Ligands; Male; Molecular Conformation; Piperazine; Piperazines; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Structure-Activity Relationship

Quantum chemical calculations have been used to model reactions which are important for understanding the chemical fate of paroxetine-derived radicals in the environment. In order to explain the experimental observation that the loss of water occurs along the (photo)degradation pathway, four different mechanisms of radical-induced dehydrations have been considered. The elimination of water from the N-centered radical cation, which results in the formation of an imine intermediate, has been calculated as the most feasible process. The predicted energy barrier (ΔG = 98.5 kJ mol(-1)) is within the barrier limits set by experimental measurements. All reaction intermediates and transition state structures have been calculated using the G3(MP2)-RAD composite procedure, and solvent effects have been determined using a mixed (cluster/continuum) solvation model. Several new products, which comply with the available experimental data, have been proposed. These structures could be relevant for the chemical fate of antidepressant paroxetine, but also for biologically and environmentally related substrates.

Topics: Alkenes; Free Radicals; Imines; Paroxetine; Photolysis; Piperidines; Quantum Theory; Selective Serotonin Reuptake Inhibitors; Thermodynamics; Water

The binding mode and affinity of isoeuxanthone (1,6-dihydroxyxanthone) (1) and its piperidinyl derivative (1-hydroxy-6-(2-(1-piperidinyl)ethoxy)xanthone) (2) with calf thymus DNA were studied using absorption spectroscopy, fluorescence spectroscopy, circular dichroism (CD) spectroscopy and viscosity measurements. Results indicate that the two xanthones can intercalate into the DNA base pairs by the plane of xanthone ring and the binding affinity of the piperidinylethoxy substituted xanthone 2 is stronger than 1. In addition, the cytotoxic effects of both compounds were evaluated with the human cervical cancer cell line (HeLa) and human hepatocellular liver carcinoma cell line (HepG2) using acid phosphatase assay. Analyses show that the piperidinylethoxy substituted xanthone exhibits more effective cytotoxic activity than isoeuxanthone against the two cancer cells. The effects on the inhibition of tumor cells in vitro agree with the studies of DNA-binding.

Topics: Animals; Antineoplastic Agents; Cattle; Cell Survival; Circular Dichroism; DNA; HeLa Cells; Hep G2 Cells; Humans; Piperidines; Spectrophotometry, Ultraviolet; Xanthones

Design of the new spin-labeled cyclodextrins can significantly extend the functionality of nitroxides. A series of new complexes based on fully methylated cyclodextrin (TRIMEB) covalently bound to the piperidine, pyrroline, pyrrolidine, and pH-sensitive imidazoline type nitroxides has been synthesized and studied using pulse and continuous wave electron paramagnetic resonance (EPR). The influence of the radical and linker properties on the structure of complexes formed has been investigated. Using the electron spin echo envelope modulation technique, we have analyzed quantitatively the accessibility of radicals to solvent molecules in studied complexes depending on the structure and length of the linkers. In all studied systems we observed different types of equilibria between conformations with radical fragment being outside the TRIMEB cavity and radical fragment capping the cavity of TRIMEB. The observed guest-induced shift of equilibrium toward the complex with radical capping TRIMEB cavity was explained by a change of macrocyclic configuration of TRIMEB. Complex with the -NH-CO- linker has been found most perspective for the applications requiring close location of nitroxide to the inclusion complex of TRIMEB. Using continuous wave EPR, we have shown that the pH-sensitive radical covalently bound to TRIMEB maintains its pH-sensitivity, but this complexation does not reduce radical reduction rate in the reaction with ascorbic acid.

Topics: Cyclodextrins; Electron Spin Resonance Spectroscopy; Hydrogen-Ion Concentration; Kinetics; Nitrogen Oxides; Piperidines; Pyrroles; Pyrrolidines; Spin Labels

A novel triple reuptake inhibitor with low potential of liabilities associated with cationic amphiphilic drug (CAD) was identified following an analysis of existing drugs. Low molecular weight (MW < ca. 300), low aromatic ring count (number = 1) and reduced lipophilicity (ClogP < 3.5) were hypothesized to be key factors to avoid the CAD associated liabilities (CYP2D6 inhibition, hERG inhibition and phospholipidosis). Based on the hypothesis, a series of piperidine compounds was designed with consideration of the common characteristic features of CNS drugs. Optimization of the side chain by adjusting overall lipophilicity suggested that incorporation of a methoxymethyl group could provide compounds with a balance of both potent reuptake inhibition and low liability potential. Compound (S)-3a showed a potent antidepressant-like effect in the mice tail suspension test (MED = 10 mg/kg, p.o.), proportional monoamine transporter occupancies and enhancement of monoamine concentrations in mouse prefrontal cortex.

Topics: Animals; Male; Mice; Mice, Inbred ICR; Models, Molecular; Neurotransmitter Uptake Inhibitors; Piperidines; Prefrontal Cortex; Structure-Activity Relationship

We report synthesis and optimization of a series of (3S,5R)-5-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamides as renin inhibitors. Chemical modification of P1', P2' and P3 portions led to a promising 3,5-disubstituted piperidine 32o showing high renin inhibitory activity and favorable oral exposure in both rats and cynomolgus monkeys with acceptable CYP and hERG current inhibition. Compound 32o exhibited a significant blood pressure lowering effect by oral administration in two hypertensive animal models, double transgenic rats and furosemide pretreated cynomolgus monkeys.

Topics: Administration, Oral; Amides; Animals; Blood Pressure; Disease Models, Animal; Furosemide; Half-Life; Hypertension; Macaca fascicularis; Piperazines; Piperidines; Protease Inhibitors; Rats; Rats, Transgenic; Renin; Structure-Activity Relationship

Ten new lycodine-type alkaloids, named casuarinines A-J (1-10), along with eight known analogues (11-18), were isolated from the whole plant of Lycopodiastrum casuarinoides . The new structures were established by spectroscopic methods and chemical transformations. Casuarinines A-D (1-4) and J (10) are common lycodine alkaloids possessing four connected six-membered rings, while tricyclic casuarinines E-H (5-8) are the piperidine ring cleavage products. In particular, casuarinine I (9) has an unprecedented five-membered tetrahydropyrrole ring instead of the piperidine ring. A plausible biosynthetic pathway to 9 is proposed. Among the compounds reported, casuarinine H (8) exhibited significant neuroprotective effect against hydrogen peroxide (H₂O₂)-induced neuronal cell damage in human neuroblastoma SH-SY5Y cells, while casuarinines C (3) and I (9) showed moderate inhibitory activity against acetylcholinesterase (AChE).

Topics: Acetylcholinesterase; Alkaloids; Cholinesterase Inhibitors; Humans; Hydrogen Peroxide; Lycopodiaceae; Molecular Structure; Neuroblastoma; Neuroprotective Agents; Nuclear Magnetic Resonance, Biomolecular; Piperidines

A four-step approach for the synthesis of dihydroxylated piperidine, quinolizidine and indolizidine systems is described employing α,β-unsaturated diazoketones as versatile building blocks. Unsaturated diazoketones were readily prepared from a Horner-Wadsworth-Emmons reaction between a diazophosphonate and amino-aldehydes. The strategy employs an asymmetric dihydroxylation reaction as the key step and is simple and straightforward enough to be extended to other nitrogen heterocycles.

Topics: Diazonium Compounds; Indolizidines; Molecular Structure; Piperidines; Quinolizidines; Stereoisomerism

A protecting-group-free synthetic strategy for the synthesis of piperidines has been explored. Key in the synthesis is an I2-mediated carbamate annulation, which allows for the cyclization of hydroxy-substituted alkenylamines into piperidines, pyrrolidines, and furans. In this work, four chiral scaffolds were compared and contrasted, and it was observed that with both d-galactose and 2-deoxy-d-galactose as starting materials, the transformations into the piperidines 1-deoxygalactonorjirimycin (DGJ) and 4-epi-fagomine, respectively, could be achieved in few steps and good overall yields. When d-glucose was used as a starting material, only the furan product was formed, whereas the use of 2-deoxy-d-glucose resulted in reduced chemo- and stereoselectivity and the formation of four products. A mechanistic explanation for the formation of each annulation product could be provided, which has improved our understanding of the scope and limitations of the carbamate annulation for piperidine synthesis.

Topics: 1-Deoxynojirimycin; Carbamates; Cyclization; Fucose; Imino Pyranoses; Molecular Structure; Piperidines; Stereoisomerism

A novel series of N-aryl-3,4-dihydro-1'H-spiro[chromene-2,4'-piperidine]-1'-carboxamides was identified as transient receptor potential melastatin 8 (TRPM8) channel blockers through analogue-based rational design, synthesis and screening. Details of the synthesis, effect of aryl groups and their substituents on in-vitro potency were studied. The effects of selected functional groups on the 4-position of the chromene ring were also studied, which showed interesting results. The 4-hydroxy derivatives showed excellent potency and selectivity. Optical resolution and screening of alcohols revealed that (R)-(-)-isomers were in general more potent than the corresponding (S)-(+)-isomers. The isomer (R)-(-)-10e (IC50: 8.9nM) showed a good pharmacokinetic profile upon oral dosing at 10mg/kg in Sprague-Dawley (SD) rats. The compound (R)-(-)-10e also showed excellent efficacy in relevant rodent models of neuropathic pain.

Topics: Administration, Oral; Amides; Analgesics; Animals; Disease Models, Animal; Half-Life; Male; Mice; Mice, Inbred C57BL; Neuralgia; Piperidines; Protein Binding; Rats; Rats, Sprague-Dawley; Spiro Compounds; Stereoisomerism; Structure-Activity Relationship; TRPM Cation Channels

Serotonin 1A (5-HT1A) receptors have been mechanistically implicated in micturition control, and there has been a need for an appropriate biomarker surrogating the potency of a provisional drug acting on this receptor system for developing a new therapeutic approach to overactive bladder (OAB). Here, we analyzed the occupancy of 5-HT1A receptors in living Sprague-Dawley rat brains by a novel candidate drug for OAB, E2110, using positron emission tomography (PET) imaging, and assessed the utility of a receptor occupancy (RO) assay to establish a pharmacodynamic index translatable between animals and humans. The plasma concentrations inducing 50% RO (EC50) estimated by both direct and effect compartment models were in good agreement. Dose-dependent therapeutic effects of E2110 on dysregulated micturition in different rat models of pollakiuria were also consistently explained by achievement of 5-HT1A RO by E2110 in a certain range (≥ 60%). Plasma drug concentrations inducing this RO range and EC50 would accordingly be objective indices in comparing pharmacokinetics-RO relationships between rats and humans. These findings support the utility of PET RO and plasma pharmacokinetic assays with the aid of adequate mathematical models in determining the in vivo characteristics of a drug acting on 5-HT1A receptors and thereby counteracting OAB.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Administration, Oral; Animals; Computer Simulation; Hippocampus; Microsomes; Piperidines; Positron-Emission Tomography; Protein Binding; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A; Reflex; Superior Colliculi; Time Factors; Urinary Bladder, Overactive; Urination

Analogues of potent 5-HT(4)R antagonists possessing a fluorinated N-alkyl chain have been synthesized in order to investigate the effect of the resulting change in basicity and lipophilicity on the affinity and selectivity profile. We demonstrate that for this series, the affinity is decreased with decreased basicity of the piperidine's nitrogen atom. In contrast, the resulting increase in lipophilicity has minimal impact on binding affinity and selectivity. 3,3,3-Trifluoropropyl and 4,4,4-trifluorobutyl derivatives 6d and 6e have shown to bind to the 5-HT(4)R while maintaining their pharmacological profile and selectivity toward other 5-HT receptors.

Topics: Animals; Drug Design; Guinea Pigs; Halogenation; Humans; Piperidines; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Antagonists

A new series of urea-based, 4-bicyclic heteroaryl-piperidine derivatives as potent SCD1 inhibitors is described. The structure-activity relationships focused on bicyclic heteroarenes and aminothiazole-urea portions are discussed. A trend of dose-dependent decrease in body weight gain in diet-induced obese (DIO) mice is also demonstrated.

Topics: Administration, Oral; Animals; Body Weight; Diet; Enzyme Activation; Enzyme Inhibitors; Mice; Mice, Inbred C57BL; Obesity; Piperidines; Protein Binding; Rats; Stearoyl-CoA Desaturase; Structure-Activity Relationship; Urea

The recognition of the mercury(II) ion (Hg(2+)) is essential because of its extreme toxicity in the environment and food. Hence we reported a novel cysteine (Cys) complex of piperidine-calix[4]arene (L) as a convenient and effective dual-signal responsive switch for Hg(2+). This switch system exhibited excellent selectivity toward Hg(2+) by fluorescence (FL), (1)H NMR spectroscopy and the atomic force microscopy (AFM). More importantly, the Hg(2+)-responsive switch had an important and potential application by water contact angle (CA) on a functional micro-nano silicon surface, including intelligent microfluidic and laboratory-on-chip devices, controllable drug delivery, and self-cleaning surfaces.

Topics: Calixarenes; Click Chemistry; Cysteine; Fluorescence; Magnetic Resonance Spectroscopy; Mercury; Models, Molecular; Molecular Structure; Particle Size; Phenols; Piperidines; Protons; Silicon; Surface Properties; Wettability

A number of new amine scaffolds with good inhibitory activity in the ADP-induced platelet aggregation assay have been found to be potent antagonists of the P2Y1 receptor. SAR optimization led to the identification of isoindoline 3c and piperidine 4a which showed good in vitro binding and functional activities, as well as improved aqueous solubility. Among them, the piperidine 4a showed the best overall profile with favorable PK parameters.

Topics: Adenosine Diphosphate; Amines; Animals; Blood Platelets; Half-Life; Humans; Microsomes, Liver; Piperidines; Platelet Aggregation Inhibitors; Protein Binding; Purinergic P2Y Receptor Agonists; Rats; Receptors, Purinergic P2Y1; Structure-Activity Relationship; Urea

A series of 4-hydroxy-3,4-dialkyl-2,6-diaryl-piperidine (7-12) have been synthesised by reduction of 3-alkyl-2,6-diarylpiperidin-4-one using the Grignard reagent. Structural assignments and conformational analysis of the compounds were established based on the spectral studies. All the piperdin-4-ol derivatives (7-12) were assayed for antibacterial, antifungal and anthelmintic activities and they exhibited significant results.

Topics: Anthelmintics; Anti-Infective Agents; Antifungal Agents; Microbial Sensitivity Tests; Molecular Structure; Piperidines; Structure-Activity Relationship

A series of peptidomimetic containing bidentate pTyr mimetics (9a-w) are reported as potent and selective PTP1B inhibitors. Compounds (9p and 9q) showed excellent selectivity towards PTP1B over various PTPs, including TCPTP (in vitro), which confirms discovery of highly potent and selective PTP1B inhibitors.

Topics: Acetates; Amides; Dipeptides; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Models, Molecular; Molecular Structure; Peptidomimetics; Piperidines; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Structure-Activity Relationship; Substrate Specificity

A novel GPR119 agonist based on the 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole scaffold was designed through lead optimization starting from pyrazole-based GPR119 agonist 1. The design is centered on the conformational restriction of the core scaffold, while minimizing the change in spatial relationships of two key pharmacophoric elements (piperidine-carbamate and aryl sulfone).

Topics: Carbamates; Humans; Piperidines; Protein Binding; Pyrazoles; Receptors, G-Protein-Coupled; Structure-Activity Relationship

A series of potent amide non-urea inhibitors of soluble epoxide hydrolase (sEH) is disclosed. The inhibition of soluble epoxide hydrolase leads to elevated levels of epoxyeicosatrienoic acids (EETs), and thus inhibitors of sEH represent one of a novel approach to the development of vasodilatory and anti-inflammatory drugs. Structure-activities studies guided optimization of a lead compound, identified through high-throughput screening, gave rise to sub-nanomolar inhibitors of human sEH with stability in human liver microsomal assay suitable for preclinical development.

Topics: Anti-Inflammatory Agents; Catalytic Domain; Epoxide Hydrolases; Humans; Inhibitory Concentration 50; Microsomes, Liver; Models, Molecular; Molecular Structure; Piperidines; Protease Inhibitors; Solubility; Structure-Activity Relationship; Urea; Vasodilator Agents

A 30-membered piperidine ring-fused aromatic sulfonamide library was synthetized, including N-arylsulfonyl 1,2,3,4-tetrahydroquinolines, 1,2,3,4-tetrahydroisoquinolines and 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoles. The compounds induced oxidative stress and glutathione depletion in HT168 melanoma and K562 leukemia cells and in micromolar concentrations exerted cytotoxic effects. Among the tested sulfonamides, compounds 21, 22, 23, 35 and 41 exhibited 100% cytotoxic effects with low (< 10 µM) EC50 values on K562 cells. The cytotoxicity of lead compound 22 was investigated in 24 different cancer cell lines, and it was found to be active against leukemia, melanoma, glioblastoma, and liver, breast and lung cancer cells, as confirmed by classical biochemical and holographic microscopic analyses.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Humans; Inhibitory Concentration 50; K562 Cells; Molecular Structure; Oxidative Stress; Piperidines; Structure-Activity Relationship; Sulfonamides

Benzylcyanide and 4-nitrobenzylcyanide condensed with triethyl orthoformate and piperidine or morpholine to yield 2-aryl-2-piperidinyl or 2-morpholinylacrylonitriles. These coupled with aromatic diazonium salts to yield the 2-arylhydrazno-2-arylethane nitriles in good yields. The latter were converted into 4-aminopyrazoles in good yields using the Thorpe-Ziegler cyclization.

Topics: Acrylonitrile; Alkylation; Cyclization; Diazonium Compounds; Dimethylformamide; Formates; Heterocyclic Compounds, 2-Ring; Microwaves; Nitriles; Piperidines; Pyrazoles; Solvents

A piperidine-modified calix[4]arene derivative was synthesized and its structure was confirmed with X-ray diffraction data. UV-visible spectroscopy was used to study its molecular recognition of rare earth ions. The results revealed the calix[4]arene derivative could separate tight metal picrate ion pairs by complexation with the rare earth metal ions in tetrahydrofuran. Resolution of the UV-visible spectra with chemometric methods revealed that the derivative and the rare earth ions Eu(3+), Dy(3+), and Tb(3+) formed ML(2) complexes with stability constants of 10(8.26), 10(8.29), and 10(7.41) respectively.

Topics: Calixarenes; Coordination Complexes; Crystallography, X-Ray; Furans; Metals, Rare Earth; Models, Molecular; Phenols; Piperidines; Spectrophotometry, Ultraviolet

Malaria is a disease that has a major impact in many developing nations, especially on the African continent. There is a need to develop new therapeutics and prophylactic treatments against it. A trisubstituted pyrrole was recently found to inhibit infection of mammalian hepatocytes by Plasmodium sporozoites, but the target of this agent is not known. In this study trisubstituted pyrrole derivatives with different substituents on a piperidinyl nitrogen were prepared. We determined if modifications of the piperidinyl nitrogen would accommodate a drug-biotin linking strategy for affinity purification of the trisubstituted pyrrole's target protein(s).

Topics: Animals; Hepatocytes; Nitrogen; Piperidines; Plasmodium; Protozoan Proteins; Pyrroles; Sporozoites

The cyclization of N-Boc-α-alkylserines to corresponding β-lactones under Mitsunobu reaction conditions and the ring opening with heterocyclic amines (pyrrolidine, piperidine, morpholine and thiomorpholine) produced N-Boc-α-alkyl-β-(sec-amino)alanines. The removal of the Boc group gives di-hydrochlorides of non-protein amino acids.

Topics: Alanine; Cyclization; Lactones; Morpholines; Piperidines; Pyrrolidines; Serine; Stereoisomerism

The exposure of electrospray droplets generated from either highly acidic or highly basic solutions to basic or acidic vapors, respectively, admitted into the counter-current drying gas, has been shown to lead to significant changes in the observed charge state distributions of proteins. In both cases, distributions of charge states changed from relatively high charge states, indicative of largely denatured proteins, to lower charge state distributions that are more consistent with native protein conformations. Ubiquitin, cytochrome c, myoglobin, and carbonic anhydrase were used as model systems. In some cases, bimodal distributions were observed that are not noted under any solution pH conditions. The extent to which changes in charge state distributions occur depends upon the initial solution pH and the pK(a) or pK(b) of the acidic or basic reagent, respectively. The evolution of charged droplets in the sampling region of the mass spectrometer inlet aperture, where the vapor exposure takes place, occurs within roughly 1 ms. The observed changes in the spectra, therefore, are a function of the magnitude of the pH change as well as the rates at which the proteins can respond to this change. The exposure of electrospray droplets in this fashion may provide means for accessing transient folding states for further characterization by mass spectrometry.

Topics: Acetic Acid; Animals; Cattle; Gases; Humans; Hydrogen-Ion Concentration; Piperidines; Protein Conformation; Protein Denaturation; Protein Refolding; Proteins; Spectrometry, Mass, Electrospray Ionization; Static Electricity

An efficient stereocontrolled preparation of (2R,R(S))-2-allyl-(N-tert-butylsulfinyl)piperidine and its enantiomer is detailed. The sequence requires only two synthetic operations with one-column chromatography and is readily scaled up. The versatility of these chiral building blocks was exemplified by the total or formal synthesis of some natural and unnatural alkaloids.

Topics: Alkaloids; Molecular Structure; Piperidines; Stereoisomerism

7-Arylsulfonyl substituted benzofuropiperidine was discovered as a novel scaffold for 5HT(6) receptor antagonists. Optimization by substitution at C-1 position led to identification of selective, orally bioavailable, brain penetrant antagonists with reduced hERG liability. An advanced analog tested in rat social recognition model showed significant activity suggesting potential utility in the enhancement of short-term memory.

Topics: Animals; Benzofurans; Brain; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Humans; Inhibitory Concentration 50; Kinetics; Memory, Short-Term; Models, Chemical; Piperidines; Rats; Receptors, Serotonin; Schizophrenia; Serotonin Antagonists; Structure-Activity Relationship

A series of novel 2-(4-(2,4-dimethoxybenzoyl)phenoxy)-1-(4-(3-(piperidin-4-yl)propyl) piperidin-1-yl)ethanone derivatives 9(a-e) and 10(a-g) were synthesized and characterized by (1) H NMR, IR, mass spectral, and elemental analysis. These novel compounds were evaluated for their antileukemic activity against two human leukemic cell lines (K562 and CEM) by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay. Some of the tested compounds showed good antiproliferative activity with IC(50) values ranging from 1.6 to 8.0 μm. Compound 9c, 9e, and 10f with an electron-withdrawing halogen substituent at the para position on the phenyl ring showed excellent in vitro potency against tested human leukemia cells (K562 and CEM).

Topics: Antineoplastic Agents; Benzophenones; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Leukemia; Piperidines

The disposition of 1-(8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H- purin-6-yl)-4-(ethylamino)-piperidine-4-carboxamide (CP-945,598), an orally active antagonist of the cannabinoid CB1 receptor, was studied after a single 25-mg oral dose of [(14)C]CP-945,598 to healthy human subjects. Serial blood samples and complete urine and feces were collected up to 672 h after dose. The mean total recovery of radioactivity was 60.1 ± 12.8 from the urine and feces, with the majority of the dose excreted in the feces. The absorption of CP-945,598 in humans was slow with T(max) at 6 h. Less than 2% of the dose was recovered as unchanged drug in the combined excreta, suggesting that CP-945,598 is extensively metabolized. The primary metabolic pathway of CP-945,598 involved N-de-ethylation to form an N-desethyl metabolite (M1), which was then subsequently metabolized by amide hydrolysis (M2), N-hydroxylation (M3), piperidine ring hydroxylation (M6), and ribose conjugation (M9). M3 was further metabolized to oxime (M4) and keto (M5) metabolites. M1, M4, and M5 were the major circulating metabolites, with AUC((0-48)) values 4.7-, 1.5-, and 1.1-fold greater than that of CP-945,598. M1, M2, and M9 accounted for 5.6, 33.6, and 6.30% of the dose, respectively, in excreta. The results from in vitro experiments with recombinant isoforms suggested that the oxidative metabolism of CP-945,598 to M1 is catalyzed primarily by CYP3A4/3A5. The molecular docking study showed that the N-ethyl moiety of CP-945,598 can access to the heme iron-oxo of CYP3A4 in an energetically favored orientation. Together, these data suggest that CP-945,598 is well absorbed and eliminated largely by CYP3A4/3A5-catalyzed metabolism.

Topics: Adult; Amides; Area Under Curve; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Feces; Humans; Hydrolysis; Hydroxylation; Male; Microsomes, Liver; Middle Aged; Oximes; Piperidines; Purines; Receptor, Cannabinoid, CB1; Young Adult

A cationic CpRu complex of chiral picolinic acid derivatives [(R)- or (S)-Cl-Naph-PyCOOCH(2)CH═CH(2)] catalyzes asymmetric intramolecular dehydrative N-allylation of N-substituted ω-amino- and -aminocarbonyl allylic alcohols with a substrate/catalyst ratio of up to 2000 to give α-alkenyl pyrrolidine-, piperidine-, and azepane-type N-heterocycles with an enantiomer ratio of up to >99:1. The wide range of applicable N-substitutions, including Boc, Cbz, Ac, Bz, acryloyl, crotonoyl, formyl, and Ts, significantly facilitates further manipulation toward natural product synthesis.

Topics: Azepines; Catalysis; Molecular Structure; Piperidines; Pyrrolidines; Ruthenium Compounds; Stereoisomerism

Synthesis of oxo-dihydrospiroindazole-based acetyl-CoA carboxylase (ACC) inhibitors is reported. The dihydrospiroindazoles were assembled in a regioselective manner in six steps from substituted hydrazines and protected 4-formylpiperidine. Enhanced regioselectivity in the condensation between a keto enamine and substituted hydrazines was observed when using toluene as the solvent, leading to selective formation of 1-substituted spiroindazoles. The 2-substituted spiroindazoles were formed selectively from alkyl hydrazones by ring closure with Vilsmeier reagent. The key step in the elaboration to the final products is the conversion of an intermediate olefin to the desired ketone through elimination of HBr from an O-methyl bromohydrin. This methodology enabled the synthesis of each desired regioisomer on 50-75 g scale with minimal purification. Acylation of the resultant spirocyclic amines provided potent ACC inhibitors.

Topics: Acetyl-CoA Carboxylase; Alkenes; Alkylation; Chemistry Techniques, Synthetic; Enzyme Inhibitors; Indazoles; Ketones; Piperidines; Pyrazoles; Stereoisomerism; Substrate Specificity

The core structure of cis-3,5-diaminopiperidine was N-alkylated with excess t-butylbromoacetate in order to exploit the successive N-quaternarization and Stevens rearrangement to access the pentaalkylated product and the bifunctional chelating agent containing a N-butanedioic acid pendant arm at the same time. The relaxometric properties of the Gd(III) complexes with these ligands were studied also in terms of pH and serum stabilities.

Topics: Alkylation; Chelating Agents; Ligands; Molecular Structure; Pentetic Acid; Piperidines

Deregulation of receptor tyrosine kinase c-Met has been reported in human cancers and is considered as an attractive target for small molecule drug discovery. In this study, a series of spiro[indoline-3, 4'-piperidine]-2-ones were designed, synthesized and evaluated as novel c-Met inhibitors. The results showed that the majority of the compounds exhibited significant inhibitory effect on c-Met with IC(50) values of 0.0147-17 μM in TR-FRET-based assay and IC(50) values of 1.56-1400 μM in cell-based assay. Furthermore, our docking experiments verified the results and explained the molecular mechanism of eminent activities to c-Met.

Topics: Binding Sites; Blotting, Western; Cell Proliferation; Drug Design; Drug Discovery; Fluorescence Resonance Energy Transfer; Humans; Inhibitory Concentration 50; Models, Molecular; Molecular Structure; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Stomach Neoplasms; Structure-Activity Relationship; Tumor Cells, Cultured

A Veratrum piperidine chiron was prepared over 11 steps (7.9% yield) from (-)-citronellal. Three methods for the installation of the propargylic side chain onto a cyclic enamide are presented.

Topics: Caprylates; Magnetic Resonance Spectroscopy; Molecular Structure; Piperidines; Stereoisomerism; Sulfonamides; Veratrum Alkaloids

A novel series of piperidine-substituted triazine derivatives have been synthesized and evaluated for anti-HIV activities in MT-4 cells. Most compounds displayed extremely promising activity against wild-type HIV-1 with EC(50) values in low nanomolar concentration, better than that of Nevirapine, Delavirdine, Zidovudine and Dideoxycitidine, and higher potency towards the resistant mutant strain K103N/Y181C than that of Nevirapine and Delavirdine. Selected compounds were also assayed against reverse transcriptase with lower IC(50) values than that of Nevirapine. The structure-activity relationship (SAR) of these novel structural congeners was also discussed.

Topics: Anti-HIV Agents; Cell Line; Chemistry Techniques, Synthetic; HIV Reverse Transcriptase; HIV-1; Inhibitory Concentration 50; Piperidines; Reverse Transcriptase Inhibitors; Structure-Activity Relationship; Triazines

New cholecystokinin-1 receptor (CCK1R) agonist 'triggers' were identified using iterative library synthesis. Structural activity relationship studies led to the discovery of compound 10e, a potent CCK1R agonist that demonstrated robust weight loss in a diet-induced obese rat model with very low systemic exposure. Pharmacokinetic data suggest that efficacy is primarily driven through activation of CCK1R's located within the intestinal wall.

Topics: Amides; Animals; Cells, Cultured; Disease Models, Animal; Drug Discovery; Humans; Inhibitory Concentration 50; Male; Mice; Mice, Obese; Piperidines; Protein Binding; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin A; Structure-Activity Relationship; Weight Loss

Sigma-1 receptors are specifically located at the endoplasmic reticulum-mitochondrion interface, but upon stimulation by ligands or under prolonged cellular stress, they translocate to other areas of the cell. Sigma-1 receptors are involved in the regulation of intracellular [Ca(2+)] by affecting the Ca(2+)-influx or the release from intracellular stores. In SK-N-SH cells, we measured the affinity of 4-methyl-1-[4-(6-methoxynaphthalen-1-yl)butyl]piperidine (PB212) at sigma-1 receptor by using a competition binding assay with specific radioligand; we obtained a K(i) value=316 ± 19 nM. PB212 also showed an antiproliferative effect in SK-N-SH cells (EC(50)=32 ± 4 μM) but had no effect in MCF7 cells, which only express sigma-2 receptor; these findings suggest that PB212 behaves as a sigma-1 receptor antagonist. We have studied the effect of PB212 on Ca(2+) homeostasis of the SK-N-SH cell line with the fluorescent probe Fura-2. 100 μM PB212 induced a Ca(2+)-efflux from the endoplasmic reticulum through the inositol (1, 4, 5)-trisphosphate (IP(3)) receptor. Moreover, [PB212] ranging from 1 to 100μM reduced the Ca(2+)-response, triggered by carbachol or bradykinin that engage the phospholipase C/IP(3) pathway; such a response is generally increased by sigma-1 receptor agonists. On the other hand, PB212 did not reduce the Ca(2+)-response mediated by IP(3) in LoVo cells, which do not express neither sigma-1 nor sigma-2 receptors, and in MCF7 cells. The fact that the activity of the sigma-1 receptor can be experimentally modulated by agonists and antagonists supports the intriguing hypothesis that some endogenous molecules, unknown at the moment, modulate the sigma-1 receptor and its cellular targets.

Topics: Calcium; Calcium Signaling; Cell Line, Tumor; Dose-Response Relationship, Drug; Endoplasmic Reticulum; Homeostasis; Humans; Inositol 1,4,5-Trisphosphate Receptors; Intracellular Space; Ligands; Naphthalenes; Piperidines; Receptors, sigma; Sigma-1 Receptor; Substrate Specificity

A series of triazole antifungal agents with piperidine side chains were designed and synthesized. Results of preliminary antifungal tests against eight human pathogenic fungi in vitro showed that all the title compounds exhibited excellent activities with broad spectrum. Moreover, a molecular model for the binding between compound 12 and the active site of CACYP51 was provided based on the computational docking results. The side chain of the compound 12 is oriented into substrate access channel 2 (FG loop) and forms hydrophobic and van der waals interactions with surrounding hydrophobic residues. The phenyl group of the side chain can interact with the phenyl group of Phe380 through the formation of π-π face-to-edge interaction.

Topics: Antifungal Agents; Catalytic Domain; Fungi; Humans; Microbial Sensitivity Tests; Models, Molecular; Mycoses; Piperidines; Sterol 14-Demethylase; Structure-Activity Relationship; Triazoles

Diastereoisomeric compounds [(18)F]cis- and [(18)F]trans-4-methylbenzyl 4-[(pyrimidin-2-ylamino)methyl]-3-fluoro-piperidine-1-carboxylates were successfully synthesized as new subtype-selective PET radiotracers for imaging the NR2B subunit containing NMDA receptors. Rat brain section autoradiographies demonstrated a high specific binding in NR2B/NMDA receptor rich regions for both radioligands. The measured logD(7.4) values as well as B(max)/K(d) ratios indicated that both radiotracers possess the adequate properties required for PET radiotracers.

Topics: Animals; Carboxylic Acids; Chemistry Techniques, Synthetic; Male; Piperidines; Positron-Emission Tomography; Radioactive Tracers; Radiochemistry; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Stereoisomerism; Structure-Activity Relationship

With the wide application of nanomaterials, the quantification of functional groups on nanomaterial surface becomes more and more necessary. A heterogeneous 9-fluorenylmethoxy carbonyl chloride (Fmoc-Cl) fluorescent method using an aqueous solution was established to determinate amino groups on nanomaterial surface. The effect factors of determination were investigated and the assay was optimised. The Fmoc fluorescent method is 200-fold more sensitive than the current UV assay using an organic solvent, and compared with chemical ninhydrin method and physical elemental analysis. Heterogeneous Fmoc-Cl fluorescent method can be used to determine amino groups on nanomaterials with big size, which is difficult to undergo a direct detection.

Topics: Amines; Fluorenes; Fluorescence; Kinetics; Nanoparticles; Piperidines; Silicon Dioxide; Spectrometry, Fluorescence

Four-component reactions of (R)-1-(1-phenylethyl)tetrahydro-4(1H)-pyridinone, aromatic aldehydes and malononitrile in a 1:2:1 molar ratio in the presence of solid sodium ethoxide under solvent free conditions afforded an inseparable mixture of two diastereomeric 4(H)-pyrans in near quantitative yields. These compounds upon 1,3-dipolar cycloaddition with nitrile oxides furnished two enantiomerically pure 1,2,4-oxadiazoles in moderate yields, which were screened for in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant M. tuberculosis (MDR-TB). Among the compounds screened, compound 10h was found to be the most active in vitro with a MIC value of 0.07 and 0.14 μM against MTB and MDR-TB respectively.

Topics: Anti-Bacterial Agents; Chemistry Techniques, Synthetic; Drug Discovery; Drug Resistance, Bacterial; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nitriles; Oxadiazoles; Oxides; Piperidines; Pyrans; Stereoisomerism

A novel series of piperidine-linked amino-triazine derivatives were designed, synthesized and evaluated for in vitro anti-HIV activity as non-nucleoside reverse transcriptase inhibitors on the basis of our previous work. Screening results indicated that most compounds showed excellent activity against wild-type HIV-1 with EC(50) values in low nanomolar concentration range (especially compound 6b3, EC(50) = 4.61 nM, SI = 5945) and high activity against K103N/Y181C resistant mutant strain of HIV-1 with EC(50) values in low micromolar concentration range. In addition, preliminary structure-activity relationship and molecular modeling of these new analogs were detailed in this manuscript.

Topics: Amines; Anti-HIV Agents; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Design; HIV Reverse Transcriptase; HIV-1; HIV-2; Humans; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Piperidines; Reverse Transcriptase Inhibitors; Structure-Activity Relationship; Triazines

The discovery of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor is described. The characterization and redressing of the issues associated with these compounds is detailed. An efficient three-step synthesis and a binding assay were relied upon as the primary means of rapidly improving potency and ADMET properties for this class of inverse agonist compounds. Compound 10 n bearing distributed polarity in the form of an imidazo-thiazole acetamide and a phenyl triazole is a unit lower in logP and has significantly improved binding affinity compared to the hit molecule 10a, providing support for further optimization of this series of compounds.

Topics: Animals; Azetidines; Drug Inverse Agonism; Humans; Microsomes, Liver; Piperidines; Rats; Receptors, Ghrelin; Structure-Activity Relationship

Pythium ultimum is a plant pathogen that causes significant yield losses on many economically important crops. Chemical treatment has been used for disease control. In searching for alternatives, venom piperidine and piperideine alkaloids from red imported fire ants were tested against P. ultimum in vitro, and piperideines were employed to control cucumber damping-off in the greenhouse as drench treatments. Results Piperidine and piperideine alkaloids of the red imported fire ant significantly inhibited mycelium growth of P. ultimum. Piperidine alkaloids were stable at both room and elevated temperatures. The inhibitory activity positively correlated with the concentrations of piperidine alkaloids in the medium, and the EC(50) = 17.0 µg ml(-1). Germination of sporangia of P. ultimum was negatively correlated with the concentrations of piperidine alkaloids in the medium, and the EC(50) = 12.3 µg ml(-1). The piperideine alkaloid drenching treatment significantly improved seedling emergence and seedling height of cucumber.. This is the first report describing the use of venom alkaloids from the red imported fire ant to inhibit P. ultimum in the laboratory and the application of piperideine alkaloids to control damping-off disease caused by P. ultimum in the greenhouse. These findings may lead to the development of a new group of fungicides.

Topics: Alkaloids; Animals; Ant Venoms; Cucumis sativus; Mycelium; Pest Control; Piperidines; Pythium; Temperature

The adducts of simple chromophore 4-N,N-dimethylamino benzoic acid with 2,2,6,6-tetrametyl-4-hydroxy- or 4-amino-piperidine were examined as fluorescence probes (spin double sensors) to monitor radical processes. The links in the adducts were either an ester or amide group, and the sterically hindered amines were in the form of -NH, -NO• and -NOR. The spectral properties of the three related derivatives (esters or amides) were quite similar. The maxima of the absorption spectra were in the range of 295-315 nm, and the maximum of fluorescence was located in the range of 330-360 nm, depending on the polarity of the solvent. In polar solvents, a red-shifted fluorescence band at 460-475 nm was observed. The fluorescence of these derivatives was rather weak as compared to anthracene under the same conditions. The Stokes shift was large, as high as 6,000 cm(-1), indicating the formation of a twisted intra-molecular charge transfer (TICT) state. No large differences in Stokes shifts were observed in polymer matrices of poly(methyl methacrylate), polystyrene and poly(vinyl chloride). The extent of intramolecular quenching was expressed as Φ(NX)/Φ(NO) (X = H, NOR) and was in the range of 1-3 in solution and as high as 8 in polymer matrices. The low efficiency of intramolecular quenching limits the application of these new adducts as fluorescence probes for the monitoring of radical processes in solution but favors their application in polymer matrices.

Topics: Amides; Amines; Fluorescent Dyes; para-Aminobenzoates; Piperidines; Spectrometry, Fluorescence

Rhodamine S could emit strong and stable room temperature phosphorescence (RTP) on polyamide membrane (PAM) in the presence of heavy atom perturber Pb(2+). When Rhodamine S-piperidine solution was dropped on PAM, the red (Rhod.S)(n)-P-SOR (Rhod.S, (Rhod.S)(n), P and SOR refer to alizarin red S, multiple Rhod.S molecules, piperidine and self-ordered ring, respectively) formed on PAM, leading to the enhancement of room temperature phosphorimetry (RTP) intensity (I(p), 117.2) of (Rhod.S)(n)-P-SOR system, which was 2.4 times higher than that without SOR (I(p), 48.1). Wheat germ agglutinin (WGA) was labelled with (Rhod.S)(n)-P-SOR by the -NH- of Rhod.S reacting with the -COOH of WGA to form WGA-(Rhod.S)(n)-P-SOR. The formation of WGA-AP-WGA-(Rhod.S)(n)-P-SOR in the affinity adsorption (AA) reaction carried out between the -COOH of WGA in WGA-(Rhod.S)(n)-P-SOR and the -NH(2) of alkaline phosphatase (AP) caused the RTP intensity (ΔI(p)) of the WGA-AP-WGA-(Rhod.S)(n)-P-SOR system 7.8 times larger than that without (Rhod.S)(n)-P-SOR. Therefore, the coupling technique of SOR and solid substrate-room temperature phosphorimetry (SS-RTP) for the determination of trace AP has been established. This method possessed good selectivity, high sensitivity (Detection limit (L.D) was 3.4×10(-16)gmL(-1)) and accuracy, and it has been applied to the determination of trace AP in human serum and the forecast of human diseases, and the results agreed well with those obtained by enzyme-linked immunoassay (ELISA). Besides, the mechanism of the coupling technique for the determination of AP was discussed.

Topics: Alkaline Phosphatase; Anthraquinones; Buffers; Disease; Humans; Limit of Detection; Luminescent Measurements; Piperidines; Rhodamines; Solvents; Substrate Specificity; Temperature; Wheat Germ Agglutinins

The Jocic-Reeve and Corey-Link type reaction of dichloromethyllithium with suitably protected 5-keto-hexofuranoses followed by treatment with sodium azide and sodium borohydride reduction gave 5-azido-5-hydroxylmethyl substituted hexofuranoses 7a-c with required geminal dihydroxymethyl group. Removal of protecting groups and converting the C-1 anomeric carbon into free hemiacetal followed by intramolecular reductive aminocyclization with in situ generated C5-amino functionality afforded corresponding 5C-dihydroxymethyl piperidine iminosugars 2a-c. Alternatively, removal of protecting groups in 7b and 7c and chopping of C1-anomeric carbon gave C2-aldehyde that on intramolecular reductive aminocyclization with C5-amino gave 4C-dihydroxymethyl pyrrolidine iminosugars 1b and 1c, respectively. On the basis of the (1)H NMR studies, the conformations of 2a/2b were assigned as (4)C(1) and that of 2c as (1)C(4). The glycosidase inhibitory activities of all five iminosugars were studied with various glycosidase enzymes and compared with natural d-gluco-1-deoxynojirimycin (DNJ). All the five compounds were found to be potent inhibitors of rice α-glucosidase with K(i) and IC(50) values in the nanomolar concentration range. Iminosugars 2b and 1b were found to be more potent inhibitors than their parent iminosugar. These results were substantiated by in silico molecular docking studies.

Topics: Enzyme Inhibitors; Glycoside Hydrolases; Imino Sugars; Models, Molecular; Molecular Conformation; Molecular Structure; Piperidines; Pyrrolidines

In this paper, we report the discovery and the synthesis of novel, potential antipsychotic piperidine-2,6-dione derivatives combining potent dopamine D(2) , D(3) and serotonin 5-HT(1A) , 5-HT(2A) , 5-HT(2C) receptor properties. We describe the structure-activity relationships that led us to the promising derivative: 1-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butyl)-4-(4-chlorophenyl)-piperidine-2,6-dione 5. The unique pharmacological features of compound 5 are a high affinity for dopamine D(2) , D(3) and serotonin 5-HT(1A) , 5-HT(2A) , 5-HT(2C) receptors, together with a low affinity for the H(1) receptor (to reduce the risk of obesity under chronic treatment). In a behavioral model predictive of positive symptoms, compound 5 inhibited apomorphine-induced climbing behavior and MK-801-induced hyperactivity with no extrapyramidal symptoms liability in mice. In particular, compound 5 was more potent than clozapine.

Topics: Animals; Antipsychotic Agents; Apomorphine; Behavior, Animal; Clozapine; Disease Models, Animal; Dizocilpine Maleate; Mice; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Receptors, Histamine H1; Receptors, Serotonin; Structure-Activity Relationship

Topics: Alkylation; Amides; Cyclization; Indole Alkaloids; Lithium; Piperidines; Stereoisomerism

Expedient routes to three classes of novel spiro-fused pyrrolidine, piperidine, and indoline heterocycle scaffolds are described. These three-dimensional frameworks, which conform to the "rule of three", are suitably protected to allow for site-selective manipulation and functionalization. Different modes of substrate control were explored, which allow for good to excellent levels of diastereoselectivity and dispense with the need for additional chiral reagents or catalysts. The concepts developed were applied in short, formal syntheses of (±)-coerulescine and (±)-horsfiline.

Topics: Aniline Compounds; Catalysis; Indoles; Lactams; Molecular Structure; Oxindoles; Piperidines; Pyrrolidines; Spiro Compounds; Stereoisomerism

A series of dual CCR3/H(1) antagonists based on a bispiperidine scaffold were discovered. Introduction of an acidic group overcame hERG liability. Bioavailability was optimised by modulation of physico-chemical properties and physical form to deliver a compound suitable for clinical evaluation.

Topics: Animals; Drug Discovery; Drug Interactions; Ether-A-Go-Go Potassium Channels; Histamine H1 Antagonists; Molecular Structure; Piperidines; Rats; Receptors, CCR3; Risk Factors

A series of novel, potent CCR1 inhibitors was developed from a moderately active hit using an iterative parallel synthesis approach. The initial hit (composed of three subunits: an amine, a central amino acid, and an N-terminal cap) became the basis for a series of parallel chemical libraries designed to generate SAR data. Libraries were synthesized that explored each of the three subunits; the CCR1 binding data obtained revealed the following: (1) changes to the amine are not well tolerated; (2) small alkylamino acids are preferred in the center of the molecule; (3) substitutions at the N-terminus are generally well tolerated. These data were used to drive the optimization of the series, ultimately providing a lead with a CCR1 binding IC(50) of 28 nM (48). This lead demonstrates high selectivity for CCR1 over other CCR-family members, high microsomal stability, and good pharmacokinetics in mice.

Topics: Animals; Calcium; Cells, Cultured; Chemotaxis; Humans; Mice; Microsomes, Liver; Monocytes; Patch-Clamp Techniques; Piperidines; Protein Binding; Rabbits; Rats; Receptors, CCR; Structure-Activity Relationship; Tissue Distribution

A series of piperamide derivatives (8a-j) was synthesized with various substituted piperidine and piperazine compounds. The prepared compounds were evaluated for antibacterial activity against gram-positive and gram-negative bacteria and antifungal activity by disc diffusion method. The antioxidant activity of the compounds was evaluated by DPPH and superoxide radical scavenging method and antidepressant activity using forced swim and tail suspension behavioral despair tests in mice. The compounds 8a, 8b and 8c were investigated for their monoamine oxidase A and B (MAO-A and MAO-B) inhibitory property. Some of the test compounds were active in forced swim test (FST) and tail suspension test (TST). Compounds 8a and 8b showed a significant effect, when compared to standard drug, clorgyline.

Topics: Amides; Animals; Anti-Bacterial Agents; Antidepressive Agents; Antifungal Agents; Antioxidants; Behavior, Animal; Candida albicans; Gram-Negative Bacteria; Gram-Positive Bacteria; Mice; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Piperazine; Piperazines; Piperidines

The aza-semi-crown pentadentate ligand rigidified by pyridine and piperidine rings was designed and synthesized. It can react with Mn(II) in water to form complex with improved longitudinal relaxivity, leading to efficient signal intensity enhancement of vascular vessels under a clinical magnetic resonance imaging scanner.

Topics: Chelating Agents; Contrast Media; Coordination Complexes; Crown Compounds; Crystallography, X-Ray; Humans; Magnetic Resonance Imaging; Manganese; Molecular Conformation; Piperidines; Pyridines; Veins

Curcumin inhibits growth of several cancer cell lines, and studies in this laboratory in bladder and pancreatic cancer cells show that curcumin downregulates specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 and pro-oncogenic Sp-regulated genes. In this study, we investigated the anticancer activity of curcumin and several synthetic cyclohexanone and piperidine analogs in colon cancer cells.. The effects of curcumin and synthetic analogs on colon cancer cell proliferation and apoptosis were determined using standardized assays. The changes in Sp proteins and Sp-regulated gene products were analysed by western blots, and real time PCR was used to determine microRNA-27a (miR-27a), miR-20a, miR-17-5p and ZBTB10 and ZBTB4 mRNA expression.. The IC50 (half-maximal) values for growth inhibition (24 hr) of colon cancer cells by curcumin and synthetic cyclohexanone and piperidine analogs of curcumin varied from 10 μM for curcumin to 0.7 μM for the most active synthetic piperidine analog RL197, which was used along with curcumin as model agents in this study. Curcumin and RL197 inhibited RKO and SW480 colon cancer cell growth and induced apoptosis, and this was accompanied by downregulation of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 and Sp-regulated genes including the epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (c-MET), survivin, bcl-2, cyclin D1 and NFκB (p65 and p50). Curcumin and RL197 also induced reactive oxygen species (ROS), and cotreatment with the antioxidant glutathione significantly attenuated curcumin- and RL197-induced growth inhibition and downregulation of Sp1, Sp3, Sp4 and Sp-regulated genes. The mechanism of curcumin-/RL197-induced repression of Sp transcription factors was ROS-dependent and due to induction of the Sp repressors ZBTB10 and ZBTB4 and downregulation of microRNAs (miR)-27a, miR-20a and miR-17-5p that regulate these repressors.. These results identify a new and highly potent curcumin derivative and demonstrate that in cells where curcumin and RL197 induce ROS, an important underlying mechanism of action involves perturbation of miR-ZBTB10/ZBTB4, resulting in the induction of these repressors which downregulate Sp transcription factors and Sp-regulated genes.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Curcumin; Cyclin D1; Cyclohexanones; Down-Regulation; ErbB Receptors; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; NF-kappa B; Piperidines; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-met; Reactive Oxygen Species; Repressor Proteins; Sp Transcription Factors

Analogs of the flexible dopamine reuptake inhibitor, GBR 12909 (1), may have potential utility in the treatment of cocaine abuse. As a first step in the 3D-QSAR modeling of the dopamine transporter (DAT)/serotonin transporter (SERT) selectivity of these compounds, we carried out conformational analyses of two analogs of 1: a piperazine (2) and a related piperidine (3). Ensembles of conformers consisting of local minima on the potential energy surface of the molecule were generated in the vacuum phase and in implicit solvent by random search conformational analysis using the Tripos and MMFF94 force fields. Some differences were noted in the conformer populations due to differences in the treatment of the tertiary amine nitrogen and ether oxygen atom types by the force fields. The force fields also differed in their descriptions of internal rotation around the C(sp³)-O(sp³) bond proximal to the bisphenyl moiety. Molecular orbital calculations at the HF/6-31G(d) and B3LYP/6-31G(d) levels of C-O internal rotation in model compound (5), designed to model the effect of the proximity of the bisphenyl group on C-O internal rotation, showed a broad region of low energy between -60° to 60° with minima at both -60° and 30° and a low rotational barrier at 0°, in closer agreement with the MMFF94 results than the Tripos results. Molecular mechanics calculations on model compound (6) showed that the MMFF94 force field was much more sensitive than the Tripos force field to the effects of the bisphenyl moiety on C-O internal rotation.

Topics: Models, Chemical; Piperazine; Piperazines; Piperidines; Solvents

The preparation of natural product-like polyhydroxylated pyrrolidine and piperidine alkaloids using a combination of solid- and solution-phase organic synthesis is described. The key intermediates, enantiopure five- or six-membered tri-O-benzyl cyclic nitrones, were efficiently prepared on solid support from accessible chiral furanosides and pyranosides, respectively. The substituent diversity was achieved by a diastereoselective addition of a variety of Grignard reagents to the cyclic nitrones in solution-phase synthesis. All reaction steps and work-up procedures were modified to allow the use of automated equipment. A 36-membered demonstration library with three diversity elements (core, configuration, and substituent) was prepared in good yield and purity.

Topics: Alkaloids; Biological Products; Hydroxylation; Nitrogen Oxides; Piperidines; Pyrrolidines; Small Molecule Libraries; Solutions; Volatilization

Neuroimaging of σ(1) receptors in the human brain has been proposed for the investigation of the pathophysiology of neurodegenerative and psychiatric diseases. However, there is a lack of suitable (18)F-labelled PET radioligands for that purpose.. The selective σ(1) receptor ligand [(18)F]fluspidine (1'-benzyl-3-(2-[(18)F]fluoroethyl)-3H-spiro[[2]benzofuran-1,4'-piperidine]) was synthesized by nucleophilic (18)F(-) substitution of the tosyl precursor. In vitro receptor binding affinity and selectivity were assessed by radioligand competition in tissue homogenate and autoradiographic approaches. In female CD-1 mice, in vivo properties of [(18)F]fluspidine were evaluated by ex vivo brain section imaging and organ distribution of intravenously administered radiotracer. Target specificity was validated by organ distribution of [(18)F]fluspidine after treatment with 1 mg/kg i.p. of the σ receptor antagonist haloperidol or the emopamil binding protein (EBP) inhibitor tamoxifen. In vitro metabolic stability and in vivo metabolism were investigated by LC-MS(n) and radio-HPLC analysis.. [(18)F]Fluspidine was obtained with a radiochemical yield of 35-45%, a radiochemical purity of ≥ 99.6% and a specific activity of 150-350 GBq/μmol (n = 6) within a total synthesis time of 90-120 min. In vitro, fluspidine bound specifically and with high affinity to σ(1) receptors (K (i) = 0.59 nM). In mice, [(18)F]fluspidine rapidly accumulated in brain with uptake values of 3.9 and 4.7%ID/g and brain to blood ratios of 7 and 13 at 5 and 30 min after intravenous application of the radiotracer, respectively. By ex vivo autoradiography of brain slices, resemblance between binding site occupancy of [(18)F]fluspidine and the expression of σ(1) receptors was shown. The radiotracer uptake in the brain as well as in peripheral σ(1) receptor expressing organs was significantly inhibited by haloperidol but not by tamoxifen. Incubation with rat liver microsomes led to a fast biotransformation of fluspidine. After an incubation period of 30 min only 13% of the parent compound was left. Seven metabolites were identified by HPLC-UV and LC-MS(n) techniques. However, [(18)F]fluspidine showed a higher metabolic stability in vivo. In plasma samples ∼ 94% of parent compound remained at 30 min and ∼ 67% at 60 min post-injection. Only one major radiometabolite was detected. None of the radiometabolites crossed the blood-brain barrier.. [(18)F]Fluspidine demonstrated favourable target affinity and specificity as well as metabolic stability both in vitro and in animal experiments. The in vivo properties of [(18)F]fluspidine offer a high potential of this radiotracer for neuroimaging and quantitation of σ(1) receptors in vivo.

Topics: Animals; Benzofurans; Female; Humans; Ligands; Male; Mice; Molecular Imaging; Piperidines; Radioactive Tracers; Rats; Receptors, sigma; Sigma-1 Receptor; Steroid Isomerases; Substrate Specificity

Acetylcholine inhibitors (AChEIs) are currently considered as potential drugs for treating Alzheimer disease. In this work, we developed a receptor-dependent 3D-QSAR (RD-3D-QSAR) models based on a series of 60 benzylpiperidine inhibitors of human acetylcholinesterase to support the design of new AChEIs. The best two models, A-F (N = 47, q(2) = 0.736, r(2) = 0.860) and C-F (N = 47, q(2) = 0.753, r(2) = =0.900) were developed and validated by a combined GA-PLS approach, available in WOLF. Residues of the aromatic gorge (Tyr341 and Trp439) and catalytic triad (His447) are related to both equations showing the consistency of these models with the SAR. Based on those models we have proposed four new benzylpiperidine derivatives and predicted the pIC(50) for each molecule. The good predicted potency of benzylpiperidine derivative, IIa, indicates that it is a potential candidate as a new HuAChE inhibitor.

Topics: Acetylcholinesterase; Binding Sites; Cholinesterase Inhibitors; Drug Design; Humans; Inhibitory Concentration 50; Models, Molecular; Molecular Conformation; Piperidines; Quantitative Structure-Activity Relationship

A novel series of diphenylbutylpiperidines as autophagy inducers was described and extensive SAR studies resulted in derivatives (15d-e, 15i-j) with 10-fold greater activity than the lead compounds 1 and 2. Meanwhile, a new synthetic route to diphenylbutyl bromide (6) from bromobenzene and γ-butyrolactone was also reported here.

Topics: Autophagy; Cell Line, Tumor; Humans; Piperidines; Structure-Activity Relationship

The collision-induced dissociation (CID) of protonated buprenorphine ([M+H](+) ) and four related compounds was studied by electrospray quadrupole/time-of-flight mass spectrometry (ESI-QTOF MS). The fragmentation pathways were investigated by using energy-dependent CID and pseudo-MS(3) (in-source CID combined with tandem mass spectrometry (MS/MS)) methods. The first steps of the fragmentation are the parallel losses of the substituents from the non-aromatic ring moieties. Depending on the applied collision energies, a large number of further fragment ions arising from the cross-ring cleavages of the core-ring structure were observed. Based on the experimental results, a generalized fragmentation scheme was developed for the five buprenorphine derivatives highlighting the differences for the alternatively substituted compounds. The collision-energy-dependent fragmentation profile of buprenorphine is visualized in a two-dimensional plot to aid its fingerprint identification.

Topics: Buprenorphine; Chemistry, Pharmaceutical; Piperidines; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

We have synthesized several nitroxides with different substituents which vary the steric and electronic environment around the N-O moiety and have systematically investigated the role of substituents on the stability of the radicals. Our results demonstrated the reactivity toward ascorbate correlates with the redox potential of the derivatives. Furthermore, ab initio calculations also indicated a correlation between the reduction rate and the computed singly occupied molecular orbital-lowest unoccupied molecular orbital energy gap, but not with solvent accessible surface area of the N-O moiety, supporting the experimental results and suggesting that the electronic factors largely determine the radicals' stability. Hence, it is possible to perform virtual screening of nitroxides to optimize their stability, which can help to rationally design novel nitroxides for their potential use in vivo.

Topics: Ascorbic Acid; Cyclic N-Oxides; Electron Spin Resonance Spectroscopy; Magnetic Resonance Spectroscopy; Piperidines; Structure-Activity Relationship

Phospholipids (PLs) are the major building block molecules of cellular membranes. Their composition varies depending on cell types and cellular compartments. Thus, the information regarding PL distribution in tissue has important physiological and pathological significance. Recent developments in imaging mass spectrometry (IMS) have allowed complete mapping of the PL species on tissue. The IMS technique can detect different classes of PLs as well as their location information directly from tissue sections. PL head groups carry either positive and/or negative charges; therefore, IMS experiments must be conducted in both positive- and negative-ion mode to detect all types of phospholipids. Several conventional matrixes were applied on tissue for better identification. This study was conducted to enable appropriate matrix selection and optimized matrix preparation for IMS experiments in both ion modes that maximize PL identification from a single brain tissue section. The optimized matrix 2,5-dihydroxybenzoic acid (DHB) and α-cyano-4-hydroxycinnamic acid (CHCA) with a mixture of trifluoroacetic acid (TFA) and piperidine as ion pairing agents showed improved stability and consistency during both ion mode experiments and successfully identified >100 peaks of PLs determined by parent ion m/z value. Further tandem mass spectrometric analysis (MS/MS) was performed to those PLs that are anatomically important according to their distribution on rat brain tissue section.

Topics: Animals; Brain; Coumaric Acids; Gentisates; Ionic Liquids; Molecular Imaging; Phospholipids; Piperidines; Principal Component Analysis; Rats; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tandem Mass Spectrometry; Trifluoroacetic Acid

A practical enantioselective synthesis of renin inhibitor MK-1597 (ACT-178882), a potential new treatment for hypertension, is described. The synthetic route provided MK-1597 in nine steps and 29% overall yield from commercially available p-cresol (7). The key features of this sequence include a catalytic asymmetric hydrogenation of a tetrasubstituted ene-ester, a highly efficient epimerization/saponification sequence of 4 which sets both stereocenters of the molecule, and a short synthesis of amine fragment 2.

Topics: Catalysis; Cresols; Cyclopropanes; Enzyme Inhibitors; Hydrogenation; Hypertension; Molecular Structure; Piperidines; Pyridines; Renin; Stereoisomerism

Structurally well-defined N-heterocyclic carbene silver chlorides and bromides supported by 1-cyclohexyl-3-benzylimidazolylidene (CyBn-NHC) or 1-cyclohexyl-3-naphthalen-2-ylmethylimidazolylidene (CyNaph-NHC) were synthesized by reaction of the corresponding imidazolium halides with silver(I) oxide while cationic bis(CyBn-NHC) silver nitrate was isolated under similar conditions using imidazolium iodide in the presence of sodium nitrate. Single-crystal X-ray diffraction revealed a dimeric structure through a nonpolar weak-hydrogen-bond supported Ag-Ag bond for 1-cyclohexyl-3-benzylimidazolylidene silver halides [(CyBn-NHC)AgX](2) (X = Cl, 1; Br, 2) but a monomeric structure for N-heterocyclic carbene silver halides with the more sterically demanding 1-cyclohexyl-3-naphthalen-2-ylmethylimidazolylidene ligand (CyNaph-NHC)AgX (X = Cl, 4; Br, 5). Cationic biscarbene silver nitrate [(CyBn-NHC)(2)Ag](+)NO(3)(-)3 assumed a cis orientation with respect to the two carbene ligands. The monomeric complexes (CyNaph-NHC)AgX 4 and 5 showed higher catalytic activity than the dimeric [(CyBn-NHC)AgX](2)1 and 2 as well as the cationic biscarbene silver nitrate 3 in the model three component reaction of 3-phenylpropionaldehyde, phenylacetylene and piperidine with chloride 4 performing best and giving product in almost quantitative yield within 2 h at 100 °C. An explanation for the structure-activity relationship in N-heterocyclic carbene silver halide catalyzed three component reaction is given based on a slightly modified mechanism from the one in literature.

Topics: Acetylene; Aldehydes; Alkynes; Amines; Bromides; Catalysis; Crystallography, X-Ray; Heterocyclic Compounds; Hydrogen Bonding; Ligands; Methane; Molecular Structure; Piperidines; Silver Compounds; Stereoisomerism; Structure-Activity Relationship; X-Ray Diffraction

With the aim of obtaining compounds possessing high SERT selectivity, in the present work we synthesized and studied the inhibition of serotonin (SERT), dopamine (DAT) and norepinephrine (NET) transporters by docking studies and experimental binding measurements of a series of 4-(aryl)piperidin-3-one O-4-benzyl oxime hydrochlorides (1-10) of both E and Z configuration. E configuration compounds showed high SERT binding affinities (K(i) = 10-98 nM) and high SERT selectivities over both NET and DAT. The molecular docking studies allowed a rationalization of the molecular basis of drug-SERT interactions both of the synthesized compounds and paroxetine and fluoxetine used as reference antidepressant drugs.

Topics: Animals; Dopamine; Humans; Models, Molecular; Neurotransmitter Agents; Norepinephrine; Piperidines; Protein Binding; Rabbits; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin Plasma Membrane Transport Proteins

The structure-human CXCR3 binding affinity relationship of a series of pyridyl-piperazinyl-piperidine derivatives was explored. The optimization campaign highlighted the pronounced effect of 2'-piperazine substitution on CXCR3 receptor affinity. Analog 18j, harboring a 2'(S)-ethylpiperazine moiety, exhibited a human CXCR3 IC(50) of 0.2 nM.

Topics: Humans; Inhibitory Concentration 50; Molecular Structure; Piperazine; Piperazines; Piperidines; Pyridines; Receptors, CXCR3; Structure-Activity Relationship

One-electron photooxidations of 5-methyl-2'-deoxycytidine (d(m)C) and 5-trideuteriomethyl-2'-deoxycytidine ([D(3)]d(m)C) by sensitization with anthraquinone (AQ) derivatives were investigated. Photoirradiation of an aerated aqueous solution containing d(m)C and anthraquinone 2-sulfonate (AQS) afforded 5-formyl-2'-deoxycytidine (d(f)C) and 5-hydroxymethyl-2'-deoxycytidine (d(hm)C) in good yield through an initial one-electron oxidation process. The deuterium isotope effect on the AQS-sensitized photooxidation of d(m)C suggests that the rate-determining step in the photosensitized oxidation of d(m)C involves internal transfer of the C5-hydrogen atom of a d(m)C-tetroxide intermediate to produce d(f)C and d(hm)C. In the case of a 5-methylcytosine ((m)C)-containing duplex DNA with an AQ chromophore that is incorporated into the backbone of the DNA strand so as to be immobilized at a specific position, (m)C underwent efficient direct one-electron oxidation by the photoexcited AQ, which resulted in an exclusive DNA strand cleavage at the target (m)C site upon hot piperidine treatment. In accordance with the suppression of the strand cleavage at 5-trideuterio-methylcytosine observed in a similar AQ photosensitization, it is suggested that deprotonation at the C5-methyl group of an intermediate (m)C radical cation may occur as a key elementary reaction in the photooxidative strand cleavage at the (m)C site. Incorporation of an AQ sensitizer into the interior of a strand of the duplex enhanced the one-electron photooxidation of (m)C, presumably because of an increased intersystem crossing efficiency that may lead to efficient piperidine-induced strand cleavage at an (m)C site in a DNA duplex.

Topics: Anthraquinones; Deoxycytidine; DNA; DNA Cleavage; DNA Methylation; Electrons; Molecular Structure; Oxidation-Reduction; Photochemistry; Piperidines; Solutions; Water

Thyroid hormone receptors (TRs) are members of the nuclear hormone receptor (NR) superfamily and regulate development, growth, and metabolism. Upon binding thyroid hormone, TR undergoes a conformational change that allows the release of corepressors and the recruitment of coactivators, which in turn regulate target gene transcription. Although a number of TR antagonists have been developed, most are analogs of the endogenous hormone that inhibit ligand binding. In a screen for inhibitors that block the association of TRβ with steroid receptor coactivator 2 (SRC2), we identified a novel methylsulfonylnitrobenzoate (MSNB)-containing series that blocks this interaction at micromolar concentrations. Here we have studied a series of MSNB analogs and characterized their structure activity relationships. MSNB members do not displace thyroid hormone T3 but instead act by direct displacement of SRC2. MSNB series members are selective for the TR over the androgen, vitamin D, and PPARγ NR members, and they antagonize thyroid hormone-activated transcription action in cells. The methylsulfonylnitro group is essential for TRβ antagonism. Side-chain alkylamine substituents showed better inhibitory activity than arylamine substituents. Mass spectrum analysis suggested that MSNB inhibitors bind irreversibly to Cys-298 within the AF-2 cleft of TRβ to disrupt SRC2 association.

Topics: Aniline Compounds; HEK293 Cells; Hep G2 Cells; Humans; Methylamines; Nitrobenzoates; Nuclear Receptor Coactivator 2; Piperidines; Protein Binding; Receptors, Thyroid Hormone; Reverse Transcriptase Polymerase Chain Reaction; Structure-Activity Relationship

Novel (4-piperidinyl)-piperazine derivatives were synthesized and evaluated as ACC1/2 non-selective inhibitors. Optimization of the substituents on the nitrogen of the piperidine ring led to the identification of the fluorine substituted tert-butoxycarbonyl group. Advanced analog, 1,1,1-trifluoro-2-methylpropan-2-yl 4-{4-[(2-amino-6-methyl-1-benzothiophen-3-yl)carbonyl]piperazin-1-yl}piperidine-1-carboxylate (12c) showed potent inhibitory activities in enzyme-assay and cell-based assays. Compound 12c also exhibited reduction of hepatic de novo fatty acid synthesis in rats after oral administration.

Topics: Acetyl-CoA Carboxylase; Administration, Oral; Animals; Fluorine; Formic Acid Esters; Molecular Structure; Piperazine; Piperazines; Piperidines; Rats; Stereoisomerism; Structure-Activity Relationship

The reaction rates for the rearrangement of eleven (Z)-arylhydrazones of 5-amino-3-benzoyl-1,2,4-oxadiazole 3a-k into the relevant (2-aryl-5-phenyl-2H-1,2,3-triazol-4-yl)ureas 4a-k in the presence of trichloroacetic acid or of piperidine have been determined in toluene at 313.1 K. The results have been related to the effect of the aryl substituent by using Hammett and/or Ingold-Yukawa-Tsuno correlations and have been compared with those previously collected in a protic polar solvent (dioxane/water) as well as with those on the analogous rearrangement of the corresponding (Z)-arylhydrazones of 3-benzoyl-5-phenyl-1,2,4-oxadiazole 1a-k in benzene. Some light can thus be shed on the general differences of chemical reactivity between protic polar (or dipolar aprotic) and apolar solvents.

Topics: Alkalies; Amines; Biological Products; Catalysis; Dioxanes; Hydrazones; Hydrophobic and Hydrophilic Interactions; Kinetics; Molecular Structure; Oxadiazoles; Piperidines; Structure-Activity Relationship; Temperature; Toluene; Trichloroacetic Acid; Urea; Water

The photocytotoxicity and photobiochemical properties of the new complex trans,trans,trans-[Pt(N(3))(2)(OH)(2)(NH(3))(piperidine)] (5) are compared with its analogue containing the less basic and less lipophilic ligand pyridine (4). The log P (n-octanol/water) values were of -1.16 and -1.84 for the piperidine and pyridine complexes, respectively, confirmed that piperidine increases the hydrophobicity of the complex. Density Functional Theory (DFT) and time-dependent density functional theory (TDDFT) calculations indicate that 5 has accessible singlet and triplet states which can promote ligand dissociation when populated by both UVA and visible white light. When activated by UVA or white light, both compounds showed similar cytotoxic potencies in various human cancer cell lines although their selectivity was different. The time needed to reach similar antiproliferative activity was noticeably decreased by introducing the piperidine ligand. Neither compound showed cross-resistance in three oxoplatin-resistant cell lines. Furthermore, both compounds showed similar anticlonogenic activity when activated by UVA radiation. Interactions of the light-activated complexes with DNA showed similar kinetics and levels of DNA platination and similar levels of DNA interstrand cross-linking (ca. 5%). Also the ability to unwind double stranded DNA were comparable for the piperidine analogue (24°, respectively), while the piperidine complex showed higher potency in changing the conformation of DNA, as measured in an ethidium bromide binding assay. These results indicate that the nature of the heterocyclic nitrogen ligand can have subtle influences on both the phototoxicity and photobiochemistry of this class of photochemotherapeutic agents.

Topics: 1-Octanol; Binding Sites; Cell Line, Tumor; Cisplatin; Cross-Linking Reagents; DNA; DNA Adducts; Ethidium; Humans; Ligands; Light; Organoplatinum Compounds; Piperidines; Pyridines

In this study, we synthesized and evaluated a new spirocyclic piperidine derivative 3, containing a 4-fluorobutyl side chain, as a PET radioligand for neuroimaging of σ₁ receptors. In vitro, compound 3 displayed high affinity for σ₁ receptors (K(i) =1.2 nM) as well as high selectivity. [¹⁸F]3 radiosynthesis was performed from the corresponding tosylate precursor, with high radiochemical yield (45-51 %), purity (>98 %), and specific activity (>201 GBq μmol⁻¹). Metabolic stability of [¹⁸F]3 in the brain of CD-1 mice was verified, and no penetration of peripheral radiometabolites into the cerebral tissue was observed. Results of ex vivo autoradiography revealed that the distribution of [¹⁸F]3 in the brain corresponded to regions with high σ₁ receptor density. The highest region-specific total-to-nonspecific ratio was determined in the facial nucleus (4.00). Biodistribution studies indicated rapid and high levels in brain uptake of [¹⁸F]3 (2.2 % ID per gram at 5 min p.i.). Pre-administration of haloperidol significantly inhibited [¹⁸F]3 uptake into the brain and σ₁ receptor-expressing organs, further confirming in vivo target specificity.

Topics: Animals; Autoradiography; Brain; Female; Fluorine Radioisotopes; Haloperidol; Isotope Labeling; Mice; Piperidines; Positron-Emission Tomography; Radiopharmaceuticals; Receptors, sigma; Spiro Compounds; Tissue Distribution

Ex-changing places: a highly enantioselective desymmetrization of 1,2-diols has been developed in which the catalyst utilizes reversible covalent bonding to the substrate to achieve both high selectivity and rate acceleration (see scheme, PMP=pentalmethylpiperidine, TBS=tert-butyldimethylsilyl). Induced intramolecularity is responsible for the enhanced rate, thus allowing the reaction to be performed at room temperature.

Topics: Alcohols; Catalysis; Crystallography, X-Ray; Molecular Conformation; Piperidines; Silanes; Stereoisomerism

An oral bioavailability issue encountered during the course of lead optimization in the renin program is described herein. The low F(po) of pyridone analogs was shown to be caused by a combination of poor passive permeability and gut efflux transport. Substitution of pyridone ring for a more lipophilic moiety (logD>1.7) had minimal effect on rMdr1a transport but led to increased passive permeability (P(app)>10 × 10(-6) cm/s), which contributed to overwhelm gut transporters and increase rat F(po). LogD and in vitro passive permeability determination were found to be key in guiding SAR and improve oral exposure of renin inhibitors.

Topics: Administration, Oral; Animals; ATP Binding Cassette Transporter, Subfamily B; Biological Availability; Biological Transport; Cell Membrane Permeability; Dose-Response Relationship, Drug; Mice; Mice, Knockout; Molecular Structure; Piperidines; Rats; Renin; Stereoisomerism; Structure-Activity Relationship

The activation of N-alkyl prolinols by XtalFluor E allowed the formation of an aziridinium intermediate that can react with tetrabutylammonium azide (nBu(4)NN(3)) to produce 3-azidopiperidines and/or 2-(azidomethyl)pyrrolidines, in a ratio up to 100/0. These 3-azidopiperidines can be reduced to the corresponding 3-aminopiperidines.

Topics: Amines; Azides; Molecular Structure; Organometallic Compounds; Oxidation-Reduction; Piperidines; Pyrrolidines; Stereoisomerism

The hypothalamic peptides orexin-A and orexin-B are potent agonists of two G-protein coupled receptors, namely the OX(1) and the OX(2) receptor. These receptors are widely distributed, though differentially, in the rat brain. In particular, the OX(1) receptor is highly expressed throughout the hypothalamus, whilst the OX(2) receptor is mainly located in the ventral posterior nucleus. A large body of compelling evidence, both pre-clinical and clinical, suggests that the orexin system is profoundly implicated in sleep disorders. In particular, modulation of the orexin receptors activation by appropriate antagonists was proven to be an efficacious strategy for the treatment of insomnia in man. A novel, drug-like bis-amido piperidine derivative was identified as potent dual OX(1) and OX(2) receptor antagonists, highly effective in a pre-clinical model of sleep.

Topics: Animals; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Discovery; Humans; Models, Molecular; Molecular Structure; Orexin Receptors; Piperidines; Rats; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Sleep Wake Disorders; Stereoisomerism; Structure-Activity Relationship

Topics: Crystallography, X-Ray; Electric Conductivity; Electric Power Supplies; Electrochemical Techniques; Electrodes; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Nanocomposites; Nanotubes, Carbon; Oxidation-Reduction; Piperidines; Polymethacrylic Acids

Alcohol is key: regio- and enantioselective hydroamination of 1,3-dienes has been achieved with the dinuclear catalyst (R)-DTBM-SEGPHOS. The rate and selectivity of the reaction are enhanced by alcohol additives like menthol, which coordinates the cationic gold(I) to generate a Brønsted acid that can participate in catalysis. Mbs=p-methoxybenzenesulfonyl.

Topics: Alkadienes; Amination; Catalysis; Gold; Menthol; Molecular Structure; Piperidines; Pyrrolidines; Stereoisomerism

Several caspases have been implicated in the pathogenesis of Huntington's disease (HD); however, existing caspase inhibitors lack the selectivity required to investigate the specific involvement of individual caspases in the neuronal cell death associated with HD. In order to explore the potential role played by caspase-2, the potent but non-selective canonical Ac-VDVAD-CHO caspase-2 inhibitor 1 was rationally modified at the P(2) residue in an attempt to decrease its activity against caspase-3. With the aid of structural information on the caspase-2, and -3 active sites and molecular modeling, a 3-(S)-substituted-l-proline along with four additional scaffold variants were selected as P(2) elements for their predicted ability to clash sterically with a residue of the caspase-3 S(2) pocket. These elements were then incorporated by solid-phase synthesis into pentapeptide aldehydes 33a-v. Proline-based compound 33h bearing a bulky 3-(S)-substituent displayed advantageous characteristics in biochemical and cellular assays with 20- to 60-fold increased selectivity for caspase-2 and ∼200-fold decreased caspase-3 potency compared to the reference inhibitor 1. Further optimization of this prototype compound may lead to the discovery of valuable pharmacological tools for the study of caspase-2 mediated cell death, particularly as it relates to HD.

Topics: Binding Sites; Caspase 2; Caspase 3; Caspase Inhibitors; Catalytic Domain; Cell Line; Cysteine Proteinase Inhibitors; Drug Design; Humans; Isoquinolines; Molecular Dynamics Simulation; Piperidines; Proline; Substrate Specificity

To generate novel human Orexin-2 Receptor (OX2R) antagonists, a spiropiperidine based scaffold was designed and a SAR study was carried out. Compound 4f possessed the highest OX2R antagonistic activity with an IC(50) value of 3nM with 450-fold selectivity against Orexin-1 Receptor (OX1R).

Topics: Drug Discovery; Ligands; Orexin Receptors; Piperidines; Receptors, G-Protein-Coupled; Receptors, Neuropeptide

We synthesized and evaluated inhibitory activity against T-type Ca(2+) channels for a series of 1-alkyl-N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]piperidine-4-carboxamide derivatives. Structure-activity relationship studies have revealed that the isopropyl substituent at the benzylic position plays an important role in exerting potent inhibitory activity, and the absolute configuration of the benzylic position was found to be opposite that of mibefradil, which was first launched as a new class of T-type Ca(2+) channel blocker. Oral administration of N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]-1-[2-(3-methoxyphenyl)ethyl]piperidine-4-carboxamide (17f) lowered blood pressure in spontaneously hypertensive rats without inducing reflex tachycardia, an adverse effect often caused by traditional L-type Ca(2+) channel blockers.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Calcium Channels, T-Type; Cell Line; Guinea Pigs; Humans; Hypertension; Male; Piperidines; Rats; Rats, Inbred SHR; Structure-Activity Relationship

In this study novel thiosemicarbazides bearing piperidine moiety were synthesized in order to investigate their possible antibacterial and antifungal activities. A structure-activity relationship (SAR) study including conformational analysis and some physicochemical descriptors was carried out to provide the guidance for further synthetic work. The significant molecular descriptors related to the compounds with antifungal activity were: electrostatic potential surface, the highest occupied molecular orbital energy, surface area, volume, and hydration energy.

Topics: Anti-Bacterial Agents; Antifungal Agents; Bacteria; Dose-Response Relationship, Drug; Fungi; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Piperidines; Semicarbazides; Structure-Activity Relationship

Inhibition of sEH is hypothesized to lead to an increase in epoxyeicosatrienoic acids resulting in the potentiation of their anti-inflammatory and vasodilatory effects. In an effort to explore sEH inhibition as an avenue for the development of vasodilatory and cardio- or renal-protective agents, a lead identified through high-throughput screening was optimized, guided by the determination of a solid state co-structure with sEH. Replacement of potential toxicophores was followed by optimization of cell-based potency and ADME properties to provide a new class of functionally potent sEH inhibitors with attractive in vitro metabolic profiles and high and sustained plasma exposures after oral administration in the rat.

Topics: Administration, Oral; Animals; Binding Sites; Computer Simulation; Enzyme Inhibitors; Epoxide Hydrolases; Humans; Microsomes, Liver; Piperidines; Rats; Urea

In the present work, a new series of bis hybrid heterocycle comprising both piperidine and thiohydantoin nuclei together namely 3-(3-alkyl-2,6-diarylpiperin-4-ylidene)-2-thioxoimidazolidin-4-ones 46-60 was synthesized by the treatment of the respective thiosemicarbazones 31-45 with chloroethyl acetate and anhydrous sodium acetate in refluxing ethanol for 4h and were characterized by melting point, elemental analysis, MS, FT-IR, one-dimensional NMR ((1)H, D(2)O exchanged (1)H and (13)C), two dimensional HOMOCOSY and NOESY spectroscopic data. In addition, the title compounds were screened for their antimicrobial activities against a spectrum of clinically isolated microbial organisms. Compounds 47-50, 52-55 and 57-60 with fluoro, chloro, methoxy or methyl functions at the para position of phenyl rings attached to C-2 and C-6 carbons of piperidine moiety along with and without methyl substituent at position C-3 of the piperidine ring exerted potent biological activities against Staphylococcus aureus, beta-Hemolytic streptococcus, Vibrio cholerae, Escherichia coli, Pseudomonas aeruginosa, Aspergillus flavus, Candida albicans, Candida 6 and Candida 51 at a minimum inhibitory concentration.

Topics: Anti-Bacterial Agents; Antifungal Agents; Imidazolidines; Microbial Sensitivity Tests; Piperidines; Thiohydantoins

An improved protocol for the synthesis of a novel series of 1,2,4-triazines possessing 1,2,3-triazole and piperidine ring using 1-(1-substituted piperidin-4-yl)-1H-1,2,3-triazole-4-carbohydrazide, benzil, ammonium acetate and ZrOCl(2).8H(2)O as a catalyst in ethanol-water has been presented. The yields obtained are in the range of 87-94%. All the synthesized compounds (4a-4l) are novel and were evaluated for their in vitro antifungal activity. SAR for the series has been developed by comparing their MIC values with miconazole and fluconazole. Based on activity data SAR for the series has been developed. Compound 4c from the series was equipotent to miconazole against Candida albicans (MIC-25), Aspergillus niger (MIC-12.5) and Cryptococcus neoformans (MIC-25). Compound 4d was equipotent with miconazole against all tested organisms except Cryptococcus neoformans. Also compound 4i was equipotent with miconazole against C. albicans, A. niger and Fusarium oxysporum.

Topics: Antifungal Agents; Catalysis; Fluconazole; Miconazole; Microbial Sensitivity Tests; Piperidines; Structure-Activity Relationship; Triazines; Zirconium

The triaryl bis-sulfone 1 was modified by converting the aryl A-ring to a piperidine ring. The piperidine ring was further elaborated to a spirocyclopropyl piperidine moiety. The effect on CB2 binding potency, rat calcium channel affinity, and CYP 2C9 inhibition is described.

Topics: Animals; Calcium Channels; Cytochrome P-450 Enzyme System; Drug Inverse Agonism; Humans; Piperidines; Rats; Receptor, Cannabinoid, CB2; Structure-Activity Relationship; Sulfonamides; Sulfones

The design and synthesis of a new class of p38alpha MAP kinase inhibitors based on 4-fluorobenzylpiperidine heterocyclic oxalyl amides are described. Many of these compounds showed low-nanomolar activities in p38alpha enzymatic and cell-based cytokine TNFalpha production inhibition assays. The optimal linkers between the piperidine and the oxalyl amide were found to be [6,5] fused ring heterocycles. Substituted indoles and azaindoles were favored structural motifs in the cellular assay.

Topics: Amides; Crystallography, X-Ray; Heterocyclic Compounds; Humans; Mitogen-Activated Protein Kinase 14; Oxalates; Piperidines; Protein Kinase Inhibitors

This Letter details the SAR of a novel series of piperidine-derived gamma-secretase modulators. Compound 10h was found to be a potent modulator in vitro, which on further profiling, was found to decrease Abeta42, increase Abeta38 and have no effect on Abeta40 levels. Furthermore, 10h demonstrated excellent pharmacokinetic parameters in the mouse, rat and dog in addition to good CNS penetration in the mouse.

Topics: Acetates; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Cell Line, Tumor; Dogs; Humans; Mice; Peptide Fragments; Piperidines; Rats; Structure-Activity Relationship; Substrate Specificity

Stimuli-responsive gate mechanisms offer potential for the controlled passage of payload molecules from a porous carrier vehicle on-demand. We describe a method for the enzyme-mediated release of macromolecular guest molecules from inorganic silica particles coated with a bioactive peptide shell, synthesized precisely by Fmoc chemistry. Specific enzymatic hydrolysis of the peptide shell removes the bulky peptide-terminated Fmoc groups, permitting the selective release of previously entrapped guest molecules.

Topics: Amines; Chromatography, High Pressure Liquid; Chymotrypsin; Dextrans; Hydrolysis; Peptides; Piperidines; Silicon Dioxide; Substrate Specificity; Thermolysin

Nitrite has long been considered a potential pre-carcinogen for gastric cancer. Acidification of salivary nitrite, derived from dietary nitrate, produces nitrosative species such as NOSCN, NO(+) and N(2)O(3), which can form potentially carcinogenic N-nitroso compounds. Ascorbic acid inhibits nitrosation by converting the nitrosative species into nitric oxide (NO). However, NO diffuses rapidly to adjacent lipids, where it reacts with oxygen to reform nitrosative species. Nitrosation has been studied in vitro in aqueous systems and less frequently in organic systems; however, there is a need to investigate acid-catalysed nitrosation in a system combining aqueous and lipid environments, hence providing a physiologically relevant model. Here, we describe a two-phase system, which can be used as a tool to understand acid-catalysed nitrosation. Using gas chromatography/ion trap tandem mass spectrometry, we investigated the nitrosation of secondary amines as a function of the lipid phase composition and reaction mixing. An increased interface surface area was a driver for nitrosation, while incorporation of unsaturated fatty acids affected morpholine and piperidine nitrosation differently. Linoleic acid methyl esters did not affect morpholine nitrosation and only had a limited effect on N-nitrosopiperidine formation, while incorporation of free linoleic acid to the lipid phase significantly reduced N-nitrosopiperidine formation, but increased N-nitrosomorpholine formation at low levels. The mechanisms driving these effects are thought to involve amine partitioning, polarity and unsaturated fatty acids acting as scavengers of nitrosating species, findings relevant to the nitrosative chemistry occurring in the stomach, where the gastric acid meets a range of dietary fats which are emulsified during digestion.

Topics: Analysis of Variance; Gas Chromatography-Mass Spectrometry; Gastric Acid; Gastric Mucosa; Linoleic Acid; Lipids; Morpholines; Nitrogen Compounds; Nitrosamines; Nitrosation; Piperidines; Water

A highly enantioselective construction of delta- and gamma-lactone[2,3-b]piperidine skeletons was accomplished by tandem aza-Diels-Alder reaction-hemiacetal formation-oxidation from N-Tos-1-aza-1,3-butadienes and aliphatic dialdehydes.

Topics: Butadienes; Catalysis; Cyclization; Lactones; Molecular Structure; Oxygen; Piperidines; Stereoisomerism; Ytterbium

Penicillins are used universally in both human and veterinary medicine. The European Union (EU) has established maximum residue levels (MRLs) for most ss-lactam antibiotics in milk and animal tissues and included them in the National Residue Monitoring Programs. In this study, a novel method is described for the determination and confirmation of eight penicillins in porcine tissues, milk and animal feed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). To prevent degradation of penicillin residues during workup, a derivatisation procedure was developed, by which penicillins were converted to stable piperidine derivatives. Deuterated piperidine derivatives were synthesised for all relevant penicillins, enabling the use of isotope dilution for accurate quantification. Penicillin residues were derivatised in the crude extract with piperidine and isolated using solid-phase extraction. The penicillin piperidine derivatives were determined by LC-MS/MS. The method was validated at the current MRLs, which range from 25-300 microg kg(-1) in muscle and kidney to 4-30 microg kg(-1) in milk as well as at the target value of 100 microg kg(-1) chosen for animal feed, according to the EU requirements for a quantitative confirmatory method. Accuracy ranged from 94-113% (muscle), 83-111% (kidney) and 87-103% (milk) to 88-116% (animal feed). Intra-day precision (relative standard deviation (RSD)(r)) ranged from 5-13% (muscle, n = 18), 4-17% (kidney, n = 7) and 5-18% (milk, n = 7) to 11-32% (animal feed, n = 18). Inter-day precision (RSD(RL), n = 18) ranged from 6-23% (muscle) to 11-36% (animal feed). From the results, it was concluded that the method was fit for purpose at the target MRLs in animal tissue and target levels for animal feed.

Topics: Animal Feed; Animals; Chromatography, Liquid; Indicator Dilution Techniques; Kidney; Milk; Molecular Structure; Muscle, Skeletal; Penicillins; Piperidines; Protons; Swine; Tandem Mass Spectrometry

Novel Y-shaped acceptor-pi-donor-pi-acceptor-type compounds, synthesized from 4,4'-hexyliminobisbenzaldehyde as electron donors and different active methylene compounds as electron acceptors, were produced by conventional Knoevenagel condensation alone, with a deep eutectic solvent, or with a lipase biocatalyst to compare the yield and recyclability among the three methods. Yield, reaction time, reaction temperature, and recyclability were compared among the three methods. The photophysical properties and thermal stability of the products were also investigated.

Topics: Biocatalysis; Coloring Agents; Diphenylamine; Ethanol; Fluorescence; Lipase; Molecular Structure; Piperidines; Solvents; Stereoisomerism; Styrenes

Isotope labeling studies performed using lysine/glucose model systems have indicated that lysine can generate piperidine, a reactive amine capable of undergoing Maillard type interactions. Two possible mechanisms were identified for the formation of piperidine: one arising through decarboxylation of lysine alone to generate cadaverine (1,5-diaminopentane) followed by deamination to form pent-4-en-1-amine which in turn can cyclize into piperidine where both Nepsilon and Nalpha atoms of lysine can be equally involved in its generation due to the symmetrical nature of the precursor diamine. On the other hand, in the presence of sugars, lysine, similarly to asparagine and phenylalanine, can undergo carbonyl-assisted decarboxylative deamination reaction to generate pent-4-en-1-amine, the counterpart of acrylamide. The pent-4-en-1-amine can then cyclize to form piperidine through the Nepsilon atom of lysine. To confirm the formation of pent-4-en-1-amine in the lysine/glucose model system, a useful strategy based on Py-GC/MS analysis was developed using isotope labeling technique to identify sugar adducts of pent-4-en-1-amine. Products simultaneously possessing five lysine carbon atoms (C2'-C6') and the Nepsilon-amino group from lysine in addition to glucose carbon atoms were targeted using specifically labeled precursors such as [(15)Nalpha]lysine.2HCl, [(15)Nepsilon]lysine.2HCl, [U-(13)C(6)]lysine.2HCl, [(13)C-6]lysine.2HCl and [U-(13)C(6)]glucose. The complete labeling studies along with structural analysis using synthetic and other available precursors have shown the presence of a peak that satisfies the above criteria, and the peak was tentatively identified as N-(5-methylfuran-2-yl)methylidene]penta-1,3-dien-1-amine incorporating pent-4-en-1-amine in its structure.

Topics: Acrylamide; Chemical Phenomena; Glucose; Lysine; Piperidines

A series of 4-substituted 4-(1H-1,2,3-triazol-1-yl)piperidine building blocks was synthesized and introduced to the C7 position of the quinolone core, 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, to afford the corresponding fluoroquinolones in 40-83% yield. The antibacterial activity of these new fluoroquinolones was evaluated using a standard broth microdilution technique. Among them, the quinolone 1-cyclopropyl-6-fluoro-7-(4-(4-formyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (34.15) exhibited comparable antibacterial activity against quinolone-susceptible and multidrug-resistant strains, especially to Staphylococcus aureus and Staphylococcus epidermidis, in comparison with ciprofloxacin and vancomycin.

Topics: Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Fluoroquinolones; Microbial Sensitivity Tests; Naphthyridines; Piperidines

Novel piperidine and piperazine derivatives have been designed and tested as inhibitors of LTA(4) hydrolase (LTA(4)H). Most potent compounds showed good potency in both enzymatic and functional human whole blood assay. Crystallography studies further confirmed observed structure-activity relationship and LTA(4)H binding mode for analogs from the piperidine series.

Topics: Anti-Inflammatory Agents; Binding Sites; Crystallography, X-Ray; Enzyme Inhibitors; Epoxide Hydrolases; Humans; Piperazine; Piperazines; Piperidines; Structure-Activity Relationship

The asymmetric C-alkylation of chiral enamines derived from terminal epoxides and lithium 2,2,6-trialkylpiperidides has previously been shown to provide alpha-alkylated aldehydes by intermolecular nucleophilic substitution in good levels of asymmetric induction. We now report a computational study of the origins of asymmetric induction in these reactions. Computational modeling with density functional theory (B3LYP/6-31G(d)) agrees closely with the experimental observations. This stereoselectivity is attributed to a preferential conformation of the enamine and the piperidine ring that places the C-6 alkyl substituent in an axial position due to A(1, 3) strain. Preferential attack occurs away from the axial group, for steric reasons. The effects of changing the C-6 substituent from methyl to isopropyl were studied, and twist transition states were found to contribute significantly in the latter alkylations.

Topics: Aldehydes; Alkylation; Molecular Conformation; Piperidines

Here, we report our second-generation synthesis of 12 artificial glutamate analogs, starting from heterotricycle intermediates 3a-3d, readily prepared in three steps including tandem Ugi/Diels-Alder reactions. The new synthesis employs imidate intermediates for the deoxygenation of pyrrolidones (10a-10d to 6a-6d), and each advanced intermediate 6a-6d was diversified into three glutamate analogs (1a-1d, 5a-5d, 7a-7d) in 1-2 steps. In vitro electrophysiological assays revealed that the new piperidine-type analog 7c alters neuronal function with lower potency than 1a. Conversely, intracranial injection of 7c into mice produced a greater degree of hypoactivity than 1a. Our recent investigation has revealed that this series of compounds antagonizes AMPA-type glutamate receptor-mediated currents in a subtype selective manner. The more efficient syntheses of this novel set of neuroactive molecules will facilitate their pharmacological characterization.

Topics: Animals; Biological Products; Electrophysiological Phenomena; Glutamic Acid; Heterocyclic Compounds; Mice; Neurons; Piperidines; Pyrrolidinones; Receptors, AMPA

Dual-acting compounds that combine H(3) antagonism with anticholinesterase properties are currently emerging as a novel and promising therapeutic approach in the treatment of multifactorial disorders primarily characterized by cholinergic deficits such as Alzheimer's disease. A series of novel nonimidazole H(3) ligands was developed from the chemical manipulation of 1,1'-octa-, -nona-, and -decamethylene-bis-piperidines--H(3) antagonists that had been the subject of previous investigations. These compounds were evaluated for in vitro binding affinity, antagonistic potency, and selectivity at rodent and human histamine H(3) receptors, inhibitory activity at rat brain cholinesterase, and in vivo CNS access and cholinomimetic effects. Within the present series, the tetrahydroaminoacridine hybrid 18 stands out as one of the most attractive molecules, synergistically combining nanomolar and selective H(3) antagonism with remarkable anticholinesterase activity. From this original starting point, it is hoped that future investigations will lead to dual-acting compounds that can selectively enhance central cholinergic neurotransmission and thus facilitate the treatment of cognitive disorders.

Topics: Animals; Cholinesterase Inhibitors; Guinea Pigs; Histamine H3 Antagonists; Humans; Piperidines; Rats; Receptors, Histamine H3; Structure-Activity Relationship

A new method for the synthesis of 5-azaindole derivatives is reported. A [3+2] dipolar cycloaddition between nitriles and a 3,4-cyclopropanopiperidine followed by SeO(2) oxidation affords the target compounds in moderate to excellent yields. The divergent nature and cost effectiveness of this method makes it very suitable for combinatorial applications in the pharmaceutical industry.

Topics: Aza Compounds; Cyclopropanes; Indoles; Nitriles; Oxidation-Reduction; Piperidines; Pyridines

A series of spiro-azetidines and azetidinones has been evaluated as novel blockers of the T-type calcium channel (Ca(V)3.2) which is a new therapeutic target for the potential treatment of both inflammatory and neuropathic pain. Confirmation and optimization of the potency, selectivity and DMPK properties of leads will be described.

Topics: Animals; Azetidines; Calcium Channel Blockers; Calcium Channels, T-Type; Drug Design; Humans; Pain; Piperidines; Protein Binding; Rats; Spiro Compounds; Structure-Activity Relationship

Design, synthesis, and SAR of a series of 3H-spiro[isobenzofuran-1,4'-piperidine] based compounds as potent, selective and orally bioavailable melanocortin subtype-4 receptor (MC4R) agonists are disclosed.

Topics: Administration, Oral; Animals; Brain; Crystallography, X-Ray; Drug Evaluation, Preclinical; Humans; Molecular Conformation; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 4; Spiro Compounds; Structure-Activity Relationship

A new tetracyclic bis-piperidine alkaloid, neopetrosiamine A (1), has been extracted from the marine sponge Neopetrosiaproxima collected off the west coast of Puerto Rico. The structure of compound 1 was elucidated by analysis of spectroscopic data coupled with careful comparisons of its (1)H and (13)C NMR data with those of a well-known 3-alkylbis-piperidine alkaloid model. The new alkaloid displayed strong in vitro cytotoxic activity against a panel of cancer cell lines as well as in vitro inhibitory activity against the pathogenic microbes Mycobacterium tuberculosis and Plasmodium falciparum.

Topics: Alkaloids; Animals; Caribbean Region; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Magnetic Resonance Spectroscopy; Molecular Conformation; Mycobacterium tuberculosis; Oceans and Seas; Piperidines; Plasmodium falciparum; Porifera

Small molecules behaving as CD4 mimics were previously reported as HIV-1 entry inhibitors that block the gp120-CD4 interaction and induce a conformational change in gp120, exposing its co-receptor-binding site. A structure-activity relationship (SAR) study of a series of CD4 mimic analogs was conducted to investigate the contribution from the piperidine moiety of CD4 mimic 1 to anti-HIV activity, cytotoxicity, and CD4 mimicry effects on conformational changes of gp120. In addition, several hybrid molecules based on conjugation of a CD4 mimic analog with a selective CXCR4 antagonist were also synthesized and their utility evaluated.

Topics: Biomimetic Materials; CD4 Antigens; Cell Line; HIV Envelope Protein gp120; HIV Fusion Inhibitors; Humans; Piperidines; Protein Binding; Receptors, CXCR4; Structure-Activity Relationship

The catalytic dynamic resolution (CDR) of rac-2-lithio-N-Boc-piperidine using chiral ligand 8 or its diastereomer 9 in the presence of TMEDA has led to the highly enantioselective syntheses of both enantiomers of 2-substituted piperidines using a wide range of electrophiles. The CDR has been applied to the synthesis of (R)- and (S)-pipecolic acid derivatives, (+)-beta-conhydrine, (S)-(+)-pelletierine, and (S)-(-)-ropivacaine and the formal synthesis of (-)-lasubine II and (+)-cermizine C.

Topics: Alkaloids; Amides; Catalysis; Heterocyclic Compounds, 2-Ring; Lithium; Molecular Conformation; Organometallic Compounds; Pipecolic Acids; Piperidines; Quinolizines; Ropivacaine; Stereoisomerism; Thermodynamics

Addition of 5-alkylaminopenta-2,4-dienals onto N-acyliminium ions, generated in situ from α-hydroxycarbamates derived from pyrrolidine or piperidine, in the presence of zinc triflate, followed by dehydrative cyclization, allowed the formation of pyridinium salts substituted at their 3-position by a five- or six-membered nitrogen heterocycle. Subsequent N-dealkylation of the pyridinium moiety and deprotection of the secondary amine or reduction of the carbamate function led to (±)-nicotine and analogs.

Topics: Acrylates; Alkylation; Amines; Imines; Ions; Molecular Structure; Nicotine; Piperidines; Pyridinium Compounds; Pyrrolidines

Addition of α-arylmethylidene- or α-alkylidene-β-keto ester enolate to N-activated aldimines via the imino aldol pathway followed by intramolecular aza-Michael reaction in a domino fashion has been developed, and a highly diastereoselective route to substituted piperidines is reported. Enantiopure piperidines are synthesized from chiral sulfinyl imines. Formation and the observed stereoselectivity of the products have been rationalized by mechanistic and computational studies.

Topics: Imines; Piperidines; Stereoisomerism; Substrate Specificity

A novel approach to 2,4,5-trisubstituted piperidines is reported, involving the 6-exo cyclization of stabilized radicals onto α,β-unsaturated esters. Only two of the four possible diastereoisomers are observed, with diastereomeric ratios ranging from 3:2 to 40:1 when the radical stabilizing group is vinyl or phenyl. Cyclization of a (triethylsilyl)vinyl-stabilized radical gives the corresponding piperidine radical as a single diastereoisomer that may either be trapped by tributyltin hydride to afford the 2,4,5-trisubstituted piperidine or undergo a second 5-endo cyclization onto the (triethylsilyl)vinyl substituent to produce the 3,5,7-trisubstituted octahydro[2]pyrindene as a single diastereoisomer.

Topics: Bromine; Cyclization; Piperidines; Stereoisomerism; Substrate Specificity

Topics: Catalysis; Gold; Molecular Structure; Piperidines; Stereoisomerism

A series of chiral non-racemic dexoxadrol analogues with various substituents in position 4 of the piperidine ring was synthesized and pharmacologically evaluated. Only the enantiomers having (S)-configuration at the 2-position of the piperidine ring and 4-position of the dioxolane ring were considered. Key steps in the synthesis were an imino-Diels-Alder reaction of enantiomerically pure imine (S)-13, which had been obtained from d-mannitol, with Danishefsky's Diene 14 and the replacement of the p-methoxybenzyl protective group with a Cbz-group. It was shown that (S,S)-configuration of the ring junction (position 2 of the piperidine ring and position 4 of the dioxolane ring) and axial orientation of the C-4-substituent ((4S)-configuration) are crucial for high NMDA receptor affinity. 2-(2,2-Diphenyl-1,3-dioxolan-4-yl)piperidines with a hydroxy moiety ((S,S,S)-5, K(i)=28nM), a fluorine atom ((S,S,S)-6, WMS-2539, K(i)=7nM) and two fluorine atoms ((S,S)-7, K(i)=48nM) in position 4 represent the most potent NMDA antagonists with high selectivity against σ(1) and σ(2) receptors and the polyamine binding site of the NMDA receptor. The NMDA receptor affinities of the new ligands were correlated with their electrostatic potentials, calculated gas phase proton affinities (negative enthalpies of deprotonation) and dipole moments. According to these calculations decreasing proton affinity and increasing dipole moment are correlated with decreasing NMDA receptor affinity.

Topics: Animals; Binding Sites; Brain; Dioxolanes; Models, Theoretical; Piperidines; Receptors, N-Methyl-D-Aspartate; Static Electricity; Stereoisomerism; Structure-Activity Relationship; Swine

The first stereoselective synthesis of (2S,3R,6S)-6-methyl-3-hydroxy-piperidine-2-carboxylic acid (-)-6 and (2R,3R,6S)-6-methyl-(2-hydroxymethyl)-piperidine-3-ol (+)-7 was achieved starting from readily available d-glucose in 14 steps with 17% overall yield for both the compounds. The key feature of the present strategy includes the Wittig-olefination for the preparation of required conjugated keto-azide 9 and construction of 2,3,6-trisubstituted piperidine skeleton 11 by applying intramolecular reductive cyclization of conjugated keto-azide intermediate. The glycosidase inhibitory activity of compounds 6 and 7 towards several glycosidases has been evaluated.

Topics: Cyclization; Enzyme Inhibitors; Geobacillus; Glycoside Hydrolases; Oxidation-Reduction; Pipecolic Acids; Piperidines; Saccharomyces cerevisiae; Stereoisomerism

We report here the construction of quinolizidine ring systems by intramolecular cyclization of suitable functionalized piperidines via a reductive amination sequence. This reaction proceeds with a total stereocontrol at C4. The preparation of the piperidine precursors is based on a chain elongation of a piperidine aldehyde either by aldolization or by Wittig reaction. We applied this second route to the total synthesis of quinolizidine (-)-217A from (S)-methyl 2-((S)-1-((R)-1-phenylethyl)piperidin-2-yl)propanoate 5.

Topics: Aldehydes; Molecular Structure; Piperidines; Quinolizines; Stereoisomerism

Positive allosteric modulation of metabotropic glutamate receptor 5 (mGluR5) is regarded as a potential novel treatment for schizophrenic patients. Herein we report the synthesis and SAR of 4-aryl piperazine and piperidine amides as potent mGluR5 positive allosteric modulators (PAMs). Several analogs have excellent activity and desired drug-like properties. Compound 2b was further characterized as a PAM using several in vitro experiments, and produced robust activity in several preclinical animal models.

Topics: Allosteric Regulation; Amides; Humans; Microsomes, Liver; Piperazine; Piperazines; Piperidines; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Schizophrenia; Structure-Activity Relationship

Serotonin (5-hydroxytryptamine, 5-HT) is an important signalling molecule in the human body. The 5-HT(4) serotonin receptor, coupled to the G protein G(s), plays important physiological and pathophysiological roles in the heart, urinary bladder, gastrointestinal tract and the adrenal gland. Both 5-HT(4) antagonists and agonists have been developed in the aim to treat diseases in these organs. 5-HT(4) agonists might have beneficial effects in the central nervous system (CNS) and therefore, 5-HT(4) antagonists might cause CNS side effects. In this study, we have developed new amphoteric 5-HT(4) antagonists. A series of cyclic indole amide derivatives possessing an oxazine ring and a piperidine alkane carboxylic acid side chain and the corresponding prodrug esters were synthesized and their binding to 5-HT(4) receptors and antagonist properties were evaluated. In addition, an indole ester without the oxazine ring and the corresponding indole amide derivatives were also tested. Octanol-water distribution (LogD(Oct7.4)) was tested for some of the synthesized ligands. The main structure-affinity characteristics of the 5-HT(4) compounds tested were that the prodrug esters show higher affinity than their corresponding free acids, indole esters show higher affinity than the corresponding amides and ligands containing the oxazine ring in the indole skeleton show higher affinity than indole derivatives not containing the ring. One representative prodrug ester and its corresponding free acid were tested for binding on a panel of receptors and showed preserved selectivity for the 5-HT(4) receptor. These new molecules may be useful to target peripheral 5-HT(4) receptors.

Topics: Amides; Esters; Humans; Indoles; Ligands; Oxazines; Piperidines; Prodrugs; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Antagonists; Structure-Activity Relationship

We have investigated important intermediates and key transition states of the organocatalyzed Knoevenagel condensation using density functional theory and two different basis sets (6-31 G(d,p) and 6-311++G(2df,2pd)), both in gas phase and simulating the bulk solvent (pyridine) using the PCM method. Calculated structures for reactants, intermediates, and key transition states suggest that the secondary amine catalyst is essential, both for activating the aldehyde for nucleophilic attack, and in the possible decarboxylation pathways. The calculated results are shown to agree with available experimental information. On the basis of the results obtained, the studied mechanism may be important in the understanding of vinylphenol production during malting and brewing of wheat and barley grains.

Topics: Benzaldehydes; Beverages; Carboxylic Acids; Catalysis; Food; Malonates; Models, Molecular; Molecular Conformation; Phenols; Piperidines; Proline; Quantum Theory; Solvents

17beta-Hydroxysteroid dehydrogenase type 3 (17beta-HSD3) is expressed at high levels in the testes and seminal vesicles but has also been shown to be present in prostate tissue, suggesting its potential involvement in both gonadal and non-gonadal testosterone biosynthesis. The role of 17beta-HSD3 in testosterone biosynthesis makes this enzyme an attractive molecular target for small molecule inhibitors for the treatment of prostate cancer. Here we report the design of selective inhibitors of 17beta-HSD3 as potential anti-cancer agents. Due to 17beta-HSD3 being a membrane-bound protein a crystal structure is not yet available. A homology model of 17beta-HSD3 has been built to aid structure-based drug design. This model has been used with docking studies to identify a series of lead compounds that may give an insight as to how inhibitors interact with the active site. Compound 1 was identified as a potent selective inhibitor of 17beta-HSD3 with an IC(50)=700nM resulting in the discovery of a novel lead series for further optimisation. Using our homology model as a tool for inhibitor design compound 5 was discovered as a novel potent and selective inhibitor of 17beta-HSD3 with an IC(50) approximately 200nM.

Topics: 17-Hydroxysteroid Dehydrogenases; Azepines; Catalytic Domain; Cell Line; Drug Design; Enzyme Inhibitors; Humans; Hydrophobic and Hydrophilic Interactions; Models, Molecular; Piperidines; Structural Homology, Protein

Previous measurements of conifer alkaloids have revealed significant variation attributable to many sources, environmental and genetic. The present study takes a complementary and intensive, common garden approach to examine genetic variation in Pinus ponderosa var. ponderosa alkaloid production. Additionally, this study investigates the potential trade-off between seedling growth and alkaloid production, and associations between topographic/climatic variables and alkaloid production.. Piperidine alkaloids were quantified in foliage of 501 nursery seedlings grown from seed sources in west-central Washington, Oregon and California, roughly covering the western half of the native range of ponderosa pine. A nested mixed model was used to test differences among broad-scale regions and among families within regions. Alkaloid concentrations were regressed on seedling growth measurements to test metabolite allocation theory. Likewise, climate characteristics at the seed sources were also considered as explanatory variables.. Quantitative variation from seedling to seedling was high, and regional variation exceeded variation among families. Regions along the western margin of the species range exhibited the highest alkaloid concentrations, while those further east had relatively low alkaloid levels. Qualitative variation in alkaloid profiles was low. All measures of seedling growth related negatively to alkaloid concentrations on a natural log scale; however, coefficients of determination were low. At best, annual height increment explained 19.4 % of the variation in ln(total alkaloids). Among the climate variables, temperature range showed a negative, linear association that explained 41.8 % of the variation.. Given the wide geographic scope of the seed sources and the uniformity of resources in the seedlings' environment, observed differences in alkaloid concentrations are evidence for genetic regulation of alkaloid secondary metabolism in ponderosa pine. The theoretical trade-off with seedling growth appeared to be real, however slight. The climate variables provided little evidence for adaptive alkaloid variation, especially within regions.

Topics: Alkaloids; Climate; Genetic Variation; Geography; Least-Squares Analysis; Likelihood Functions; Models, Biological; Pacific States; Pinus ponderosa; Piperidines; Plant Extracts; Plant Leaves; Seedlings

The diphenylsulfonyl sulfonamide scaffold represented by 1 (WAY-316606) are small molecule inhibitors of the secreted protein sFRP-1, an endogenous antagonist of the secreted glycoprotein Wnt. Modulators of the Wnt pathway have been proposed as anabolic agents for the treatment of osteoporosis or other bone-related disorders. Details of the structure-activity relationships and biological activity from the first structural class of this scaffold will be discussed.

Topics: Animals; Cell Line, Tumor; Genes, Reporter; Humans; Inhibitory Concentration 50; Intracellular Signaling Peptides and Proteins; Isomerism; Mice; Molecular Structure; Piperidines; Protein Binding; Proteins; Signal Transduction; Skull; Structure-Activity Relationship; Sulfanilamides; Wnt Proteins

Unprecedented hydroformylation of homoallylic azides combined with useful one-pot operations provides an expeditive access to alkaloids.

Topics: Alkaloids; Azides; Piperidines; Time Factors

alpha-cyanation of N-protected cyclic amines was achieved using a direct electrochemical method. Unsubstituted N-protected cyclic amines were easily cyanated at the alpha-position using an undivided cell in high yields; moreover, alpha-cyanation of alpha'-substituted pyrrolidine and alpha'-,beta'- or gamma-substituted piperidines smoothly proceeded in high yield and with high to excellent diastereoselectivity. alpha-Substituted N-cyano-pyrrolidines and -piperidines were also cyanated at the more substituted position (the alpha-position) using a divided cell with high yield and high regioselectivity.

Topics: Amines; Cyanates; Electrochemistry; Molecular Structure; Oxidation-Reduction; Piperidines; Pyrrolidines; Stereoisomerism

Although, there have been many published bacterial strains aerobically degrading the heterocyclic amine compounds, only one strain to date has been reported to degrade pyrrolidine under denitrifying conditions. In this study, denitrifying bacteria degrading pyrrolidine and piperidine were isolated from diverse geological and ecological origins through selective enrichment procedures. Based on the comparative sequence results of 16S rRNA genes, 30 heterocyclic amine-degrading isolates were grouped into ten distinct phylotypes belonging to the genera Thauera, Castellaniella, Rhizobium, or Paracoccus of the phylum Proteobacteria. The representative isolates of individual phylotypes were characterized by phylogenetic, phenotypic and chemotaxonomical traits, and dissimilatory nitrite reductase gene (nirK and nirS). All isolates completely degraded pyrrolidine and piperidine under both aerobic and anaerobic conditions. The anaerobic degradations were coupled to nitrate reduction. A metabolic pathway for the anaerobic degradation of pyrrolidine was proposed on the basis of enzyme activities implicated in pyrrolidine metabolism from three isolates. The three key pyrrolidine-metabolizing enzymes pyrrolidine dehydrogenase, gamma-aminobutyrate/alpha-ketoglutarate aminotransferase, and succinic semialdehyde dehydrogenase, were induced by heterocyclic amines under denitrifying conditions. They were also induced in cells grown aerobically on heterocyclic amines, suggesting that the anaerobic degradation of pyrrolidine shares the pathway with aerobic degradation.

Topics: Anaerobiosis; Biodegradation, Environmental; Genes, rRNA; Nitrates; Nitrite Reductases; Phenotype; Phylogeny; Piperidines; Proteobacteria; Pyrrolidines; RNA, Bacterial; RNA, Ribosomal, 16S

Recently, we disclosed a series of potent pyrimidine benzamide-based thrombopoietin receptor agonists. Unfortunately, the structural features required for the desired activity conferred physicochemical properties that were not favorable for the development of an oral agent. The physical properties of the series were improved by replacing the aminopyrimidinyl group with a piperidine-4-carboxylic acid moiety. The resulting compounds possessed favorable in vivo pharmacokinetic properties, including good bioavailability.

Topics: Administration, Oral; Animals; Benzoates; Biological Availability; Caco-2 Cells; Humans; Hydrazines; Piperidines; Pyrazinamide; Pyrazoles; Pyrimidines; Rats; Receptors, Thrombopoietin

Stable, water-soluble aminosugar staurosporine, K-252a and rebeccamycin analogs have been prepared by nucleophilic opening of C(2)-symmetric N-activated bis-aziridines by bis-indolylmaleimides. This divergent strategy allows the synthesis of unsymmetrical substituted derivatives and provides an easy access to the piperidine and pyrrolidine analogs.

Topics: Aza Compounds; Aziridines; Drug Stability; Piperidines; Pyrrolidines; Solubility; Staurosporine

The aim of this study was to investigate (1) whether Rhodobryum roseum, a traditional Chinese medicine used to treat cardiac disease, can protect myocardium damage due to isoproterenol-induced injury, (2) whether the cardioprotective effect of the R. roseum extract is related to its antioxidant activity, and (3) to identify the active components of R. roseum using the oxidant-mediated injury in cardiomyocytes. R. roseum was extracted with 95% EtOH (RE-95), 50% EtOH (RE-50) and water (Re-H2O) and the rats were treated orally for 11 days at doses of 250 mg and 63 mg/kg respectively after cardiac necrosis was induced by administering ISO subcutaneously at a dose of 85 mg/kg body weight. Levels of marker enzymes (LDH, GOT and CK) were assessed in serum whilst the antioxidant parameters, superoxide dismutase (SOD), and malondialdehde (MDA) were assayed in heart homogenate. Significant myocardial necrosis, depletion of endogenous antioxidants and an increase in serum levels of marker enzymes was observed in ISO-treated animals when compared with the normal animals. The RE-50 elicited a significant cardioprotective effect by lowering the levels of serum marker enzymes, lipid peroxidation (MDA). To extend this work, we sought to investigate the antioxidant effects of the components of R. roseum, using the neonatal rat cardiomyocytes model of H2O2-induced oxidant injury. Among the four major components, piperine and methyl piperate significantly reduced the medium level of CK and LDH at a variety of dosages. Moreover, piperine and methyl piperate significantly attenuated 2',7'-dichlorofluorescein (DCF) fluorescence by 63.9% and 52.6%, respectively. The present findings demonstrate that the cardioprotective effects of extracted R. roseum in ISO-induced oxidative damage may be due to an augmentation of the endogenous antioxidants and inhibition of lipid peroxidation of the membranes. Moreover, its components piperine and methyl piperate exert significant protectective effects on cardiac myocytes.

Topics: Adrenergic beta-Agonists; Animals; Animals, Newborn; Antioxidants; Aspartate Aminotransferases; Bryophyta; Cardiomyopathies; Cell Survival; Creatine Kinase; Dioxolanes; Free Radical Scavengers; Hydrogen Peroxide; Hydroxyl Radical; Isoproterenol; L-Lactate Dehydrogenase; Myocytes, Cardiac; Oxidants; Oxidative Stress; Piperidines; Rats

Several series of CCR5 antagonists have been discovered by derivatization at the N-terminal of the piperidine ring of the core template 2. Some derivatives exhibited potent inhibition against HIV-1infection. The pharmacokinetic properties of the lead compounds 11a, 14a, 15b, and 16b have been evaluated in vivo.

Topics: Animals; Anti-HIV Agents; CCR5 Receptor Antagonists; Chemistry, Pharmaceutical; CHO Cells; Cricetinae; Cricetulus; Drug Design; HIV Infections; HIV-1; Inhibitory Concentration 50; Molecular Conformation; Piperidines; Protein Structure, Tertiary; Rats; Receptors, CCR5

Topics: Ethers; Humans; Ligands; Molecular Structure; Piperidines; Receptors, Histamine H3

Hydrogen migration reactions in piperidine radicals and their protonated counterparts were studied by quantum chemical calculations. G3B3 and G3(MP2)-RAD levels of theory were used as reference procedures in order to evaluate the efficiency of other computational models. In the gas phase, the 1,4-[N<-->C]-H and 1,4-[C<-->C]-H shifts are the most feasible rearrangements in the piperidine radical cation and neutral piperidine radical, respectively. However, if one explicit water molecule is well placed to facilitate hydrogen migrations, the 1,2-[N<-->C]-H shift becomes the most favorable process in both cases. Three different water-catalyzed [N<-->C]-H shift mechanisms were considered for piperidine radical cation, and only one is found to be operative in the case of neutral piperidine radical. We found that explicit solvation and protonation of piperidine-derived radicals strongly influence the overall mechanism of hydrogen migration reactions.

Topics: Anions; Cations; Computer Simulation; Hydrogen; Kinetics; Molecular Structure; Nitrogen; Piperidines; Quantum Theory

To characterize the binding sites and the mechanisms of inhibition of bupropion on muscle-type nicotinic acetylcholine receptors (AChRs), structural and functional approaches were used. The results established that bupropion (a) inhibits epibatidine-induced Ca(2+) influx in embryonic muscle AChRs, (b) inhibits adult muscle AChR macroscopic currents in the resting/activatable state with approximately 100-fold higher potency compared to that in the open state, (c) increases the desensitization rate of adult muscle AChRs from the open state and impairs channel opening from the resting state, (d) inhibits binding of [(3)H]TCP and [(3)H]imipramine to the desensitized/carbamylcholine-bound Torpedo AChR with higher affinity compared to the resting/alpha-bungarotoxin-bound AChR, (e) binds to the Torpedo AChR in either state mainly by an entropy-driven process, and (f) interacts with a binding domain located between the serine (position 6') and valine (position 13') rings, by a network of van der Waals, hydrogen bond, and polar interactions. Collectively, our data indicate that bupropion first binds to the resting AChR, decreasing the probability of ion channel opening. The remnant fraction of open ion channels is subsequently decreased by accelerating the desensitization process. Bupropion interacts with a luminal binding domain shared with PCP that is located between the serine and valine rings, and this interaction is mediated mainly by an entropy-driven process.

Topics: Animals; Binding, Competitive; Biological Transport; Bridged Bicyclo Compounds, Heterocyclic; Bupropion; Calcium; Cell Line; Drug Discovery; Electric Conductivity; Humans; Imipramine; Immobilized Proteins; Ion Channel Gating; Kinetics; Mice; Models, Molecular; Muscles; Nicotinic Antagonists; Piperidines; Protein Binding; Protein Conformation; Pyridines; Receptors, Nicotinic; Thermodynamics; Torpedo

A series of 1-substituted-N-(4,5-dihydro-1-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl) piperidine-4-carboxamides has been synthesized and evaluated for positive inotropic activity by measuring left atrium stroke volume in isolated rabbit-heart preparations. Some of these derivatives exhibited favorable activity compared with the standard drug, milrinone, among which 1-(2-fluorobenzyl)-N-(4,5-dihydro-1-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)piperidine-4-carboxamide 6a was the most potent, increasing stroke volume by 11.92+/-0.35% (milrinone: 6.36+/-0.13%) at 1x10(-4)M.

Topics: Animals; Cardiotonic Agents; Chemistry, Organic; Chemistry, Pharmaceutical; Drug Design; Heart; Isonipecotic Acids; Milrinone; Models, Chemical; Myocardium; Piperidines; Quinolines; Rabbits

We report an approach that allows the efficient synthesis of the designed sphingoid base analogues in which the conformational restriction is introduced by incorporation of a cyclic moiety between the 2-amino group and the C-4 carbon atom of the sphingoid base. Our synthesis features a tandem enyne/diene-ene metathesis reaction that provides access to the designed framework. The diene moiety of the metathesis product is stereoselectively elaborated for the synthesis of the designed analogues. The preliminary biological evaluation indicates that the designed constrained analogues are much more effective than prototype natural sphingoid bases at inhibiting cancer cell growth.

Topics: Drug Design; Molecular Conformation; Piperidines; Sphingosine

Endocannabinoids are lipid signaling molecules that regulate a wide range of mammalian behaviors, including pain, inflammation, and cognitive/emotional state. The endocannabinoid anandamide is principally degraded by the integral membrane enzyme fatty acid amide hydrolase (FAAH), and there is currently much interest in developing FAAH inhibitors to augment endocannabinoid signaling in vivo. Here, we report the discovery and detailed characterization of a highly efficacious and selective FAAH inhibitor, PF-3845. Mechanistic and structural studies confirm that PF-3845 is a covalent inhibitor that carbamylates FAAH's serine nucleophile. PF-3845 selectively inhibits FAAH in vivo, as determined by activity-based protein profiling; raises brain anandamide levels for up to 24 hr; and produces significant cannabinoid receptor-dependent reductions in inflammatory pain. These data thus designate PF-3845 as a valuable pharmacological tool for in vivo characterization of the endocannabinoid system.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Brain; Crystallography, X-Ray; Endocannabinoids; Enzyme Inhibitors; Humans; Male; Pain; Piperazine; Piperazines; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Structure-Activity Relationship; Urea

The title compound, piperidinium 6-amino-3-methyl-5-nitroso-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ide 6-amino-3-methyl-5-nitrosopyrimidine-2,4(1H,3H)-dione, C(5)H(12)N(+).C(5)H(5)N(4)O(3)(-).C(5)H(6)N(4)O(3), (I), crystallizes with Z' = 2 in the space group P1. There is an intramolecular N-H...O hydrogen bond in each pyrimidine unit and within the selected asymmetric unit the six independent components are linked by 11 hydrogen bonds, seven of the N-H...O type and four of the N-H...N type. These six-component aggregates are linked into sheets by five further hydrogen bonds, three of the N-H...O type and one each of the N-H...N and C-H...O types.

Topics: Crystallography, X-Ray; Hydrogen Bonding; Molecular Structure; Piperidines; Pyrimidinones

An asymmetric synthesis of (+)-castanospermine is presented in which enol ether metathesis-hydroboration/oxidation is used for stereoselective installation of the trans-trans hydroxyl groups on the piperidine ring of the alkaloid.

Topics: Alkaloids; Catalysis; Cyclization; Ether; Ethers; Indolizines; Oxidation-Reduction; Piperidines; Stereoisomerism

PC-1 (NPP-1) inhibitors may be useful as therapeutics for the treatment of CDDP (calcium pyrophosphate dehydrate) deposition disease and osteoarthritis. We have identified a series of potent quinazolin-4-piperidin-4-ethyl sulfamide PC-1 inhibitors. The series, however, suffers from high affinity binding to hERG potassium channels, which can cause drug-induced QT prolongation. We used a hERG homology model to identify potential key interactions between our compounds and hERG, and the information gained was used to design and prepare a series of quinazolin-4-piperidin-4-methyl sulfamides that retain PC-1 activity but lack binding affinity for hERG.

Topics: Drug Design; Enzyme Inhibitors; Ether-A-Go-Go Potassium Channels; Humans; Long QT Syndrome; Osteoarthritis; Phosphoric Diester Hydrolases; Piperidines; Protein Binding; Pyrophosphatases; Quinazolines; Sulfonamides

A series of alpha-sulfone piperidine hydroxamate TACE inhibitors 11a-n bearing a quinolinyl methyl P1' group was prepared, and their activity was compared to analogous alpha- and beta-sulfone piperidine hydroxamates with a butynyloxy P1' group. The quinolinyl methyl P1' group affords increased inhibitory enzyme activity relative to the corresponding butynyloxy P1' analogs in the alpha-sulfone piperidine hydroxamate series, and greater selectivity than the corresponding butynyloxy P1' analogs in the beta-sulfone piperidine hydroxamate series.

Topics: ADAM Proteins; ADAM17 Protein; Animals; Humans; Hydroxamic Acids; Mice; Piperidines; Protease Inhibitors; Sulfones

Amantadine has been used for decades as an inhibitor of the influenza A virus M2 protein (AM2) in the prophylaxis and treatment of influenza A infections, but its clinical use has been limited by its central nervous system (CNS) side effects as well as emerging drug-resistant strains of the virus. With the goal of searching for new classes of M2 inhibitors, a structure-activity relation study based on 2-[3-azaspiro(5,5)undecanol]-2-imidazoline (BL-1743) was initiated. The first generation BL-1743 series of compounds has been synthesized and tested by two-electrode voltage-clamp (TEV) assays. The most active compound from this library, 3-azaspiro[5,5]undecane hydrochloride (9), showed an IC(50) as low as 0.92 +/- 0.11 microM against AM2, more than an order of magnitude more potent than amantadine (IC(50) = 16 microM). (15)N and (13)C solid-state NMR was employed to determine the effect of compound 9 on the structure and dynamics of the transmembrane domain of AM2 (AM2-TM) in phospholipid bilayers. Compared to amantadine, spiro-piperidine 9 (1) induces a more homogeneous conformation of the peptide, (2) reduces the dynamic disorder of the G34-I35 backbone near the water-filled central cavity of the helical bundle, and (3) influences the dynamics and magnetic environment of more residues within the transmembrane helices. These data suggest that spiro-piperidine 9 binds more extensively with the AM2 channel, thus leading to stronger inhibitory potency.

Topics: Amantadine; Animals; Antiviral Agents; Humans; Imidazoles; Influenza A virus; Oocytes; Piperidines; Protein Conformation; Spiro Compounds; Structure-Activity Relationship; Viral Matrix Proteins; Xenopus

In the scope of the research program aiming to perform the synthesis and pharmacological evaluation of novel possible anti-inflammatory compounds, in this manuscript, we report the synthesis of novel carboxamide 9a-d and thioamide 10a-d derivatives from the benzophenone and piperidine nucleus. Variation in the functional group at the N-terminal of piperidine led to two sets of compounds, bearing the carboxamide and thioamide, respectively. The characterization of this new class of compounds was performed with (1)H-NMR, LC-MS, IR, and elemental analysis. The newly synthesized compounds were screened for their anti-inflammatory activity by carrageenan-induced foot pad oedema assay and were compared with a standard drug. All the compounds exhibited anti-inflammatory activity at the dose of 30 mg/kg p.o. with varying degree from 52 to 67% inhibition of oedema. The compounds 9d and 10d with dichloro and fluoro substitution showed more potent activity at 30 mg/kg p.o. than the standard drug.

Topics: Animals; Anti-Inflammatory Agents; Benzophenones; Carrageenan; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Edema; Male; Molecular Structure; Piperidines; Rats; Rats, Inbred Strains; Structure-Activity Relationship

Topics: Aldehydes; Aza Compounds; Butadienes; Catalysis; Crystallography, X-Ray; Electrons; Molecular Conformation; Piperidines; Stereoisomerism

An efficient and flexible synthetic approach to the core structures of pinnaic acid and halichlorine is described using spirocyclic nitrone 4 as a key intermediate. 1,3-Dipolar cycloaddition of 4 with dipolarophile 8 provides access to the azaspirocyclic core of pinnaic acid 5 while the spiroquinolizidine core of halichlorine 6 has been synthesised via cycloaddition of 4 with dipolarophile 29. Nitrone 4 is accessed by oxidative ring opening of isoxazolidine 9. The utility of this synthetic strategy in the synthesis of C5 substituted analogues of pinnaic acid is also demonstrated.

Topics: Alkaloids; Crystallography, X-Ray; Nitrogen Oxides; Oxidation-Reduction; Piperidines; Quinazolines; Spiro Compounds; Stereoisomerism

Two efficient and scaleable synthetic routes to previously unknown bifunctional tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate are described. This compound and related intermediates described herein are useful for further selective derivation on the azetidine and cyclobutane rings providing a convenient entry point to novel compounds accessing chemical space complementary to piperidine ring systems.

Topics: Aza Compounds; Molecular Structure; Piperidines; Spiro Compounds; Stereoisomerism

3,3-Disubstituted piperidine-derived trisubstituted urea entA-2b was discovered as a highly potent and selective soluble epoxide hydrolase (sEH) inhibitor. Despite the good compound oral exposure, excellent sEH inhibition in whole blood, and remarkable selectivity, compound entA-2b failed to lower blood pressure acutely in spontaneously hypertensive rats (SHRs). This observation further challenges the premise that sEH inhibition can provide a viable approach to the treatment of hypertensive patients.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Blood Pressure; Epoxide Hydrolases; Humans; Hypertension; Models, Molecular; Piperidines; Protein Binding; Rats; Rats, Inbred SHR; Structure-Activity Relationship; Urea

The kinetics of enantiomerization and dynamic thermodynamic resolution (DTR) of N-Boc-2-lithiopiperidine have been measured, revealing significant differences in enthalpy and entropy for these processes and a role for the achiral ligand TMEDA; the racemization and the DTR are catalytic and first order in [TMEDA], and this has implications for asymmetric synthesis with chiral organolithiums.

Topics: Catalysis; Ethylenediamines; Kinetics; Piperidines; Stereoisomerism; Thermodynamics

The symmetrically connected spiro[[2]benzopyran-1,4'-piperidines] 1 are highly potent and selective sigma(1) receptor ligands. Changing the position of the spirocyclic nitrogen atom led to the unsymmetrically connected spiro[[2]benzopyran-1,3'-piperidines] 2 with a reduced distance between the aromatic system and the basic nitrogen atom. The synthesis of 2 was performed by halogen-metal exchange at the aryl bromide 3 followed by addition to the piperidone 5 and intramolecular transacetalization. The yield of 2a was considerably improved by transmetallation of the aryllithium intermediate 4a with CeCl(3) (4c). The cis and trans diastereomers cis-2 and trans-2 were separated and characterized by nuclear Overhauser effect. After removal of the benzyl group, the secondary amine 2b was alkylated with various alkyl and arylalkyl halides. The sigma(1) and sigma(2) receptor affinity of the spirocyclic piperidines 2 were determined with receptor binding studies. Compared with the spirocyclic piperidines 1, the unsymmetrically connected piperidines 2 show remarkably reduced sigma(1) receptor affinities, whereas the selectivity over sigma(2) and NMDA receptors was retained. A stereoselective interaction of the sigma(1) receptor protein with the cis- or trans-configured spirocyclic compounds 2 was not observed. It was shown that alkyl residues at the N-atom can replace the lipophilic N-arylalkyl groups and interact with the primary hydrophobic binding site of the sigma(1) receptor protein.

Topics: Animals; Guinea Pigs; Molecular Structure; Piperidines; Protein Binding; Rats; Receptors, sigma; Spiro Compounds; Structure-Activity Relationship

Total synthesis of the Galbulimima alkaloid G. B. 13 was achieved utilizing a functionalized pyridine moiety as a piperidine surrogate. Key to the success of the synthesis was the development of an unprecedented rhodium-catalyzed 1,2-addition of an arylboronic ester into an unactivated ketone.

Topics: Alkaloids; Boron; Catalysis; Esters; Ketones; Models, Molecular; Molecular Conformation; Oxidation-Reduction; Piperidines; Pyridines; Rhodium

The reaction of 2-oxo-N-arylpropanehydrazonoyl chlorides 3a-e with 3-methyl-2-benzofurancarboxylic acid hydrazide (7) furnished N-(aryl)propanehydrazonoyl chlorides 8a-e. X-Ray of 8c revealed the (1Z,2E) configuration of structure 8. Nucleophilic substitution reaction of 8a or 8d with piperidine resulted in the formation of 1-(piperidin-1-yl)-N(2)-arylamidrazones 9a, b. The X-ray diffraction of 9b showed its (1E,2E) configuration and it confirmed the stereoselectivity of the latter reaction. (1E,2Z,3E)-1-(Piperidin-1-yl)-1-(arylhydrazono)-2-[(3-methylbenzofuran-2-oyl)hydrazono]-4-arylbut-3-enes 11 were synthesized in stereoselective reaction from 8 or alternatively from 9. X-ray analysis of 11b showed a conversion of configuration respect to 8d or 9b. X-Ray analysis of 9b and 11b revealed the role of hydrogen interactions in the stereochemistry of their solid state structure. The in vitro antimicrobial activity of the newly synthesized compounds demonstrated an excellent growth inhibition of compounds 9 and 11 against clinically isolated strains of human fungal pathogens and exhibited a significant potency against gram-positive bacteria. Griseofulvin and Amoxicilline were used as references for antifungal and antibacterial screening. The effect of most potent antifungal compound 9b on morphological features of Aspergillus fumigatus and Candida albicans using image analyzer was studied. Furthermore, the effect of 9b on the ultra-structures of the latter fungi was occurred by transmission electron microscope.

Topics: Amides; Anti-Infective Agents; Antifungal Agents; Bacteria; Benzofurans; Crystallography, X-Ray; Fungi; Humans; Hydrazones; Microbial Sensitivity Tests; Molecular Structure; Piperidines; Stereoisomerism

Piperazinyl-glutamate-pyrimidines were prepared with oxygen, nitrogen, and sulfur substitution at the 4-position of the pyrimidine leading to highly potent P2Y12 antagonists. In particular, 4-substituted piperidine-4-pyrimidines provided compounds with exceptional potency. Pharmacokinetic and physicochemical properties were fine-tuned through modifications at the 4-position of the piperidine ring leading to compounds with good human PRP potency, selectivity, clearance and oral bioavailability.

Topics: Animals; Fibrinolytic Agents; Glutamic Acid; Humans; Male; Piperidines; Platelet Aggregation; Purinergic P2 Receptor Antagonists; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Structure-Activity Relationship

We have investigated phenol replacements in a series of diaryl amino piperidine delta opioid agonists. From this study we have demonstrated that the hydroxy functional group can be replaced with a primary amide group, giving enhanced activity at the delta receptor, increased selectivity versus mu and kappa as well as improved in vitro metabolic stability.

Topics: Analgesics; Animals; Diphenylamine; Humans; Microsomes, Liver; Piperidines; Rats; Receptors, Opioid, delta; Structure-Activity Relationship

Detailed chemical studies on the roots of Piper sarmentosum and Piper nigrum have resulted in several alkaloids. The roots of P. sarmentosum gave a new aromatic compound, 1-nitrosoimino-2,4,5-trimethoxybenzene (1). Piper nigrum roots gave pellitorine (2), (E)-1-[3',4'-(methylenedioxy)cinnamoyl]piperidine (3), 2,4-tetradecadienoic acid isobutyl amide (4), piperine (5), sylvamide (6), cepharadione A (7), piperolactam D (8) and paprazine (9). Structural elucidation of these compounds was achieved through NMR and MS techniques. Cytotoxic activity screening of the plant extracts indicated some activity.

Topics: Alkaloids; Aporphines; Benzodioxoles; Cell Survival; Fatty Acids, Unsaturated; HeLa Cells; HL-60 Cells; Humans; Magnetic Resonance Spectroscopy; Mass Spectrometry; Molecular Structure; Piper; Piper nigrum; Piperidines; Plant Roots; Polyunsaturated Alkamides

In this study, we show that compound 3 (osanetant) binds with a pseudoirreversible, apparent noncompetitive mode of antagonism at the guinea pig NK(3), while it behaves competitively at the human NK(3). This difference is caused by a slower dissociation rate of compound 3 at the guinea pig NK(3) compared to human NK(3). The only amino acid difference between the human and guinea pig NK(3) in the binding site (Thr139(2.58) in human, corresponding to Ala114(2.58) in guinea pig) has been shown to be responsible for the different behavior. Compound 1 (talnetant), however, behaves competitively at both receptors. Using these data, 3D homology modeling, and site-directed mutagenesis, a model has been developed to predict the mode of antagonism of NK(3) antagonists based on their binding mode. This model was successfully used to predict the mode of antagonism of compounds of another chemical series including piperidine-based structures at human and guinea pig NK(3).

Topics: Amino Acid Sequence; Animals; Cattle; Cell Line; Cell Membrane; Dogs; Guinea Pigs; Humans; Inositol Phosphates; Isotope Labeling; Kinetics; Models, Molecular; Molecular Conformation; Molecular Sequence Data; Mutagenesis, Site-Directed; Mutation; Piperidines; Protein Structure, Tertiary; Rats; Receptors, Neurokinin-3; Reproducibility of Results; Tritium

A knowledge based approach has been adopted to identify novel NOP receptor agonists with simplified hydrophobes. Substitution of the benzimidazol-2-one piperidine motif with a range of hydrophobic groups and pharmacophore guided bio-isosteric replacement of the benzimidazol-2-one moiety was explored. Compound 51 was found to be a high affinity, potent NOP receptor agonist with reduced affinity for the hERG channel.

Topics: Animals; Benzimidazoles; Cricetinae; Narcotic Antagonists; Nociceptin Receptor; Piperidines; Receptors, Opioid; Structure-Activity Relationship

Novel multifunctional compounds have been designed, synthesized, and evaluated as potential drugs for the treatment of Alzheimer's disease (AD). With an L-glutamic moiety as a suitable biocompatible linker, three pharmacophoric groups were joined: (1) an N-benzylpiperidine fragment selected to inhibit acetylcholinesterase by interacting with the catalytic active site (CAS), (2) an N-protecting group of the amino acid, capable of interacting with the acetylcholinesterase (AChE)-peripheral anionic site (PAS) and protecting neurons against oxidative stress, and (3) a lipophilic alkyl ester that would facilitate penetration into the central nervous system by crossing the blood-brain barrier. At submicromolar concentration, they inhibit AChE and butyrylcholinesterase (BuChE) of human origin, displace the binding of propidium iodide from the PAS of AChE, and could thus inhibit Abeta aggregation promoted by AChE. They also display neuroprotective properties against mitochondrial free radicals, show low toxicity, and could be able to penetrate into the CNS.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Catalytic Domain; Cattle; Cell Death; Cell Line, Tumor; Cell Survival; Cholinergic Agents; Cholinesterase Inhibitors; Esters; Glutamic Acid; Humans; Hydrophobic and Hydrophilic Interactions; Neuroprotective Agents; Permeability; Piperidines; Protein Binding

Based on reported structures, a focused library of biarylmethyl bound to the nitrogen atom of spiropiperidine was designed. Systematic modifications allowed the discovery of a synthetically feasible and highly potent ORL1 antagonist 37, 1'-{[1-(3-chloropyridin-2-yl)-1H-pyrazol-4-yl]methyl}-3H-spiro[2-benzofuran-1,4'-piperidine], which exhibits excellent selectivity to mu, kappa, and human ether-a-go-go related gene potassium channel.

Topics: Binding, Competitive; Chemistry, Pharmaceutical; Drug Design; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Humans; Inhibitory Concentration 50; Models, Chemical; Molecular Conformation; Molecular Structure; Narcotic Antagonists; Nociceptin Receptor; Piperidines; Protein Binding; Receptors, Opioid; Spiro Compounds; Structure-Activity Relationship

The N arylation of primary and secondary aliphatic amines, anilines, and imidazoles with novel potassium aryl triolborates was carried out in the presence of a reoxidant and a catalytic amount of Cu(OAc)(2) (10 mol %). Aryl triolborates were found to be better reagents than aryl boronic acids or potassium aryl trifluoroborates as the former achieved high yields under mild conditions. Coupling of primary and secondary aliphatic amines to give N-aryl amines in excellent yields was performed under oxygen atmosphere. The reactions of anilines and imidazoles to provide N-aryl anilines and N-aryl imidazoles in good yields proceeded smoothly when trimethylamine N-oxide was used as an oxidant.

Topics: Amines; Aniline Compounds; Borates; Catalysis; Copper; Hydrogen; Imidazoles; Molecular Structure; Nitrogen; Piperidines

A six-year old mixed-breed dog presented with severe trauma to the oral mucosa suggestive of chemical burn. Sixteen Harmonia axyridis (Coccinellidae) were removed from the oral cavity, which revealed trauma consistent with chemical burn. The beetles had become embedded in mucosa covering the hard palate and required manual removal. A diagnosis of beetle induced chemical burn was warranted and consistent with the nature of the chemical constituents of H. axyridis hemolymph.

Topics: Animals; Burns, Chemical; Coleoptera; Dog Diseases; Dogs; Hemolymph; Insect Bites and Stings; Mouth Mucosa; Piperidines; Tongue

We explore the application of a previously suggested formula for determining the degree of charge transfer in surface-enhanced Raman scattering (SERS). SERS is often described as a phenomenon which obtains its enhancement from three major sources, namely the surface plasmon resonance, charge-transfer resonances as well as possible molecular resonances. At any chosen excitation wavelength, it is possible to obtain contributions from several sources and this has led to considerable confusion. The formula for the degree of charge transfer enables one to separate these effects, but it requires that spectra be obtained either at two or more different excitation wavelengths or as a function of applied potential. We apply this formula to several examples, which display rather large charge-transfer contributions to the spectrum. These are p-aminothiophenol (PATP), tetracyano-ethylene (TCNE) and piperidine. In PATP we can show that several lines of the same symmetry give the same degree of charge transfer. In TCNE we are able to identify the charge-transfer transition, which contributes to the effect, and are able to independently determine the degree of charge transfer by wavenumber shifts. This enables a comparison of the two techniques of measurement. In piperidine, we present an example of molecule to metal charge transfer and show that our definition of charge transfer is independent of direction.

Topics: Chemistry, Physical; Electrons; Ethylenes; Nitriles; Phenols; Piperidines; Spectrum Analysis, Raman; Sulfhydryl Compounds; Surface Plasmon Resonance

Evidence is accumulating that compounds of plant origin (phytochemicals) exert anti-cancer effects. The purpose of this study was to determine if resveratrol, cinnamaldehyde, and piperine (from red grapes, cinnamon, black pepper respectively) have anti-proliferative effects on colon cancer.. Quantitative effects of each phytochemical on concentration responses and time courses of proliferation of cultured human colon cancer cells (DLD-1) were assessed.. Research was performed at Saint Louis University.. Responses were measured by spectrophotometry of surviving cells stained by a dye method.. Phytochemicals displayed anti-proliferative effects on DLD-1 cells in concentration- and kinetic-dependent manners. Cinnamaldehyde offered statistically significant effects at 24 hours [200 microM], 48 hours [100 - 200 microM], and 72 hours [200 microM]. Piperine displayed a trend towards anti-proliferation at 24 hours and statistically significant inhibition at 48 and 72 hours [100 - 200 microM]. Resveratrol displayed significant anti-proliferative effects at 24 hours [50-200 microM], 48 hours [10-200 microM], and 72 hours [10-200 microM].. Cinnamaldehyde, piperine, and resveratrol offer significant in vitro anti-proliferative effects on cultured human colon cancer cells. While each phytochemical exhibited significant anti-proliferative effects, resveratrol results were most impressive in that lower concentrations administered at regular intervals were significantly effective. These results taken together with everyday dietary availability of concentrations used in this study strongly suggest that regular intake of low doses of these phytochemicals offer preventive effects against colon cancer.

Topics: Acrolein; Adenocarcinoma; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Piperidines; Plant Extracts; Resveratrol; Stilbenes

Total syntheses of (+)-nankakurine A (2) and (+)-nankakurine B (3) were accomplished by a sequence that employs an intramolecular dipolar cycloaddition of an azomethine imine intermediate to form the azatricyclic moiety and establish the relative configuration of the spiropiperidine ring. These syntheses, together with the synthesis of the originally purported structure 1 of nankakurine A, rigorously establish the relative and absolute configuration of these structurally unusual Lycopodium alkaloids. The syntheses are sufficiently concise that gram quantities of (+)-nankakurine A (2) and (+)-nankakurine B (3) will be available for further biological studies.

Topics: Alkaloids; Aza Compounds; Azo Compounds; Heterocyclic Compounds, Bridged-Ring; Imines; Lycopodium; Models, Chemical; Piperidines; Stereoisomerism; Thiosemicarbazones

The redox potentials of 25 cyclic nitroxides from four different structural classes (pyrrolidine, piperidine, isoindoline, and azaphenalene) were determined experimentally by cyclic voltammetry in acetonitrile, and also via high-level ab initio molecular orbital calculations. It is shown that the potentials are influenced by the type of ring system, ring substituents and/or groups surrounding the radical moiety. For the pyrrolidine, piperidine, and isoindolines there is excellent agreement (mean absolute deviation of 0.05 V) between the calculated and experimental oxidation potentials; for the azaphenalenes, however, there is an extraordinary discrepancy (mean absolute deviation of 0.60 V), implying that their one-electron oxidation might involve additional processes not considered in the theoretical calculations. This recently developed azaphenalene class of nitroxide represents a new variant of a nitroxide ring fused to an aromatic system and details of the synthesis of five derivatives involving differing aryl substitution are also presented.

Topics: Acetonitriles; Algorithms; Aza Compounds; Cyclic N-Oxides; Electrochemistry; Isoindoles; Models, Theoretical; Oxidation-Reduction; Piperidines; Pyrrolidines

An efficient nitro-Mannich/lactamization cascade of gamma-nitro esters with cyclic imines for the preparation of architecturally complex multicyclic piperidinone ring-containing structures has been developed. The reaction is broad in scope and stereoselective and may be coupled to an enantioselective nitroolefin Michael addition reaction as part of a highly enantio- and diastereoselective multicomponent process.

Topics: Imines; Lactams; Piperidines; Stereoisomerism; Substrate Specificity

Several indole phytoalexins exhibit antiproliferative and/or cancer chemopreventive properties in vitro. However, the potency and selectivity of their anticancer effects were reported to be relatively weak. In order to improve the anticancer activity of the natural phytoalexin 1-methoxyspirobrassinol, its new 2-amino analogues were synthesized and evaluated.. Cis-1-Boc-, trans-1-Boc-, cis-1-methoxy- and trans-1-methoxy-2-deoxy-2-(1-piperidyl)spirobrassinols (compounds 4-7) were synthesized by spirocyclization reaction and their potency evaluated by SRB assay on the NCI(60) panel of human cancer cells. The COMPARE program was employed to analyze patterns of activity of compounds 4-7 against the NCI(60) panel for prediction of their probable targets and mode of action. Cellular glutathione, a predicted target, was quantified by DTNB assay.. Compounds 4-7 exhibit growth inhibitory effects across the NCI(60) panel and, consistent with COMPARE prediction, a glutathione-depleting effect on MCF-7 cells.. Considering their remarkable glutathione-depleting effects, compounds 4-7 could be developed as radio- and/or chemosensitizing agents for combination cancer chemotherapy.

Topics: Antineoplastic Agents; Biological Products; Cell Line, Tumor; Cell Proliferation; Drug Evaluation, Preclinical; Humans; Indoles; Molecular Structure; Piperidines; Spiro Compounds; Structure-Activity Relationship

We describe robust chemical approaches toward putative CCR5 scaffolds designed in our laboratories. Evaluation of analogues in the (125)I-[MIP-1beta] binding and Ba-L-HOS antiviral assays resulted in the discovery of 64 and 68 in the 4,4-disubstitited piperidine class H, both potent CCR5 ligands (pIC 50 = 8.30 and 9.00, respectively) and HIV-1 inhibitors (pIC 50 = 7.80 and 7.84, respectively, in Ba-L-HOS assay). In addition, 64 and 68 were bioavailable in rodents, establishing them as lead molecules for further optimization toward CCR5 clinical candidates.

Topics: Antiviral Agents; Drug Evaluation, Preclinical; HIV-1; Ligands; Molecular Structure; Piperidines; Receptors, CCR5; Structure-Activity Relationship

Herein, the synthesis and pharmacological evaluation of thiophene bioisosteres of the highly potent spirocyclic benzopyran 1 are detailed. The synthesis of 1-benzyl-6'-methoxy-6',7'-dihydrospiro[piperidine-4,4'-thieno[3.2- c]pyran] (2a) was performed starting with 3-bromothiophene (3). After introduction of the acetaldehyde substructure (7), halogen metal exchange, addition of 1-benzylpiperidin-4-one, and cyclization led to the spirocyclic thienopyran 2a. The removal of the benzyl group afforded the secondary amine 2f, which was substituted with various residues. With respect to sigma 1 affinity the N-benzyl derivative 2a, the N-cyclohexylmethyl derivative 2d, and the N-p-fluorobenzyl derivative 2i represent the most potent compounds of this series binding with K i values of 0.32, 0.29, and 0.62 nM, respectively. Electronic properties of the substituents have only little impact on sigma 1 affinity. The most potent sigma 1 ligands display high selectivity against sigma 2, 5-HT 1A, 5-HT 6, 5-HT 7, alpha 1A, alpha 2, and NMDA receptors. The activity of 2a in the mouse capsaicin assay seems to indicate sigma 1 antagonistic activity.

Topics: Alkylation; Animals; Cyclization; Ligands; Mice; Models, Molecular; Molecular Structure; Oxidation-Reduction; Pain; Piperidines; Protein Binding; Pyrans; Rats; Receptors, sigma; Spiro Compounds; Structure-Activity Relationship; Thiophenes

The discovery of a novel series of potent and selective T-type calcium channel antagonists is reported. Initial optimization of high-throughput screening leads afforded a 1,4-substituted piperidine amide 6 with good potency and limited selectivity over hERG and L-type channels and other off-target activities. Further SAR on reducing the basicity of the piperidine and introducing polarity led to the discovery of 3-axial fluoropiperidine 30 with a significantly improved selectivity profile. Compound 30 showed good oral bioavailability and brain penetration across species. In a rat genetic model of absence epilepsy, compound 30 demonstrated a robust reduction in the number and duration of seizures at 33 nM plasma concentration, with no cardiovascular effects at up to 5.6 microM. Compound 30 also showed good efficacy in rodent models of essential tremor and Parkinson's disease. Compound 30 thus demonstrates a wide margin between CNS and peripheral effects and is a useful tool for probing the effects of T-type calcium channel inhibition.

Topics: Animals; Calcium Channel Blockers; Calcium Channels, T-Type; Cardiovascular System; Drug Evaluation, Preclinical; Humans; Molecular Structure; Piperidines; Rats; Structure-Activity Relationship

This letter describes the further synthesis and SAR, developed through an iterative analog library approach, of analogs of the highly selective M1 allosteric agonist TBPB by deletion of the distal basic piperidine nitrogen by the formation of amides, sulfonamides and ureas. Despite the large change in basicity and topology, M1 selectivity was maintained.

Topics: Allosteric Regulation; Allosteric Site; Amides; Benzimidazoles; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Drug Design; Humans; Models, Chemical; Nitrogen; Piperidines; Receptor, Muscarinic M1; Structure-Activity Relationship; Sulfonamides; Urea

We report the synthesis and characterization of N,N-bis[(7-dimethylamino)phenothiazin-5-ium-3-yl]-4,4-ethylenedipiperidine diiodide (3), consisting of two photosensitizing phenothiazinium rings attached to a central ethylenedipiperidine linker. At all time points (10, 30, 60 min) and all wavelengths (676, 700, 710 nm) tested, photocleavage of pUC19 plasmid DNA (22 degrees C and pH 7.0) was markedly enhanced by 1 microM of 3 in comparison to 1 microM of the parent phenothiazine methylene blue (MB). At concentrations of phenothiazine ranging from 5 to 0.5 microM, the photocleavage levels produced by compound 3 were consistently higher than the cleavage produced using approximately twice the amount of MB (e.g., 710 nm irradiation of 5 microM of 3 and 10 microM of MB cleaved the plasmid DNA in 93% and 71% yields, respectively). Scavenger assays provided evidence for the involvement of singlet oxygen and, to a lesser extent, hydroxyl radicals in DNA damage. Analysis of photocleavage products at nucleotide resolution revealed that direct strand breaks and alkaline-labile lesions occurred predominantly at guanine bases. While compound 3 and MB were both shown to stabilize duplex DNA, the DeltaTm values of calf thymus (CT) and C. perfringens DNAs were approximately three fold higher in the presence of compound 3. Finally, viscometric data indicated that CT DNA interacts with compound 3 and MB by a combination of groove binding and monofunctional intercalation, and with compound 3 by a third, bisintercalative binding mode.

Topics: DNA; DNA Cleavage; Electrons; Indicators and Reagents; Intercalating Agents; Nucleic Acid Denaturation; Nucleotides; Phenothiazines; Photochemistry; Photosensitizing Agents; Piperidines; Spectrophotometry, Ultraviolet; Transition Temperature; Viscosity

A series of lobelane homologues has been synthesized and evaluated for their [(3)H]DTBZ binding affinity at the vesicular monoamine transporter-2 (VMAT2). The structure-activity relationships (SAR) indicate that for retention of binding affinity at VMAT2, the lengths of the methylene linkers should be no shorter than one methylene unit at C-6 of the piperidine ring, and no shorter than two methylene units at C-2 of the piperidine ring. These results indicate that the intramolecular distances between the piperidine ring and two phenyl rings in lobelane analogues are an important criterion for retention of high affinity at VMAT2.

Topics: Animals; Binding Sites; Chemistry, Pharmaceutical; Drug Design; Humans; Kinetics; Lobeline; Models, Chemical; Oxygen; Piperidines; Rats; Structure-Activity Relationship; Vesicular Biogenic Amine Transport Proteins; Vesicular Monoamine Transport Proteins

The synthesis and structure-activity relationship of a series of 7-azaindole piperidine derivatives are described. SAR studies led to the discovery of the potent CCR2 antagonists displaying IC(50) values in the nanomolar range. The representative compound 15 showed reasonable P450 and pharmacokinetics profile.

Topics: Alcohols; Binding Sites; Chemistry, Pharmaceutical; Chemokine CCL2; Drug Design; Humans; Indoles; Inhibitory Concentration 50; Molecular Structure; Piperidines; Receptors, CCR2; Stereoisomerism; Structure-Activity Relationship

A new concerted silver ion-mediated Grob fragmentation process is described in which a 1,2-dihydropyridinium ion is formed and trapped in situ with Grignard reagents in a highly regio- and diastereoselective fashion. Using this methodology, 2,3,6-trisubstituted piperidines were synthesized in good yields and further derivatized to polysubstituted indolizidine.

Topics: Iodides; Piperidines; Silver; Stereoisomerism; Substrate Specificity

The synthesis of a new series of 1beta-methylcarbapenems having pyrrolidine and piperidine moieties is described. Their in-vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of substituents on the pyrrolidine ring was investigated. A particular compound III b having an oxime-pyrrolidine moiety showed the most potent antibacterial activity.

Topics: Anti-Bacterial Agents; Carbapenems; Gram-Negative Bacteria; Gram-Positive Bacteria; Microbial Sensitivity Tests; Piperidines; Pyrrolidines; Structure-Activity Relationship

The reported structures of reaction products of enaminones with malononitrile in ethanolic piperidine are revised. A novel route to 2,3-dihydropyridazine-4-carboxylic acids 4a-c via reactions of 2-cyano-5-(dimethylamino)-5-arylpenta-2,4-dienamides 8a-c with nitrous acid or with benzenediazonium chloride is reported. Compounds 8a-c are converted to 1,2-dihydropyridine-3-carboxylic acid and 1,2-dihydropyridine-3-carbonitrile derivatives upon reflux in EtOH/ HCl and in AcOH.

Topics: Carboxylic Acids; Ethanol; Nitriles; Piperidines; Pyridazines

A series of 2-oxopiperazine, 4-aminomethyl-, 3-amino- and 3-aminomethylpiperidine analogues of DM235 (sunifiram) and MN19 (sapunifiram), two previously reported potent cognition-enhancers, have been synthesized and tested in the mouse passive-avoidance test. The compounds display minimal effective doses in the range 0.3-10mg/kg. Although the new substances do not show improved activity when compared to the parent compounds, some useful information has been obtained to understand structure-activity relationships. In addition, the 3-aminopiperidine moiety appears to be a promising scaffold to synthesize new drugs endowed with cognition-enhancing activity.

Topics: Acylation; Animals; Cognition; Drug Design; Mice; Molecular Structure; Piperidines; Structure-Activity Relationship; Sulfur

A close-packed monolayer of zinc 5,10,15,20-tetrakis(3-carboxyphenyl)porphyrin has been prepared and deposited on the thin native oxide covering the surface of an SOI-MOSFET (silicon-on-insulator metal-oxide-semiconductor field effect transistor) using Langmuir-Blodgett techniques. When the device is exposed to amine vapors in a nitrogen atmosphere, the amine coordinates to the zinc atom. The resulting change in electron distribution within the porphyrin leads to a large change in the drain current of the transistor, biased via a back gate. This change is sensitive to both the amount of amine present and the base strength of the amine. Only very small changes in drain current were observed with a monolayer of free base porphyrin or palmitic acid. After exposure to high pyridine concentrations, the device response saturates, but partially recovers after overnight exposure to flowing nitrogen gas. Interestingly, the device response is instantaneously reset by exposure to visible light, suggesting that photode-ligation occurs. An electrical model for the hybrid device that describes its response to ligand binding in terms of a change in the work function of the porphyrin monolayer has been developed. A transistor response to a few hundred attomoles of bound pyridine can be readily detected. This extreme sensitivity, coupled with the ability to reset the device using light, suggests that such systems might be useful as sensors.

Topics: Amines; Electrochemistry; Hydrogen-Ion Concentration; Kinetics; Light; Metalloporphyrins; Models, Molecular; Oxides; Piperidines; Pyridines; Semiconductors; Silicon; Volatilization; Zinc

Density functional theory calculations at the B3LYP/6-311G** level were performed to predict the heats of formation (HOFs) for three eight-membered ring compounds and four six-membered ring compounds via designed isodesmic reactions. In the isodesmic reactions designed for the computation of HOFs (CH(3)CH(2))(2)NNO(2) and piperidine were chosen as reference compounds. The HOFs for -NO(2) substituted derivations are larger than those of -NF(2) substituent groups. Thermal stability were evaluated via bond dissociation energies (BDE) at the UB3LYP/6-311G** level. As a whole, the homolysis of CNF(2) or CNO(2) bonds is the main step for bond dissociation of the title compounds. Detonation properties of seven title compounds were evaluated by using the Kamlet-Jacobs equation based on the calculated densities and HOFs. It is found that 3,3,7,7-tetrakis(difluoroamino)octahydro-1,5-dinitro-1,5-diazocine (HNFX) and 3,3,5,5-tetrakis (difluoroamino)-1-nitro piperidine (N-nitro TDFAPP), with predicted density of ca. 2.0 g/cm(3), detonation velocity (D) about 9.9 km/s, and detonation pressure (P) of 47GPa that are lager than those of HMX, are expected to be the novel candidates of high energy density materials (HEDMs). The detonation data of 1,3,3,5,7,7-hexanitro-1,5-diazacyclooctane (HNDZ) and TNBDFAPP show that they meet the requirements for HEDMs.

Topics: Nitro Compounds; Piperidines; Thermodynamics

A hit-to-lead optimization process was carried out on the high throughput screening hit compound 1 resulting in the identification of several potent and selective CCR1 receptor antagonists. Compound 37 shows the best overall profile with IC(50) values of <100 nM in binding and functional assays.

Topics: Calcium; Cell Line; Cell Movement; Chemokine CCL3; Chemotaxis; Humans; Molecular Structure; Monocytes; Piperidines; Receptors, CCR1; Structure-Activity Relationship

We describe the synthesis of a series of DNA-threading bis(9-aminoacridine-4-carboxamides) comprising ethylpiperidino and N-methylpiperidin-4-yl sidechains, joined via neutral flexible alkyl chains, charged flexible polyamine chains and a semi-rigid charged piperazine linker. Their cytotoxicity towards human leukaemic cells gives IC(50) values ranging from 99 to 1100 nM, with the ethylpiperidino series generally being more cytotoxic than the N-methylpiperidin-4-yl series. Measurements with supercoiled DNA indicate that they bisintercalate.

Topics: Aminoacridines; Cell Cycle; Cell Line, Tumor; Dimerization; DNA; Humans; Molecular Structure; Piperidines; Structure-Activity Relationship

D-Glucose was converted to synthetic equivalent of meso-pentodialdose, namely 3-C-(1'-aminoethyl)-alpha-d-ribo-pentodialdo-1,4-furanose 10 that gives an easy access to manipulate the aldehyde functionalities on either sides to get enantiomeric pair of 3. Thus, reduction of C5-aldehyde followed by hydrolysis of 1,2-acetonide functionality and reductive aminocyclization with C1-aldehyde afforded gamma-1,2-dihydroxyethyl piperidine iminosugar 3. On the other hand, first reductive aminocyclization with C5-aldehyde gave piperidine ring skeleton 12 that on removal of 1,2-acetonide and reduction of C1-aldehyde gave ent-3 while chopping of C1-aldehyde in 12 and reduction afforded gamma-hydroxymethyl piperidine iminosugar 4.

Topics: Alkylation; Glucose; Hydroxylation; Imino Sugars; Molecular Structure; Piperidines

A practical and efficient synthesis of spirobarbiturates of type III is reported when NH acidity of the imide function of the hydrophilic linker element allowed the introduction of different substituents. Structural characterization, which was based on both X-ray crystallography and spectroscopic investigations, indicated type II beta-turn formation. Introduction of the molecular scaffold into solid phase peptide synthesis gave rise to spirocyclic neuropeptide analogs.

Topics: Barbiturates; Crystallography, X-Ray; Models, Molecular; Molecular Structure; Piperidines; Proline; Spiro Compounds

A lead benzamide, 3, was identified as a potent and low molecular weight histone deacetylase (HDAC) inhibitor. Optimization led to 16d, demonstrating an excellent balance of efficacy and non-efficacy properties, along with very desirable in vivo DMPK. The final compounds presented are >1000-fold more potent than the initial screen hit, an improvement in potency which was achieved with a concomitant significant improvement in all the main non-efficacy properties.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Crystallography, X-Ray; Dogs; Dose-Response Relationship, Drug; Drug Design; Enzyme Inhibitors; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Mice; Models, Molecular; Molecular Structure; Piperidines; Rats; Structure-Activity Relationship; Thiazoles; Xenograft Model Antitumor Assays

The aim of this work was to formulate transdermal therapeutic system (TTS) of an antihypertensive drug, enalapril maleate (EM) using a new penetration enhancer, piperidine hydrochloride (PH), belonging to the class of Dihydropyridines. The TTS of EM was prepared by solvent evaporation technique using polymers Eudragit E100 and polyvinyl pyrrolidone K-30 in varying ratios, 5% w/w dibutylphthalate as plasticizer and 10% w/w PH as penetration enhancer. The TTS was evaluated for in-vitro drug release using paddle over disc method and ex-vivo skin permeation using modified Keshary and Chein diffusion cell. The interaction studies were carried out by comparing the results of assay, UV and TLC analysis for pure drug and medicated and TTS formulation. Skin irritation potential of TTS was assessed by visual examination of treated rat skin. Stability studies were conducted according to ICH guidelines at a temperature of 40+/-0.5 degrees C and 75+/-5% RH. The optimized formulation was evaluated for preclinical bioavailability and antihypertensive efficacy using albino rat model. The optimized formulation provided 87.3% drug release in-vitro and a flux of 380 microg/cm(2)/hr over a period of 48 hours. No chemical interaction was found between the drug and excipients and there were no signs of skin irritation on application of patch. The optimized formulation was stable with a tentative shelf life of two years. Significant fall in BP (p<0.001) was observed in experimental hypertensive rats which was maintained for 2 days. There was 3 fold improvement in bioavailability with TTS vis-à-vis marketed tablet (AUC(0 to t) : 1253.9 ng.h/ml vs. 422.88 ng.h/ml). These preclinicial studies indicate the feasibility of matrix-type TTS of EM for 2 day management of hypertension. Further studies on human beings are warranted to establish clinical utility of the above TTS.

Topics: Acrylates; Administration, Cutaneous; Animals; Antihypertensive Agents; Biological Availability; Blood Pressure; Disease Models, Animal; Drug Stability; Drug Storage; Enalapril; Excipients; Female; Hypertension; Male; Permeability; Piperidines; Polymers; Povidone; Rats; Skin Absorption

Two cyclic hydroxylamines (cHA) bearing pyrrolidine (CPH) and piperidine moieties (TMTH) were evaluated to trap hydroxyl, peptide and phospholipid free radicals using mass spectrometry for their detection. The cHA ionized as [M+H](+) ions, showing higher relative abundances when compared to the DMPO, probably due to higher ionization efficiency. In the presence of hydroxyl radicals, both cHA generated new ions that could be attributed to loss of (*)H and (*)CH(3), most likely deriving from decomposition reactions of the nitroxide spin adduct. Addition of cHA to Leucine-enkephalin and palmitoyl-lineloyl-glycerophosphatidylcholine free radicals promoted the formation of cHA biomolecule adducts, which were confirmed by MS/MS data. Results suggest that the cHA are not suitable for hydroxyl radical trapping but can be used for trapping biomolecule radicals, having the advantage, over the most used cyclic nitrones, of being water soluble. The biomolecule adducts identified by MS are ESR silent, evidencing the importance of MS detection.

Topics: Electron Spin Resonance Spectroscopy; Free Radicals; Hydroxyl Radical; Hydroxylamine; Ions; Mass Spectrometry; Models, Chemical; Peptides; Phospholipids; Piperidines; Pyrrolidines; Spectrometry, Mass, Electrospray Ionization; Spin Labels; Spin Trapping

Starting from [{Rh(cod)Cl}(2)] and 1,3-dimesitylimidazole-2-ylidenes the novel [RhCl(cod)(carbene)] complexes 1-5 have been synthesized, characterized, and tested in the hydroaminomethylation of aromatic olefins. The influence of different ligands and reaction parameters on the catalytic activity was investigated in detail applying 1,1-diphenylethylene and piperidine as a model system. The scope and limitations of the novel catalysts is shown in the preparation of 16 biologically active 1-amino-3,3-diarylpropenes. In general, high chemo- and regioselectivity as well as good yields of the desired products were achieved.

Topics: Alkenes; Amines; Catalysis; Hydrocarbons; Imidazoles; Ligands; Methane; Methylation; Models, Chemical; Molecular Structure; Organometallic Compounds; Pharmaceutical Preparations; Piperidines; Propane; Rhodium; Styrenes

[reaction: see text] An SN2 mechanism for the copper-catalyzed amination of diorganozinc reagents by O-benzoyl-N,N-dialkylhydroxylamines is supported by following stereochemically defined organometallics through the reaction and by employing the endocyclic restriction test. A copper-catalyzed electrophilic amination of organomagnesium compounds is also described in which the use of zinc halides has been eliminated.

Topics: Amination; Bromides; Catalysis; Copper; Cyclization; Electrons; Molecular Structure; Piperidines; Zinc

[reaction: see text] A new approach for the stereoselective synthesis of the piperidine alkaloid (+)-alpha-conhydrine and its pyrrolidine derivative has been developed using a palladium(II)-catalyzed, MOM-ether-directed aza-Claisen rearrangement and ring-closing metathesis to effect the key steps.

Topics: Alkaloids; Aza Compounds; Ether; Molecular Structure; Piperidines; Propanols; Pyrrolidines; Stereoisomerism

The synthesis and in vitro activities of a series of succinyl-nitrile-based inhibitors of Cathepsin S are described. Several members of this class show nanomolar inhibition of the target enzyme as well as cellular potency. The inhibitors displaying the greatest potency contain N-alkyl substituted piperidine and pyrrolidine rings spiro-fused to the alpha-carbon of the P1 residue.

Topics: Catalytic Domain; Cathepsins; Chemistry, Pharmaceutical; Dipeptides; Drug Design; Humans; Models, Chemical; Molecular Conformation; Nitriles; Peptides; Piperidines; Pyrrolidines; Structure-Activity Relationship

A spectroscopic and kinetic study of the reaction of methyl beta-methylthio-alpha-nitrocinnamate (4-SMe) with morpholine, piperidine, and hydroxide ion in 50% DMSO/50% water (v/v) at 20 degrees C is reported. The reactions of 4-SMe with piperidine in a pH range from 10.12 to 11.66 and those with morpholine at pH 12.0 are characterized by two kinetic processes when monitored at lambdamax (364 nm) of the substrate, but by only one process when monitored at lambdamax (388) nm of the product. The rate constants obtained at 388 nm were the same as those determined for the slower of the two processes at 364 nm. These rate constants refer to product formation, whereas the faster process observed at 364 nm is associated with the loss of reactant to form an intermediate. In contrast, for the reaction of 4-SMe with morpholine at pH 8.62 the rates of product formation and disappearance of the substrate were the same, i.e., there is no accumulation of an intermediate. Likewise, the reaction of 4-SMe with OH- did not yield a detectable intermediate. The factors that allow the accumulation of intermediates in certain SNV reactions but not in others are discussed in detail, and structure-reactivity comparisons are made with reactions of piperidine and morpholine with other highly activated vinylic substrates.

Topics: Amines; Cinnamates; Hydrogen-Ion Concentration; Hydrolysis; Kinetics; Morpholines; Nitro Compounds; Piperidines; Spectrophotometry, Ultraviolet

An expanded substrate scope and in-depth analysis of the reaction mechanism of the copper(II) carboxylate-promoted intramolecular carboamination of unactivated alkenes is described. This method provides access to N-functionalized pyrrolidines and piperidines. Both aromatic and aliphatic gamma- and delta-alkenyl N-arylsulfonamides undergo the oxidative cyclization reaction efficiently. N-Benzoyl-2-allylaniline also underwent the oxidative cyclization. The terminal olefin substrates examined were more reactive than those with internal olefins, and the latter terminated in elimination rather than carbon-carbon bond formation. The efficiency of the reaction was enhanced by the use of more organic soluble copper(II) carboxylate salts, copper(II) neodecanoate in particular. The reaction times were reduced by the use of microwave heating. High levels of diastereoselectivity were observed in the synthesis of 2,5-disubstituted pyrrolidines, wherein the cis substitution pattern predominates. The mechanism of the reaction is discussed in the context of the observed reactivity and in comparison to analogous reactions promoted by other reagents and conditions. Our evidence supports a mechanism wherein the N-C bond is formed via intramolecular syn aminocupration and the C-C bond is formed via intramolecular addition of a primary carbon radical to an aromatic ring.

Topics: Alkenes; Amination; Carboxylic Acids; Copper; Crystallography, X-Ray; Cyclization; Free Radicals; Models, Molecular; Molecular Structure; Nitrogen; Oxidation-Reduction; Piperidines; Pyrrolidines; Solvents; Stereoisomerism; Sulfonamides; Temperature; Water

A series of piperidine amide inhibitors of human 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) were identified via modifications of the HTS hit compound 1. The synthesis, in vitro biological evaluation, and structure-activity relationship of these compounds are presented.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Amides; Binding Sites; Enzyme Inhibitors; Humans; Immunoenzyme Techniques; Models, Chemical; Piperidines; Structure-Activity Relationship

Sigma (sigma)-receptor agonists attenuate brain injury after experimental focal cerebral ischemia in several species. We tested the hypothesis that the potent, prototypical sigma(1)-receptor agonist, 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP), protects neurons by a mechanism involving the antiapoptotic protein bcl-2.. Primary cortical neuronal cultures were exposed to either 2 h of oxygen-glucose deprivation (OGD) or glutamate (100 microM). PPBP treatment was initiated either 15 min prior to the insult or at 15 min postinsult then continued for 24 h. In another set of experiments, cultured neurons were preincubated for 2 h prior to PPBP treatment with sigma1-receptor antagonist, rimcazole, in a dose-dependent manner. Alive and dead cells were detected with calcein-AM and propidium iodide respectively. Bcl-2 and bax expression were determined by quantitative real time reverse transcription polymerase chain reaction and western blotting, and DNA damage was detected by TUNEL staining.. PPBP pretreatment attenuated neuronal injury induced by OGD or glutamate (50 or 100 microM). This protection was reversed with rimcazole (cell death: OGD 48 +/- 2%, OGD plus PPBP 31 +/- 3%, OGD plus PPBP with rimcazole 46 +/- 2%). PPBP treatment increased bcl-2 but not bax mRNA levels. PPBP's ability to preserve bcl-2 protein after OGD by PPBP was fully abolished by rimcazole. Lastly, PPBP reduced the number of TUNEL-positive cells after OGD, suggesting fewer cells with overt DNA damage.. These data demonstrate that PPBP reduces cell death in vitro by a mechanism involving receptor-dependent preservation of protective genes such as bcl-2.

Topics: Animals; Apoptosis; Cell Death; Cells, Cultured; DNA Damage; Dose-Response Relationship, Drug; Neurons; Neuroprotective Agents; Piperidines; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Receptors, sigma

Topics: Alanine; Carboxylic Acids; Electrolysis; Methanol; Piperidines; Proline; Silica Gel; Silicon Dioxide

Piperidine was stereoselectively alpha-alkynylated in a four-step sequence made up of transformation to a chiral nonracemic N-sulfinylpiperidine, anodic oxidation to N-sulfinyliminium ion equivalent, alkynylation through addition of a mixed organoaluminum derivative, and final acidic deprotection of the sulfoxide. Overall yields are around 50%, and the diastereoselectivity of the nucleophilc addition was between 92 and 99% de, allowing isolation of the final product with 99% enantiomeric purity.

Topics: Alkynes; Aluminum Compounds; Imines; Methylation; Molecular Structure; Piperidines; Salts; Stereoisomerism; Sulfur

A synthesis of highly functionalized nitroalkenes is reported that utilizes a cross metathesis (CM) reaction between simple aliphatic nitro compounds and a range of substituted alkenes. This chemistry offers a simple and attractive route to nitroalkenes that would otherwise be difficult to prepare, and that have a very useful application as precursors to a variety of heterocyclic entities.

Topics: Alkenes; Cyclization; Cyclopentanes; Indicators and Reagents; Isoxazoles; Nitro Compounds; Piperidines

DNA structure has recently emerged as one of the key factors governing the ability of 5-bromodeoxyuridine (BrdU) to radiosensitize DNA. Here, we report the dependence of the specific damage induced by BrdU for different DNA conformations. Strand breaks are specific for B-form DNA, whereas A-DNA only undergoes formation of piperidine-sensitive DNA lesions. Interstrand cross-links are only found in semi-complementary B-DNA. DNA conformation was altered by gradually rehydrating lyophilized DNA samples, which induces an A- to B-form transition. These results were also validated by irradiating DNA in solution, in the presence or absence of 80% ethanol to induce an A- or B-form, respectively. Alkali-labile DNA lesions were revealed using hot piperidine to transform both base and sugar lesions into strand breaks. We also analyzed the location of damage as a function of DNA structure: piperidine-sensitive lesions were observed exclusively at the site of BrdU substitution, whereas strand breaks were able to migrate along the DNA strand, with a clear preference for the adenine 5' of the BrdU. Thus, not only the hybridization state but also the DNA conformation affect the degree of sensitization by BrdU by influencing the amount and type of damage produced. Although clinical trials using BrdU as a radiosensitizer have been disappointing up to this point, these new findings point to several key features of BrdU radiosensitization that may alter future radiotherapeutic studies.

Topics: Base Sequence; Bromodeoxyuridine; DNA; DNA Breaks; DNA Damage; DNA, Single-Stranded; Ethanol; Gamma Rays; Models, Biological; Nitrous Oxide; Nucleic Acid Conformation; Oligodeoxyribonucleotides; Piperidines; Radiation-Sensitizing Agents; Water

With the goal of developing Alzheimer's disease therapeutics, we have designed and synthesized new piperidine derivatives having dual action of acetylcholinesterase (AChE) and beta-amyloid peptide (Abeta) aggregation inhibition. For binding with the catalytic site of AChE, an ester with aromatic group was designed, and for the peripheral site, another aromatic group was considered. And for intercalating amyloid-beta oligomerization, long and linear conformation with a lipophilic group was considered. The synthetic methods employed for the structure with dual action depended on alcohols with an aromatic ring and the substituted benzoic acids, which are esterificated in the last step of the synthetic pathway. We screened these new derivatives through inhibition tests of acetylcholinesterase, butyrylcholinesterase (BChE), and Abeta(1-42) peptide aggregation, AChE-induced Abeta(1-42) aggregation. Our results displayed that compound 12 showed the best inhibitory potency and selectivity of AChE, and 29 showed the highest selectivity of BChE inhibition. Compounds 15 and 12 had inhibitory activities against Abeta(1-42) aggregation and AChE-induced Abeta aggregation. In the docking model, we confirmed that 4-chlorobenzene of 12 plays the parallel pi-pi stacking against the indole ring of Trp84 in the bottom gorge of AChE. Because the benzyhydryl moiety of 12 covered the peripheral site of AChE in a funnel-like shape, 12 showed good inhibitory potency against AChE and could inhibit AChE-induced Abeta(1-42) peptide aggregation.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Butyrylcholinesterase; Cell Line; Cell Survival; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Models, Molecular; Molecular Structure; Peptide Fragments; Piperidines; Protein Structure, Tertiary; Structure-Activity Relationship

The first asymmetric synthesis of the trans-3,4-dimethyl-4-arylpiperidine opioid antagonist scaffold is reported. C-3 stereochemistry was established via CBS reduction and stereoselective anti-SN2' cuprate displacement of the derived allylic phosphonate. The resultant vinyl bromide was then elaborated to the target compound by Suzuki coupling and trans-selective 4-methylation. Extension of this methodology should allow general enantioselective access to highly substituted piperidine ring systems.

Topics: Magnetic Resonance Spectroscopy; Methylation; Molecular Structure; Narcotic Antagonists; Piperidines; Receptors, Opioid; Stereoisomerism

A series of 6-mono-, di-, and trifluoro analogs of S-phenyl 2,3,4-tri-O-benzyl-D- or L-thiorhamnopyranoside has been synthesized and used as donors in glycosylation reactions, with activation by the 1-benzenesulfinyl piperidine/triflic anhydride system. The stereochemical outcome of the glycosylation reactions was found to depend on the electron-withdrawing capability of the disarming substituent at the 6-position, i.e., on the number of fluorine atoms present. The results are explained with regard to the increased stability of the glycosyl triflates, shown to be intermediates in the reaction by low-temperature 1H NMR experiments, with increased fluorine content.

Topics: Benzylidene Compounds; Carbohydrate Conformation; Carbohydrate Sequence; Fluorine; Furans; Glycosylation; Magnetic Resonance Spectroscopy; Models, Chemical; Molecular Sequence Data; Piperidines; Rhamnose; Stereoisomerism; Sulfonamides; Thioglycosides

SAR about the piperidine core in a series of MC4R agonists is described. A number of alkyl substituents that furnish compounds with good affinity and functional potency are reported.

Topics: Alkanes; Amides; Humans; Molecular Structure; Nitriles; Piperidines; Receptor, Melanocortin, Type 4; Structure-Activity Relationship; Tetrazoles

This paper describes the development of a new catalytic transformation, the ruthenium-catalyzed decarbonylative arylation of cyclic 2-amino esters, which replaces the ester group with an aryl ring at the sp3 carbon center. For example, proline ester amidine 1 is converted to 2-arylpyrrolidine 3 in the presence of arylboronic acids or esters as arene donors and Ru(3)(CO)(12) as the catalyst. This process provides a rapid access to a variety of 2-arylpyrrolidines and piperidines from commercially available proline, hydroxyproline, and pipecolinate esters. The examination of the substrate scope also showed that many arene boronic acids and boronate esters serve as coupling partners. The high chemoselectivity of this process was demonstrated and ascribed to the significant rate difference between the decarbonylative arylation and the C-H arylation. The decarbonylative arylation complements the C-H arylation, since the latter process lacks control over the extent of functionalization, affording a mixture of mono- and bis-arylpyrrolidines. When applied in tandem, these two processes provide 2,5-diarylpyrrolidines in two steps from the corresponding proline esters. It was also demonstrated that the required amidine or iminocarbamate directing group fulfills two major functions: first, it is essential for the ester activation step, which occurs via the coordination-assisted metal insertion into the acyl C-O bond; second, it facilitates the decarbonylation, via the stabilization of a metallacycle intermediate, assuring the formation of the 2-arylated products instead of the corresponding ketones observed before by others.

Topics: Boronic Acids; Carbon; Catalysis; Esters; Hydrocarbons, Aromatic; Hydroxyproline; Ketones; Models, Chemical; Piperidines; Proline; Pyrrolidines; Ruthenium; Stereoisomerism

Development of a lead series of piperidinylurea CXCR3 antagonists has led to the identification of molecules with alternative linkages which retain good potency. A novel 5-(piperidin-4-yl)amino-1,2,4-thiadiazole derivative was found to have satisfactory in vitro metabolic stability and to be orally bioavailable in mice, giving high plasma concentrations and a half life of 5.4h.

Topics: Amination; Animals; Azoles; CHO Cells; Cricetinae; Cricetulus; Humans; Mice; Models, Molecular; Molecular Structure; Piperidines; Receptors, CXCR3; Structure-Activity Relationship; Water

High-level ab initio calculations have been used to determine the oxidation and reduction potentials of a large number of nitroxides including derivatives of piperidine, pyrrolidine, isoindoline, and azaphenalene, substituted with COOH, NH2, NH3+, OCH3, OH, and NO2 groups, with a view to (a) identifying a low-cost theoretical procedures for the determination of electrode potentials of nitroxides and (b) studying the effect of substituents on these systems. Accurate oxidation and reduction potentials to within 40 mV (3.9 kJ mol(-1)) of experimental values were found using G3(MP2)-RAD//B3-LYP/6-31G(d) gas-phase energies and PCM solvation calculations at the B3-LYP/6-31G(d) level. For larger systems, an ONIOM method in which G3(MP2)-RAD calculations for the core are combined with lower-cost RMP2/6-311+G(3df,2p) calculations for the full system, was able to approximate G3(MP2)-RAD values (to within 1.6 kJ mol(-1)) at a fraction of the computational cost. The overall ring structure has more effect on the electrode potentials than the inclusion of substituents. Azaphenalene derivatives display the lowest oxidation potentials and least negative reduction potentials and are thus the most promising target to function as antioxidants in biological systems. Piperidine and pyrrolidine derivatives have intermediate oxidation potentials but on average pyrrolidine derivatives display more negative reduction potentials. Isoindoline derivatives show higher oxidation potentials and more negative reduction potentials. Within a ring, the substituents have a relatively small effect with electron donating groups such as amino and hydroxy groups stabilizing the oxidized species and electron withdrawing groups such as carboxy groups stabilizing the reduced species, as expected.

Topics: Antioxidants; Electrodes; Electrons; Models, Chemical; Nitrogen Oxides; Oxazoles; Oxidation-Reduction; Piperidines; Pyrrolidines; Thermodynamics

The dihydroxo(tetraphenylporphyrinato)antimony(V) complex (SbTPP) demonstrates bactericidal activity under visible-light irradiation. This phototoxic effect could be caused by photodamage to biomolecules, but the mechanism has not been well understood. In this study, to clarify the mechanism of phototoxicity by SbTPP, DNA damage photosensitized by SbTPP was examined using [(32)P]-5'-end-labeled DNA fragments. SbTPP induced markedly severe photodamage to single-stranded rather than to double-stranded DNA. Photo-irradiated SbTPP frequently caused DNA cleavage at the guanine residue of single-stranded DNA after Escherichia coli formamidopyrimidine-DNA glycosylase or piperidine treatment. HPLC measurement confirmed the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), an oxidation product of 2'-deoxyguanosine, and showed that the content of 8-oxodG in single-stranded DNA is larger than that in double-stranded DNA. The effects of scavengers of reactive oxygen species on DNA damage suggested the involvement of singlet oxygen. These results have shown that the mechanism via singlet oxygen formation mainly contributes to the phototoxicity of SbTPP. On the other hand, SbTPP induced DNA damage specifically at the underlined G of 5'-GG, 5'-GGG, and 5'-GGGG in double-stranded DNA. The sequence-specificity of DNA damage is quite similar to that induced by the type I photosensitizers, suggesting that photo-induced electron transfer slightly participates in the phototoxicity of SbTPP. In conclusion, SbTPP induces DNA photodamage via singlet oxygen formation and photo-induced electron transfer. A similar mechanism can damage other biomacromolecules, such as protein and the phospholipid membrane. The damage to biomacromolecules via these mechanisms may participate in the phototoxicity of SbTPP.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Deoxyguanosine; DNA; DNA Damage; DNA-Formamidopyrimidine Glycosylase; DNA, Single-Stranded; Electron Transport; Escherichia coli Proteins; Guanine; Light; Membrane Lipids; Metalloporphyrins; Oxidation-Reduction; Phospholipids; Photosensitizing Agents; Piperidines; Proteins; Singlet Oxygen

A novel series of 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives has been prepared and their synthesis described herein. In vitro affinities for delta-, mu-, and kappa-opioid receptors, as well as the functional activity in the [(35)S]GTPgammaS assay are reported. The most potent and selective delta-opioid agonist 18a exhibited a K(i) of 18 nM, and was >258-fold and 28-fold selective over mu- and kappa-receptors, respectively; the compound is a full agonist with an EC(50) value of 14 nM.

Topics: Binding, Competitive; Drug Design; Drug Industry; Imidazoles; Kinetics; Models, Chemical; Peptides; Piperidines; Receptors, Opioid, delta; Structure-Activity Relationship

Quinolinones and naphthyridinones with C7 N-t-butyl piperidine substituents were found to be potent p38 MAP kinase inhibitors. These compounds significantly suppress TNF-alpha release in both cellular and LPS-stimulated whole blood assays. They also displayed excellent PK profiles across three animal species. Quinolinone at 10 mpk showed comparable oral efficacy to that of dexamethasone at 1 mpk in a murine collagen-induced arthritis model.

Topics: Animals; Arthritis, Experimental; Collagen; Dexamethasone; Dogs; Enzyme Inhibitors; Haplorhini; Humans; Inhibitory Concentration 50; Lipopolysaccharides; Mice; Models, Chemical; Naphthyridines; p38 Mitogen-Activated Protein Kinases; Piperidines; Quinolones; Rats; Time Factors; Tumor Necrosis Factor-alpha

A novel series of non-imidazole H(3)-receptor antagonists was developed, by chemical modification of a potent lead H(3)-antagonist composed by an imidazole ring connected through an alkyl spacer to a 2-aminobenzimidazole moiety (e.g., 2-[[3-[4(5)-imidazolyl]propyl]amino]benzimidazole), previously reported by our research group. We investigated whether the removal of the imidazole ring could allow retaining high affinity for the H(3)-receptor, thanks to the interactions undertaken by the 2-aminobenzimidazole moiety at the binding site. The imidazole ring of the lead was replaced by a basic piperidine or by a lipophilic p-chlorophenoxy substituent, modulating the spacer length from three to eight methylene groups; moreover, the substituents were moved to the 5(6) position of the benzimidazole nucleus. Within both the 2-alkylaminobenzimidazole series and the 5(6)-alkoxy-2-aminobenzimidazole one, the greatest H(3)-receptor affinity was obtained for the piperidine-substituted compounds, while the presence of the p-chlorophenoxy group resulted in a drop in affinity. The optimal chain length was different in the two series. Even if the new compounds did not reach the high receptor affinity shown by the imidazole-containing lead compound, it was possible to get good H(3)-antagonist potencies with 2-aminobenzimidazoles having a tertiary amino group at appropriate distance.

Topics: Animals; Benzimidazoles; Binding Sites; Brain; Cells, Cultured; Chlorophenols; Histamine Antagonists; Imidazoles; Piperidines; Rats; Receptors, Histamine H3; Structure-Activity Relationship

Second-order rate constants (k(N)) have been determined spectrophotometrically for the reactions of 2,4-dinitrophenyl X-substituted benzoates (1 a-f) and Y-substituted phenyl benzoates (2 a-h) with a series of alicyclic secondary amines in MeCN at 25.0 +/- 0.1 degrees C. The k(N) values are only slightly larger in MeCN than in H2O, although the amines studied are approximately 8 pK(a) units more basic in the aprotic solvent than in H2O. The Yukawa-Tsuno plot for the aminolysis of 1 a-f is linear, indicating that the electronic nature of the substituent X in the nonleaving group does not affect the rate-determining step (RDS) or reaction mechanism. The Hammett correlation with sigma- constants also exhibits good linearity with a large slope (rho(Y) = 3.54) for the reactions of 2 a-h with piperidine, implying that the leaving-group departure occurs at the rate-determining step. Aminolysis of 2,4-dinitrophenyl benzoate (1 c) results in a linear Brønsted-type plot with a beta(nuc) value of 0.40, suggesting that bond formation between the attacking amine and the carbonyl carbon atom of 1 c is little advanced in the transition state (TS). A concerted mechanism is proposed for the aminolysis of 1 a-f in MeCN. The medium change from H2O to MeCN appears to force the reaction to proceed concertedly by decreasing the stability of the zwitterionic tetrahedral intermediate (T+/-) in aprotic solvent.

Topics: Acetonitriles; Amines; Benzoates; Kinetics; Morpholines; Piperidines

The interaction of the natural alkaloid berberine with various G-quadruplex DNA structures and its ability to inhibit telomerase have been examined and compared with those of a synthetic piperidino derivative and the related compound coralyne. The results show that these molecules have selectivity for G-quadruplex compared to duplex DNA, and that their aromatic moieties play a dominant role in quadruplex binding.

Topics: Antineoplastic Agents; Berberine Alkaloids; DNA; Humans; Intercalating Agents; Ligands; Nucleic Acid Denaturation; Nucleic Acid Heteroduplexes; Piperidines; Telomerase; Telomere

A series of competitive, reversible cathepsin S (CatS) inhibitors was investigated. An earlier disclosure detailed the discovery of the 4-(2-keto-1-benzimidazolinyl)-piperidin-1-yl moiety as an effective replacement for the 4-arylpiperazin-1-yl group found in our screening hit. Continued investigation into replacements for the 4-aryl piperazine resulted in the identification of potentially useful CatS inhibitors with enzymatic and cellular activity similar to that of JNJ 10329670 as disclosed in a previous publication.

Topics: Animals; Binding Sites; Bridged Bicyclo Compounds; Cathepsins; Cell Line, Tumor; Enzyme Inhibitors; Mice; Piperidines; Structure-Activity Relationship

The bradykinin 1 (B1) receptor is upregulated during times of inflammation and is important for maintaining inflamed and chronic pain states. Blocking this receptor has been shown to reverse and/or ameliorate pain and inflammation in animal models. In this report, we describe a new class of B1 receptor antagonists that contain the piperidine acetic acid tetralin core. A structure-activity relationship for these analogs is described in this paper. The most potent compounds from this class have IC50s<20 nM in a B1 receptor functional assay. One of these compounds, 13g, shows modest oral bioavailability in rats.

Topics: Acetic Acid; Administration, Oral; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biological Availability; Bradykinin B1 Receptor Antagonists; Inhibitory Concentration 50; Piperidines; Rats; Structure-Activity Relationship; Tetrahydronaphthalenes

Analysis of large, flexible molecules, such as the dopamine reuptake inhibitor GBR 12909 (1), is complicated by the fact that they can take on a wide range of closely related conformations. The first step in the analysis is to classify the conformers into groups. Here, Singular Value Decomposition (SVD) was used to group conformations of GBR 12909 analogs by the similarity of their nonring torsional angles. The significance of the present work, the first application of SVD to the analysis of very flexible molecules, lies in the development of a novel scaling technique for circular data and in the grouping of molecular conformations using a technique that is independent of molecular alignment. Over 700 conformers each of a piperazine (2) and piperidine (3) analog of 1 were studied. Analysis of the score and loading plots showed that the conformers of 2 separate into three large groups due to torsional angles on the naphthalene side of the molecule, whereas those of 3 separate into nine groups due to torsional angles on the bisphenyl side of the molecule. These differences are due to nitrogen inversion at the unprotonated piperazinyl nitrogen of 2, which results in a different ensemble of conformers than those of 3, where no inversion is possible at the corresponding piperidinyl carbon.

Topics: Computer Simulation; Dopamine Uptake Inhibitors; Molecular Structure; Piperazine; Piperazines; Piperidines

Many rhythmic behaviors are continuously modulated by endogenous peptides and amines, but whether neuromodulation is critical to the expression of a rhythmic behavior often remains unknown, particularly in mammals. Here, we address this issue in the respiratory network that was isolated in spontaneously rhythmic medullary slice preparations from mice. Under control conditions, the respiratory network generates fictive eupneic activity. We hypothesized previously that this activity depends on two types of pacemaker neurons. The bursting properties of one pacemaker rely on the persistent sodium current (INa(p)) and are insensitive to blockade of calcium channels with cadmium (CI-pacemakers), whereas bursting mechanisms of a second pacemaker are sensitive to cadmium (CS-pacemakers) and the calcium-dependent nonspecific cation current blocker flufenamic acid. During hypoxia, fictive eupneic activity is supplanted by the neural correlate of gasping, which is proposed to depend only on CI-pacemakers. Because CI-pacemakers require endogenous activation of 5-HT2A receptors, we tested the hypothesis that 5-HT2A receptor activation is critical for gasping. Here, we demonstrate that fictive gasping and CI-pacemaker bursting were selectively eliminated by the 5-HT2A receptor antagonist piperidine or ketanserin. Neither 5-HT2A antagonist eliminated bursting by CS-pacemakers and ventral respiratory group (VRG) population activity. However, this VRG activity was very different from eupneic activity. In the presence of 5-HT2A antagonists, VRG activity was eliminated by flufenamic acid and could not be reliably restored by adding substance P. These data support the hypothesis that two types of pacemaker bursting mechanisms underlie fictive eupnea, whereas only one burst mechanism is critical for gasping.

Topics: Action Potentials; Analysis of Variance; Animals; Animals, Newborn; Biological Clocks; Dose-Response Relationship, Drug; Drug Interactions; Flufenamic Acid; In Vitro Techniques; Ketanserin; Mice; Nerve Net; Neurons; Oxygen; Patch-Clamp Techniques; Piperidines; Receptor, Serotonin, 5-HT2A; Respiratory Burst; Respiratory Center; Respiratory Mechanics; Serotonin Antagonists; Substance P; Synaptic Transmission; Time Factors

Synthetic nitroxide antioxidants attenuate oxidative damage in various experimental models. Their protective effect reportedly depends on ring size and ring substituents and is greater for nitroxides having lower oxidation potential. The present study focuses on the kinetics and mechanisms of the reactions of piperidine, pyrrolidine and oxazolidine nitroxides with HO2*/O2*-, *NO2 and CO3*- radicals, which are key intermediates in many inflammatory and degenerative diseases. It is demonstrated that nitroxides are the most efficient scavengers of *NO2 at physiological pH (k = (3-9) x 10(8) M(-1) s(-1)) and among the most effective metal-independent scavengers of CO3*- radicals (k = (2 - 6) x 10(8) M(-1) s(-1)). Their reactivity toward HO2*, though not toward *NO2 and CO3*-, depends on the nature of the ring side-chain and particularly on the ring-size. All nitroxide derivatives react slowly with O2*- and are relatively inefficient SOD mimics at physiological pH. Even piperidine nitroxides, having the highest SOD-like activity, demonstrate a catalytic activity of about 1000-fold lower than that of native SOD at pH 7.4. The present results do not indicate any correlation between the kinetics of HO2*/O2*-, *NO2 and CO3*- removal by nitroxides and their protective activity against biological oxidative stress and emphasize the importance of target-oriented nitroxides, i.e., interaction between the biological target and specific nitroxides.

Topics: Antioxidants; Carbonates; Cyclic N-Oxides; Free Radical Scavengers; Free Radicals; Hydrogen-Ion Concentration; Kinetics; Molecular Mimicry; Nitrogen Dioxide; Oxazoles; Oxidation-Reduction; Piperidines; Pulse Radiolysis; Pyrrolidines; Structure-Activity Relationship; Superoxide Dismutase; Superoxides

The development of compound 1, a piperidine-based CCR5 receptor antagonist with Type I CYP2D6 inhibition, into the tropane-derived analogue 5, is described. This compound, which is devoid of CYP2D6 liabilities, is a highly potent ligand for the CCR5 receptor and has broad-spectrum activity against a range of clinically relevant HIV isolates. The identification of human ether a-go-go-related gene channel inhibition within this series is described and the potential for QTc interval prolongation discussed. Furthermore, structure activity relationship (SAR) around the piperidine moiety is also described.

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Cytochrome P-450 CYP2D6 Inhibitors; HIV-1; Humans; Models, Molecular; Piperidines; Receptors, CCR5; Structure-Activity Relationship; Tropanes

Tetrahydropapaveroline (THP), a metabolite of dopamine, has been suspected to be associated with dopaminergic neurotoxicity of L-DOPA. THP induced apoptosis in human leukemia cell line HL-60 cells, but did not in its hydrogen peroxide (H(2)O(2))-resistant clone HP100. THP-induced DNA ladder formation in HL-60 cells was inhibited by a metal chelator. THP induced damage to (32)P-labeled DNA fragments in the presence of metals. In the presence of Fe(III)EDTA, THP caused DNA damage at every nucleotide. The DNA damage was inhibited by free hydroxy radical ((.)OH) scavengers and catalase, suggesting that the Fe(III)EDTA-mediated DNA damage is mainly due to (.)OH generation. In the presence of Cu(II), THP caused DNA damage mainly at T and G of 5'-TG-3' sequence. The inhibitive effect of catalase and bathocuproine on Cu(II)-mediated DNA damage suggested that H(2)O(2) and Cu(I) participate in the DNA damage. This study demonstrated that THP-induced apoptosis via reactive oxygen species generated from reaction of H(2)O(2) and metals plays an important role in cytotoxicity of L-DOPA.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Apoptosis; Calcium Channel Blockers; Cattle; Copper; Deoxyguanosine; DNA Damage; DNA Fragmentation; Dopamine; Edetic Acid; Ferric Compounds; Free Radical Scavengers; HL-60 Cells; Humans; Ions; Iron Chelating Agents; Metals; Molecular Structure; Phenanthrolines; Piperidines; Tetrahydropapaveroline

The synthesis of d- and l-glycero-alpha-manno-thioheptopyranosides, protected with 4,6-O-alkylidene-type acetals is described. In glycosylations carried out with preactivation with the 1-benzenesulfinylpiperidine/trifluoromethanesulfonic anhydride couple, both the D- and L-glycero series exhibit excellent beta-selectivity with a range of glycosyl acceptors. In contrast, a 4,7-O-alkylidene acetal was found not to afford beta-selectivity. With a 4,6-O-[1-cyano-2-(2-iodophenyl)ethylidene] acetal protected thioglycoside, excellent beta-selectivity was obtained in glycosylation reactions, and subsequent treatment with tributyltin hydride and azoisobutyronitrile brought about clean fragmentation to the 6-deoxy-glycero-beta-D-manno-heptopyranosides. This chemistry was applied to the stereocontrolled synthesis of methyl alpha-L-rhamno-pyranosyl-(1-->3)-D-glycero-beta-D-manno-heptopyranosyl-(1-->3)-6-deoxy-glycero-beta-D-manno-heptopyranosyl-(1-->4)-alpha-L-rhamno-pyranoside, a component of the lipopolysaccharide from Plesimonas shigelloides.

Topics: Acetals; Alkenes; Azo Compounds; Carbohydrate Conformation; Carbohydrate Sequence; Deoxy Sugars; Glycosylation; Heptoses; Lipopolysaccharides; Mesylates; Methylglycosides; Models, Chemical; Molecular Sequence Data; Nitriles; Oligosaccharides; Piperidines; Plesiomonas; Rhamnose; Stereoisomerism; Sulfinic Acids; Trialkyltin Compounds

The present QSAR study attempts to explore the structural and physicochemical requirements of substituted 1-(3,3-diphenylpropyl)-piperidinyl amides and ureas for CCR5 binding affinity using linear free energy-related (LFER) model of Hansch. QSAR models have been developed using electronic (Hammett sigma), hydrophobicity (pi), and steric (molar refractivity and STERIMOL L, B1, and B5) parameters of phenyl ring substituents of the compounds along with appropriate dummy variables. Whole molecular descriptor like partition coefficient (logP(calcd)) was also tried as an additional descriptor. Statistical techniques like stepwise regression, multiple linear regression with factor analysis as the data preprocessing step (FA-MLR), partial least squares with factor analysis as the preprocessing step (FA-PLS), principal component regression analysis (PCRA), multiple linear regression with genetic function approximation (GFA-MLR), and genetic partial least squares (G/PLS) were applied to identify the structural and physicochemical requirements for the CCR5 binding affinity. The generated equations were statistically validated using leave-one-out technique. The quality of equations obtained from stepwise regression, FA-MLR, FA-PLS, and PCRA is of acceptable statistical range (explained variance ranging from 71.9% to 80.4%, while predicted variance ranging from 67.4% to 77.0%). The GFA-derived models show high intercorrelation among predictor variables used in the equations while the G/PLS model shows lowest statistical quality among all types of models. The best models were also subjected to leave-25%-out crossvalidation.

Topics: Amides; Piperidines; Quantitative Structure-Activity Relationship; Receptors, CCR5; Urea

Mycobacterium sp. strain THO100 and Rhodococcus sp. strain TM1 were isolated from a morpholine-containing enrichment culture of activated sewage sludge. Strain THO100, but not strain TM1, was able to degrade alicyclic amines such as morpholine, piperidine, and pyrrolidine. The mixed strains THO100 and TM1 showed a better growth on piperidine as the substrate than the pure strain THO100 because strain TM1 was able to reduce the level of glutaraldehyde (GA) produced during piperidine degradation. GA was toxic to strain THO100 (IC(50) = 28.3 microM) but less toxic to strain TM1 (IC(50) = 215 microM). Strain THO100 possessed constitutive semialdehyde dehydrogenases, namely Sad1 and Sad2, whose activities toward succinic semialdehyde (SSA) were strongly inhibited by GA. The two isozymes were identified as catalase-peroxidase (KatG = Sad1) and semialdehyde dehydrogenase (Sad2) based on mass spectrometric analyses of tryptic peptides and database searches of the partial DNA sequences of their genes. In contrast, strain TM1 containing another constitutive enzyme Gad1 could oxidize both SSA and GA. This study suggested that strain TM1 possessing Gad1 played a synergistic role in reducing the toxic and inhibitory effects of GA produced in the degradation of piperidine by strain THO100.

Topics: Amines; Amino Acid Sequence; Biodegradation, Environmental; Catalysis; Glutaral; Molecular Sequence Data; Molecular Structure; Morpholines; Mycobacterium; Piperidines; Pyrrolidines; Rhodococcus; RNA, Ribosomal, 16S; Sewage; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Succinate-Semialdehyde Dehydrogenase

In this paper, we report the synthesis of diastereomerically pure N-(4-substituted-2,4-diaminobutanoyl)piperidines. These compounds were prepared to investigate the influence of the 4-substitution on the dipeptidyl peptidase II (DPP II) activity and selectivity of the parent N-(2,4-diaminobutanoyl)piperidine. The (4S)-methyl compound showed subnanomolar inhibition, comparable with the parent compound. The (4R)-methyl group or bigger substituents decreased the activity.

Topics: Amination; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Inhibitory Concentration 50; Molecular Structure; Piperidines; Protease Inhibitors; Stereoisomerism

In our continuing effort to identify CGRP receptor antagonists for the acute treatment of migraine, we have undertaken a study to evaluate alternative 4-substituted piperidines to the lead dihydroquinazolinone 1. In this regard, we have identified the piperidinyl-azabenzimidazolone and phenylimidazolinone structures which, when incorporated into the benzodiazepine core, afford potent CGRP receptor antagonists (e.g., 18 and 29). These studies produced a potent analog (18) which overcomes the instability issues associated with the lead structure 1. A general pharmacophore for the 4-substituted piperidine component of these CGRP receptor antagonists is also presented.

Topics: Benzodiazepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Cyclic AMP; Drug Stability; Humans; Migraine Disorders; Piperidines; Protein Binding; Structure-Activity Relationship

Mycobacterium sp. strain THO100 was isolated from a morpholine-containing culture of activated sewage sludge. This strain was able to utilize pyrrolidine, morpholine, piperidine, piperazine, and 1,2,3,6-tetrahydropyridine as the sole sources of carbon, nitrogen, and energy. The degradation pathway of pyrrolidine as the best substrate for cellular growth was proposed based on the assays of substrate-induced cytochrome P450 and constitutive enzyme activities toward 4-aminobutyric acid (GABA) and succinic semialdehyde (SSA). Its 16S ribosomal RNA gene sequence (16S rDNA) was identical to that of Mycobacterium tokaiense ATCC 27282(T). The morABC genes responsible for alicyclic amine degradation were nearly identical among different species of Mycobacteria. Remarkably, repetitive sequences at the intergenic spacer (IGS) region between morC and orf1' were detected by comparison of the nearly identical mor gene cluster regions. Considering the strain activity for alicyclic amine degradation, the deleted 65-bp DNA segment did not significantly alter the open reading frames, and the expression and functions of the P450(mor) system remained unaltered. In addition, we found a spontaneous deletion of P450(mor) from another strain HE5 containing the archetypal mor gene cluster, which indicated a possible occurrence of DNA recombination to rearrange the DNA.

Topics: Amines; Biodegradation, Environmental; Genes, Bacterial; Germany; Industrial Microbiology; Morpholines; Multigene Family; Mycobacterium; Phylogeny; Piperidines; Pyrrolidines; Sequence Homology; Sewage; Species Specificity; Waste Disposal, Fluid

All the nine 1,3-dialkylated-pyrimidin-2,4-diones investigated are active against all the 59 human tumor cell lines. Compounds 2, 3, 4, and 6 show significant anti-cancer activities at some specific cell lines while compounds 7 and 9 exhibit anti-cancer activities against more number of cell lines. The structure-activity relationship studies indicate that the presence of piperidine/pyrrolidine at the end of C-6 chain, benzoyl group at C-5, and benzyl groups at N-1, N-3 of the pyrimidine ring increases the anti-cancer activities of these molecules.

Topics: Antineoplastic Agents; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Neoplasms; Piperidines; Propanolamines; Pyrimidines; Pyrimidinones; Pyrrolidines; Structure-Activity Relationship

This Letter describes the synthesis and SAR, developed through an iterative analog library approach, of potent and selective non-sarcosine-derived GlyT1 inhibitors.

Topics: Amides; Animals; Benzamides; Glycine Plasma Membrane Transport Proteins; Humans; Methylation; Mice; Molecular Structure; Morpholines; Piperidines; Rats; Structure-Activity Relationship

The access to piperidine homoazasugars (dideoxyiminoheptitols) from pyranoses via formal one-carbon chain elongation and exchange of the ring oxygen with the NH group is described. The key process involves the stereoselective addition of 2-thiazolylmagnesium bromide to an N-glycosylhydroxylamine, i.e., a hidden open-chain sugar nitrone. The N-thiazolylalkylhydroxylamine formed in this way is reduced to amine, and this transformed into a substituted piperidine via intramolecular cyclization by an S(N)2 process. Cleavage of the thiazole residue attached to C2 of the piperidine ring reveals the formyl group, and this is reduced to hydroxymethyl to give the target homoazasugar. A collection of six stereodiversified compounds with free OH and NH groups and isolated as hydrochlorides has been prepared.

Topics: Amines; Glycosides; Imino Sugars; Monosaccharides; Piperidines; Stereoisomerism; Thiazoles

A series of sulfonamides has been obtained by reacting sulfanilamide or 5-amino-1,3,4-thiadiazole-2-sulfonamide with omega-chloroalkanoyl chlorides, followed by replacement of the omega-chlorine atom with secondary amines. Tails incorporating heterocyclic amines belonging to the morpholine, piperidine and piperazine ring systems have been attached to these sulfonamides, by means of an alkanoyl-carboxamido linker containing from two to five carbon atoms. The new derivatives prepared in this way were tested as inhibitors of three carbonic anhydrase (CA, EC 4.2.1.1) isozymes, the cytosolic isozymes CA I and II, and the catalytic domain of the transmembrane, tumor-associated isozyme CA IX. Several low nanomolar CA I and CA II inhibitors were detected both in the aromatic and heterocyclic sulfonamide series, whereas the best hCA IX inhibitors (inhibition constants in the range of 22-35 nM) all belonged to the acetazolamide-like derivatives.

Topics: Acetazolamide; Amines; Biomarkers, Tumor; Carbonic Anhydrase Inhibitors; Catalysis; Cytosol; Heterocyclic Compounds; Humans; Isoenzymes; Morpholines; Piperazine; Piperazines; Piperidines; Structure-Activity Relationship; Sulfanilamide; Sulfanilamides

Oxidative guanine lesions were analyzed, at the nucleotide level, within DNA exposed to nanosecond ultraviolet (266 nm) laser pulses of variable intensity (0.002-0.1 J/cm(2)). Experiments were carried out, at room temperature, in TE buffer (20 mM Tris-HCl, pH 7.5; 1 mM EDTA) containing 35 mM NaCl, on 5'-end radioactively labeled double-stranded and single-stranded oligomer DNA at a size of 33-37 nucleobases. Lesions were analyzed on polyacrylamide gel electrophoresis by taking advantage of the specific removal of 8-oxodG from DNA by the formamidopyrimidine DNA glycosylase (Fpg protein) and of the differential sensitivity of 8-oxodG and oxazolone to piperidine. The quantum yields of lesions at individual sites, determined from the normalized intensities of bands, were plotted against the irradiation energy levels. Simplified model fitting of the experimental data enabled to evaluate the spectroscopic parameters characterizing excitation and photoionization processes. Results show that the distribution of guanine residues, excited to the lowest triplet state or photoionized, is heterogeneous and depends on the primary and secondary DNA structure. These findings are generalized in terms of excitation energy and charge-migration mediated biphotonic ionization. On the basis of the changes in the yield of the guanyl radical resulting from local helical perturbations in the DNA pi-stack, it can be assessed that the distance range of migration is <6-8 bp.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Base Sequence; Biophysical Phenomena; Biophysics; Cations; Deoxyguanosine; Dimerization; DNA; DNA-Formamidopyrimidine Glycosylase; Edetic Acid; Electrophoresis, Polyacrylamide Gel; Free Radicals; Guanine; Ions; Lasers; Models, Chemical; Models, Statistical; Molecular Sequence Data; Nucleic Acid Conformation; Oligonucleotides; Oxazolone; Oxygen; Photolysis; Photons; Piperidines; Polymers; Pyrimidine Dimers; RNA; Spectrophotometry; Temperature; Ultraviolet Rays

In this paper we describe the stereoselective synthesis of functionalized lactam 7 via two enantiospecific piperidine-forming techniques and its employment in a general synthetic approach to Nuphar alkaloids. Specifically, the formation of piperidine 18 by formal [3 + 3] cycloaddition and stepwise annelation processes is described; the latter technique was found to be significantly more efficient than the Pd-catalyzed TMM addition process. Finally, exploitation of the exocyclic alkene installed in the piperidine-forming reaction in the transformation of 18 to (-)-deoxynupharidine ((-)-2), (-)-castoramine ((-)-3), and (-)-nupharolutine ((-)-4) via intermediate lactam 7 is delineated.

Topics: Alkaloids; Catalysis; Combinatorial Chemistry Techniques; Lactams; Molecular Structure; Nuphar; Palladium; Piperidines; Plants, Medicinal; Quinolizines; Stereoisomerism

The design and synthesis of a potentially more therapeutically-viable azinomycin analogue 4 based upon 3 has been completed. It involved coupling of a piperidine mustard to the acid chloride of the azinomycin chromophore. Both the designed azinomycin analogue 4 and the natural product 3 bind to DNA and cause unwinding, supporting an intercalative mode of binding.

Topics: Antibiotics, Antineoplastic; Azabicyclo Compounds; Cell Line, Tumor; Cell Survival; Dipeptides; DNA; Glycopeptides; Humans; Intercalating Agents; Nucleic Acid Denaturation; Piperidines; Structure-Activity Relationship

We have evaluated the cytotoxic properties against the protozoan Leishmania infantum of four water soluble cationic trans-Pt(II)Cl(2) compounds containing as inert groups NH3 and piperazine (1), 4-picoline and piperazine (2), n-butylamine and piperazine (3), and NH3 and 4-piperidino-piperidine (4). The leishmanicidal activity of compounds 3 and 4 against promastigotes of the parasite Leishmania infantum was 2.5- and 1.6-times higher than that of the cytotoxic drug cis-diamminedichloroplatinum(II), respectively. Interestingly, compounds 3 and 4 produce in Leishmania infantum promastigotes a higher amount of programmed cell death than cisplatin, which is associated with cell cycle arrest in G2/M. In contrast to cis-diamminedichloroplatinum(II), binding of compounds 3 and 4 to calf thymus DNA induces conformational changes more similar to those of trans-diamminedichloroplatinum(II) that may be attributed to denaturation of the double helix. Similarly to cis-diamminedichloroplatinum(II) and trans-diamminedichloroplatinum(II), the interaction of compounds 3 and 4 with ubiquitin results in an increase of the alpha-helix content of the protein as observed by circular dichroism spectroscopy. However, fluorescence studies indicate that compounds 3 and 4 produce a decrease in the fluorescence of the tyrosine 59 residue of ubiquitin higher than both cis-diamminedichloroplatinum(II) and trans-diamminedichloroplatinum(II). Altogether, our results suggest that the biochemical mechanism of cytotoxic activity of compounds 3 and 4 against Leishmania infantum must be different from that of cis-diamminedichloroplatinum(II). To the best of our knowledge, compounds 3 and 4 are the first reported trans-platinum complexes that show antiparasitic activity.

Topics: Amino Acid Sequence; Animals; Antineoplastic Agents; Apoptosis; Binding Sites; Butylamines; Cations; Cisplatin; DNA; Leishmania infantum; Molecular Sequence Data; Picolines; Piperazine; Piperazines; Piperidines; Platinum Compounds; Stereoisomerism; Structure-Activity Relationship; Tumor Cells, Cultured; Ubiquitin; Water

The formation of covalent cross-links between amino acid side chains and DNA bases in DNA-protein complexes is a significant pathway in oxidative damage to the genome, yet much remains to be learned about their chemical structures and mechanisms of formation. In the present study, DNA-protein cross-links (DPCs) were formed between synthetic oligodeoxynucleotides containing an 8-oxo-7,8-dihydro-2'deoxyguanosine (OG) or an 8-oxo-7,8-dihydro-2'-deoxyadenosine (OA) nucleotide and Escherichia coli singled-stranded binding protein (SSB) under oxidative conditions. Studies with various sequences indicated that DNA homopolymers and those lacking 8-oxopurines were less reactive toward DPC formation. DPCs were formed in the presence of HOCl, peroxynitrite, and the one-electron oxidants Na(2)IrCl(6), Na(2)IrBr(6), and Na(3)Fe(CN)(6). Protein-protein cross-linking was also observed, particularly for oxidants of high reduction potential such as Na(2)IrCl(6). The adducted oligodeoxynucleotides were sensitive to hot piperidine treatment leading to strand scission at the site of cross-linking. In addition, the covalent cross-links were somewhat heat and acid labile, which may be related to the difficulties encountered in obtaining complete characterization of trypsin digests of the DPCs. However, model reactions involving the single amino acids lysine, arginine, and tyrosine, residues known to be involved in base contacts in the DNA:SSB complex, could be studied, and the adduct formed between N(alpha)-acetyllysine methyl ester and an 18-mer containing OG was tentatively characterized by electrospray ionization mass spectrometry as analogues of spiroiminodihydantoin and guanidinohydantoin. A mechanism involving nucleophilic attack of an amino acid side chain (e.g. the epsilon-amino group of lysine) at C5 of a 2-electron oxidized form of OG is proposed.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Amino Acids; Base Sequence; Binding Sites; Cross-Linking Reagents; Deoxyguanosine; DNA Adducts; DNA-Binding Proteins; DNA, Bacterial; DNA, Single-Stranded; Escherichia coli; Escherichia coli Proteins; Hot Temperature; Hydrogen-Ion Concentration; Macromolecular Substances; Models, Molecular; Nucleic Acid Conformation; Oligodeoxyribonucleotides; Oxidation-Reduction; Piperidines; Protein Conformation; Spectrometry, Mass, Electrospray Ionization

Vapor adsorption is an important process influencing the migration and the fate of many organic pollutants in the environment. In this study, vibrational sum frequency generation (SFG) spectroscopy was used to study the adsorption of two surface acidity probe molecules, 4-picoline (pKa = 5.94) and piperidine (pKa = 11.24), onto the amorphous SiO2 surface. The adsorption of 4-picoline onto the silica surface occurs by forming weak hydrogen bonds between the nitrogen atoms of 4-picoline molecules and the hydrogen atoms of surface silanol OH groups. Piperidine molecules are strongly chemisorbed onto the SiO2 surface through the protonation of piperidine molecules by surface silanol OH groups. The SFG results indicate that the surface acidity constant of silanol OH groups (pKa-(HOSi triple bond)) is in the range of 5.94-11.24 at the air/solid interface. Although this range of surface acidity constants is quite wide, it is possible to narrow it by choosing probe molecules with a smaller pKa range. Together with theoretical prediction methods, adsorption studies using vibrational SFG spectroscopy are capable of quantifying the surface acidity of mineral oxides by carefully choosing the acidity probe molecules.

Topics: Adsorption; Air Pollutants; Hydrogen-Ion Concentration; Picolines; Piperidines; Silicon Dioxide; Spectrum Analysis; Volatilization

Five new piperidine alkaloids were designed from natural (-)-3-O-acetyl-spectaline and (-)-spectaline that were obtained from the flowers of Senna spectabilis (sin. Cassia spectabilis, Leguminosae). Two semi-synthetic analogues (7 and 9) inhibited rat brain acetylcholinesterase, showing IC50 of 7.32 and 15.1 microM, and were 21 and 9.5 times less potent against rat brain butyrylcholinesterase, respectively. Compound 9 (1mg/kg, i.p.) was fully efficacious in reverting scopolamine-induced amnesia in mice. The two active compounds (7 and 9) did not show overt toxic effects at the doses tested in vivo.

Topics: Acetylcholinesterase; Alkaloids; Amnesia; Animals; Brain; Butyrylcholinesterase; Cholinesterase Inhibitors; Drug Design; Flowers; Male; Mice; Molecular Structure; Muscarinic Antagonists; Piperidines; Plant Extracts; Plants, Medicinal; Rats; Rats, Wistar; Scopolamine; Structure-Activity Relationship

Since its discovery 12 years ago, aminoethylglycyl peptide nucleic acid (aeg-PNA) has emerged as one of the successful DNA mimics for potential therapeutic and diagnostic applications. An important requisite for in vivo applications that has received inadequate attention is engineering PNA analogues for able discrimination between DNA and RNA as binding targets. Our approach toward this aim is based on structural preorganization of the backbone to hybridization-competent conformations to impart binding selectivity. This strategy has allowed us to design locked PNAs to achieve specific hybridization with DNA or RNA with aims to increase the binding strength without losing the binding specificity. This Account presents results of our rationale in design of different conformationally constrained PNA analogues, their synthesis, and evaluation of hybridization specificities.

Topics: Amino Acid Sequence; Directed Molecular Evolution; DNA; Molecular Sequence Data; Nucleic Acid Conformation; Peptide Nucleic Acids; Piperidines; Proline; Pyrrolidines; RNA; Substrate Specificity

A series of 3-aryl piperidine analogs with 2-piperidinoalkylamino or 2-piperidinoalkyloxy fused bicyclic rings were prepared and found to be potent and efficacious human dopamine D4 agonists. The synthesis and structure-activity relationship (SAR) studies that led to the identification of these compounds are discussed.

Topics: Cell Line; Dopamine Agonists; Humans; Ligands; Molecular Structure; Piperidines; Receptors, Dopamine D2; Receptors, Dopamine D4; Structure-Activity Relationship

The current research aimed to investigate the importance of the heterocyclic ring system in the structure of the cardiovascular drug diltiazem for its calcium channel blocking activity. The manuscript describes the design, synthesis, and biological testing of a total of 10 S-(p-methoxybenzyl), N-substituted thiosalicylamides as a series of non-cyclic compounds derived from diltiazem's structure. The new compounds maintained all diltiazem pharmacophores except the thiazepine ring system. In vitro evaluation of the new series for calcium channel blocking effects revealed moderate activities with IC50 values in the range of 4.8-56.0 microM. The data suggest that the ring system is not essential for activity; however, its absence leads to a considerable drop of activity relative to that of diltiazem (IC50=0.3 microM). Compounds of the current series showed optimum activity when the aliphatic alkyl chain on the salicylamide nitrogen is part of a piperidine or piperazine ring system substituted at the terminal nitrogen with a benzyl group.

Topics: Animals; Aorta; Calcium Channel Blockers; Calcium Channels; Diltiazem; Drug Design; Male; Molecular Structure; Piperazine; Piperazines; Piperidines; Rats; Rats, Wistar; Salicylamides; Structure-Activity Relationship

DNA shuffling is widely used for optimizing complex properties contained within DNA and proteins. Demonstrated here is the amplification of a gene library by PCR using uridine triphosphate (dUTP) as a fragmentation defining exchange nucleotide with thymidine, together with the three other nucleotides. The incorporated uracil bases were excised using uracil-DNA-glycosylase and the DNA backbone subsequently cleaved with piperidine. These end-point reactions required no adjustments. Polyacrylamide urea gels demonstrated adjustable fragmentation size over a wide range. The oligonucleotide pool was reassembled by internal primer extension to full length with a proofreading polymerase to improve yield over Taq. We present a computer program that accurately predicts the fragmentation pattern and yields all possible fragment sequences with their respective likelihood of occurrence, taking the guesswork out of the fragmentation. The technique has been demonstrated by shuffling chloramphenicol acetyltransferase gene libraries. A 33% dUTP PCR resulted in shuffled clones with an average parental fragment size of 86 bases even without employment of a fragment size separation, and revealed a low mutation rate (0.1%). NExT DNA fragmentation is rational, easily executed and reproducible, making it superior to other techniques. Additionally, NExT could feasibly be applied to several other nucleotide analogs.

Topics: Chloramphenicol O-Acetyltransferase; Deoxyribonuclease (Pyrimidine Dimer); Deoxyuracil Nucleotides; Directed Molecular Evolution; DNA Fragmentation; DNA Shuffling; DNA-Directed DNA Polymerase; Electrophoresis, Polyacrylamide Gel; Gene Library; Nucleotides; Piperidines; Polymerase Chain Reaction; Software; Taq Polymerase; Thymine Nucleotides

SAR and DMPK studies led to the identification of substituted N-alkyl-N-[1-(3,3-diphenylpropyl)piperidin-4-yl]-2-phenylacetamides as potent and orally bioavailable ligands for the human CCR5 chemokine receptor.

Topics: Animals; Benzeneacetamides; Biological Availability; CCR5 Receptor Antagonists; Humans; Inhibitory Concentration 50; Ligands; Molecular Structure; Piperidines; Rats; Receptors, CCR5; Structure-Activity Relationship

The reactions of [RuHCl(CO)(PPh3)2(B)] (B = PPh3, pyridine or piperidine) and 2'-hydroxychalcones led to the formation of [RuCl(CO)(PPh3)(L)(B)] (L = chalconate). The new complexes have been characterized by analytical and spectral (IR, electronic, 1H NMR and 31P NMR) data. They have been assigned an octahedral structure. The complexes have been used as catalysts for the aerial oxidation of cinnamyl alcohol. Some of the complexes have been tested in vitro for growth inhibitory activity against the bacteria E. coli, S. typhi and Pseudomonas sp. and the fungi A. fumigatus.

Topics: Anti-Bacterial Agents; Antifungal Agents; Aspergillus fumigatus; Carbon Monoxide; Catalysis; Chalcones; Chlorides; Gram-Negative Bacteria; Hydrogen; Magnetic Resonance Spectroscopy; Molecular Structure; Oxidation-Reduction; Piperidines; Pyridines; Ruthenium; Staphylococcaceae

The synthesis and biological evaluation of novel 3-amino indazole melanin concentrating hormone receptor-1 antagonists are reported, several of which demonstrated functional activity of less than 100nM. Compounds 19 and 28, two of the more potent compounds identified in this study, were characterized by high exposure in the brain and demonstrated robust efficacy when dosed in diet-induced obese mice.

Topics: Administration, Oral; Animals; Anti-Obesity Agents; Humans; Indazoles; Mice; Piperidines; Receptors, Somatostatin; Tissue Distribution

[reaction: see text] Spiro-ladder oligomers of designed shape were assembled from a set of two enantiomeric bis-amino acid monomers. Two tetramers of differing monomer sequence were synthesized to study the effect of monomer stereochemistry upon macromolecular shape. Two-dimensional NMR experiments were used to determine the conformational preference of the monomers within the context of the oligomers. The results of this structural study were used to design two pentamers: one resembling a rod and another with a curved shape. The pentamers were end-labeled with naphthyl and dansyl groups. The design hypothesis was confirmed by measuring the efficiency of fluorescence resonance energy transfer between the naphthyl and dansyl fluorophore pair.

Topics: Amino Acids; Magnetic Resonance Spectroscopy; Molecular Structure; Piperidines; Stereoisomerism

Synthesis of novel piperidinyl linker based ET cassettes and terminators is described These novel terminators are evaluated in the DNA sequencing experiments using thermostable DNA polymerase.

Topics: DNA; DNA-Directed DNA Polymerase; Energy Transfer; Fluorescent Dyes; Hot Temperature; Indicators and Reagents; Models, Chemical; Nucleic Acid Conformation; Nucleic Acid Denaturation; Piperidines; Sequence Analysis, DNA; Spectrometry, Fluorescence

Anthranilamide analogues such as 23 are potent and highly selective muscarinic M2 antagonists that also show good oral bioavailability and in vivo activity.

Topics: Animals; Avoidance Learning; Biochemistry; Biological Availability; CHO Cells; Cricetinae; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Muscarinic Antagonists; ortho-Aminobenzoates; Piperidines; Rats; Receptor, Muscarinic M2; Structure-Activity Relationship

Topics: Base Sequence; DNA; Electron Transport; Electrons; Molecular Sequence Data; Molecular Structure; Oligodeoxyribonucleotides; Photochemistry; Piperidines; Ultraviolet Rays

Insight in the steric and electronic parameters governing isomerization processes in artificial molecular motors is essential in order to design more advanced motor systems. A subtle balance of steric parameters and the combination of helical and central chirality are key features of light-driven unidirectional rotary molecular motors constructed so far. In an approach to decrease the steric hindrance around the central olefinic bond (rotary axis) and thereby lowering the energy barrier for helix inversion resulting in an increased rotation rate, the boundaries of our molecular motor design are explored. In a new design of a light-driven molecular motor based on a sterically overcrowded alkene the methyl substituent adjacent to the stereogenic center, which is responsible for the control of the direction of rotation, is shifted one position away from the fjord region of the molecule compared to the second-generation motor systems. In contrast to previously developed light-driven molecular motors, there is a preference for the methyl substituent to adopt a pseudo-equatorial orientation. Nevertheless, this new type of motor is capable of functioning as a rotary molecular motor, albeit not with full unidirectionality. Under the combined influence of light and heat, there is a preferred clockwise rotation of one half of the molecule. Surprisingly, the effect of shifting the methyl substituent on the energy barrier for helix inversion is small and even a slight increase in the barrier is observed.

Topics: Alkenes; Circular Dichroism; Crystallography, X-Ray; Cyclization; Heterocyclic Compounds, 3-Ring; Hot Temperature; Hydrazones; Isomerism; Light; Models, Molecular; Molecular Conformation; Naphthalenes; Nitriles; Photochemistry; Piperidines; Rotation; Spectrophotometry, Ultraviolet; Stereoisomerism; Sulfhydryl Compounds; Sulfur Compounds; Thermodynamics

Cellular proliferation of HIV-1 requires the cooperative assistance of both the CCR5 and CD4 receptors. Our medicinal chemistry efforts in this area have resulted in the identification of N-alkyl piperidine sulfones as CCR5 antagonists. These compounds display potent binding and show antiviral properties in HIV-1 spread cell-based assays.

Topics: Anti-HIV Agents; Binding Sites; CCR5 Receptor Antagonists; CD4 Antigens; Cell Line; Drug Design; Humans; Inhibitory Concentration 50; Piperidines; Receptors, CCR5; Stereoisomerism; Structure-Activity Relationship; Sulfones

Several 1-aryl-2-phenyl-4-piperidino-4-thioalkyl-1,3-diazabuta-1,3-dienes were prepared by the treatment of N-arylimino isothiocyanate with piperidine followed by S-alkylation with alkyl iodides in the presence of dry acetone and potassium hydroxide. The constitution of the products was supported by IR, PMR and mass spectral study. The compounds synthesized were tested in in vitro against E. coli, S. aureus, P. aeruginosa, B. cereus and B. subtilis and fungal stains, Candida albicans and Aspergillus niger. Standard drugs were also tested under identical conditions for comparing the results.

Topics: Alkylation; Amidines; Anti-Bacterial Agents; Antifungal Agents; Butadienes; Candida albicans; Gram-Negative Bacteria; Gram-Positive Bacteria; Isothiocyanates; Molecular Structure; Piperidines

A series of new 1-[4-(indol-3-yl)butyl]-4-arylpiperazines was prepared to identify highly selective and potent 5-HT(1A) agonists as potential pharmacological tools in studies of mood disorders. The combination of structural elements (indole-alkyl-amine and aryl-piperazine) known to introduce 5-HT(1A) receptor affinity and the proper selection of substituents (R on the indole moiety and R' on the aryl moiety) led to compounds with high receptor specificity and affinity. In particular, the introduction of the methyl ether or the unsubstituted carboxamide as substituents in position 5 of the indole (R) guaranteed serotonergic 5-HT(1A) affinity compared to the unsubstituted analogue. Para-substituted arylpiperazines (R') decreased dopaminergic D(2) binding and increased selectivity for the 5-HT(1A) receptor. Agonistic 5-HT(1A) receptor activity was confirmed in vivo in the ultrasonic vocalization test, and the results suggest that the introduction of the carboxamide residue leads to better bioavailability than the corresponding methyl ether. 3-[4-[4-(4-Carbamoylphenyl)piperazin-1-yl]butyl]-1H-indole-5-carboxamide 54 was identified as a highly selective 5-HT(1A) receptor agonist [GTPgammaS, ED(50) = 4.7 nM] with nanomolar 5-HT(1A) affinity [IC(50) = 0.9 nM] and selectivity [D(2), IC(50) > 850 nM]. 3-[4-[4-(4-Methoxyphenyl)piperazin-1-yl]butyl]-1H-indole-5-carboxamide 45 is one of the most potent and selective 5-HT(1A) agonists known [5-HT(1A), IC(50) = 0.09 nM; D(2), IC(50) = 140 nM].

Topics: Animals; Biological Availability; Butylamines; Hippocampus; Humans; Indoles; Inhibitory Concentration 50; Male; Molecular Structure; Oxindoles; Piperidines; Pyridines; Rats; Receptor, Serotonin, 5-HT1A; Serotonin 5-HT1 Receptor Agonists; Structure-Activity Relationship; Substrate Specificity

The diepoxide mycotoxin (2R, 3R, 8R, 9R)-4,6-decadiyne-2,3:8,9-diepoxy-1,10-diol (repandiol) was both isolated from the mushroom Hydnum repandum and synthesized de novo. Repandiol was found to form interstrand cross-links within a restriction fragment of DNA, linking deoxyguanosines on opposite strands primarily within the 5'-GNC and 5'-GNNC sequences preferred by diepoxyoctane. However, repandiol was a significantly less efficient cross-linker than either of the diepoxyalkanes (diepoxyoctane and diepoxybutane) to which it was compared.

Topics: Alkynes; Base Sequence; Cross-Linking Reagents; Cytotoxins; DNA; Epoxy Compounds; Molecular Sequence Data; Piperidines; Structure-Activity Relationship

Six cadmium(II) halide complexes with dl-piperidine-2-carboxylic acid (DL-Hpipe-2), dl-piperidine-3-carboxylic acid (DL-Hpipe-3), and piperidine-4-carboxylic acid (Hpipe-4), have been prepared and characterized by means of IR and Raman spectra and thermal analysis. The crystal structures of [CdCl2(DL-Hpipe-2)(H2O)], [CdBr2(DL-Hpipe-3)], and [CdCl2(Hpipe-4)] have been determined by X-ray diffraction. These three complexes have one-dimensional polymer structures bridged by halide atoms. The crystal of [CdCl2(DL-Hpipe-2)(H2O)] is orthorhombic with the space group Pca2(1). The cadmium atom is in an octahedral geometry, ligated by a carboxyl oxygen atom, two bridging chlorine atoms, a terminal chlorine atom, a water molecule and a carboxyl oxygen atom of a neighboring molecule. The carboxyl oxygen atoms of DL-Hpipe-2 are coordinated to two cadmium atoms. The unit cell consists of two types of one-dimensional polymer structures: [CdCl2(D-Hpipe-2)(H2O)] and [CdCl2(L-Hpipe-2)(H2O)]. Therefore, it is better to write [CdCl2(DL-Hpipe-2)(H2O)] as [CdCl2(D-Hpipe-2)(H2O)][CdCl2(L-Hpipe-2)(H2O)]. The crystal structure of [CdBr2(DL-Hpipe-3)] is monoclinic with space group P2(1). The cadmium atom is in a distorted octahedral geometry ligated by two carboxyl oxygen atoms and four bridging bromine atoms. This complex consists of either D-Hpipe-3 or L-Hpipe-3. Therefore [CdBr2(DL-Hpipe-3)] is written as [CdBr2(D or L-Hpipe-3)]. The crystal of [CdCl2(Hpipe-4)] is monoclinic with space group P2(1)/n. The structure is similar to that of [CdBr2(D or L-Hpipe-3)].

Topics: Amino Acids; Cadmium; Carboxylic Acids; Ligands; Molecular Conformation; Piperidines; Spectrophotometry, Infrared; Spectrum Analysis, Raman; Water; X-Ray Diffraction

2-methyl-1,4-naphthoquinone (menadione, MQ) was linked to synthetic oligonucleotides and exposed to near-UV light to generate base radical cations in DNA. This model system of electron transfer induced alkali-labile breaks at GG doublets, similar to anthraquinone and metallointercalators systems. In sharp contrast to other systems, the photolysis of MQ-DNA duplexes gave interstrand cross-links and alkali-labile breaks at bases on the complementary strand opposite the MQ moiety. For sequences with an internal MQ, the formation of cross-links with A and C opposite the MQ moiety was 2- to 3-fold greater than that with G and T. The yield of cross-links was more than 10-fold greater than that of breaks opposite MQ, which in turn was more than 2-fold greater than breaks at GG doublets. The yield of damage at GG doublets greatly increased for a sequence with a terminal MQ. The distribution of base damage was measured by enzymatic digestion and HPLC analysis (dAdo > dThd > dGuo > dCyd). The formation of novel products in MQ-DNA duplexes was attributed to the ability of excited MQ to generate the radical cations of all four DNA bases; thus, this photochemical reaction provides an ideal model system to study the effects of ionizing radiation and one-electron oxidants.

Topics: Chromatography, High Pressure Liquid; DNA; DNA Damage; Electrons; Electrophoresis, Polyacrylamide Gel; Oligonucleotides; Piperidines; Ultraviolet Rays; Vitamin K 3

The reactions of 2-chloropyrimidine with methylamine, ethylamine and piperidine gave the corresponding 2-N-methylamino-, 2-N-ethylamino- and 2N- piperidinopyrimidines, respectively. The fluorescence properties of these alkylamino derivatives in chloroform, ethyl acetate, carbon tetrachloride, acetone, ether, ethanol and methanol were studied. All the alkylamino derivatives showed the highest fluorescence intensity in polar protic solvents; thus 2-N-methylaminopyrimidine (highest fluorescence intensity at 377 nm when excited at 282 nm) and 2-N-ethylaminopyrimidine (highest fluorescence intensity at 375 nm, when excited at 286 nm) showed the highest fluorescence in methanol. In ethanol, 2-N-piperidinopyrimidine showed a fluorescence peak at 403 nm when excited at 360 nm and in chloroform it fluoresced at 392 nm when excited at 356 nm.

Topics: Fluorescence; Piperidines; Pyrimidines; Solvents

As part of a systematic study of the basic principles that govern the formation and reactivity of Pt-protein adducts, we report the effect of substituting the amine ligand of cis- and trans-[PtCl(2)(NH(3))(2)] complexes with bulkier planar aromatic or nonplanar cyclic amine ligands on the binding properties of the complexes to ubiquitin and to horse heart myoglobin. The ligand replacement had a different effect on the cis or trans isomers investigated. In the cis-Pt complexes, replacing one or both amine ligands by piperidine or 4-picoline dramatically decreased the binding of the complexes to the proteins studied, whereas in the substituted trans-Pt complexes replacement of the amine by a piperidine or 4-picoline increased the binding rate. This behavior may have to do with the different preferred binding sites of the cis- and trans-Pt complexes. The bulkier cis- or trans-Pt complexes investigated also did not display a preference for Met1 of ubiquitin, possibly owing to steric constraints imposed by the substituted ligands. The introduction of a charged piperazine ligand significantly decreased the rate of binding to the protein, possibly owing to electrostatic interactions or hydrogen-bond formations with the surface of the protein. The binding of the complexes to ubiquitin and myoglobin does not disrupt the folding of the proteins as judged by electrospray ionization mass spectrometry.

Topics: Amines; Animals; Binding Sites; Horses; Hydrogen Bonding; Isomerism; Ligands; Methionine; Myoglobin; Organoplatinum Compounds; Picolines; Piperazine; Piperazines; Piperidines; Protein Binding; Protein Folding; Spectrometry, Mass, Electrospray Ionization; Static Electricity; Ubiquitin

The 4-(3-phenylprop-1-yl)piperidine moiety of the 1,3,4-trisubstituted pyrrolidine CCR5 antagonist 1 was modified with electron deficient aromatics as well as replacement of the benzylic methylene with sulfones, gem-difluoromethylenes and alcohols in an effort to balance the antiviral potency with reasonable pharmacokinetics.

Topics: Animals; Anti-HIV Agents; CCR5 Receptor Antagonists; Dogs; Half-Life; Humans; Leukocytes, Mononuclear; Macaca mulatta; Metabolic Clearance Rate; Piperidines; Pyrrolidines; Radioligand Assay; Rats; Structure-Activity Relationship; Tumor Cells, Cultured

Topics: Base Pair Mismatch; DNA; DNA Mutational Analysis; Electrophoresis; Hydroxylamine; Piperidines; Potassium Permanganate; Silicon Dioxide

Topics: Galactosamine; Galactose; Molecular Structure; Piperidines; Polymers; Stereoisomerism

We examined whether replacement of imidazole by a piperidine or pyrrolidine moiety will affect the potency and affinity of six H3-receptor antagonists. Potencies were determined in superfused mouse brain cortex slices preincubated with [3H]noradrenaline, in which the interaction of the antagonists with histamine with respect to its inhibitory effect on the electrically evoked tritium overflow was studied. Affinities were determined in mouse brain cortex membranes, using the radioligand [3H] N(alpha)-methylhistamine. The concentration-response curve of histamine for its effect on the evoked overflow from mouse brain cortex slices was shifted to the right by the 13 compounds under study. Replacement of the imidazole by a piperidine ring affected the p A2 value as follows: thioperamide, -2.7 log units; clobenpropit, -1.9; proxyfan, -1.3; FUB 138, -1.2. Potency hardly changed (< or =0.4 log units) when imidazole was replaced by piperidine in FUB 181 and by piperidine or pyrrolidine in FUB 153. Binding of [3H] N (alpha)-methylhistamine to mouse brain cortex membranes was inhibited monophasically by all compounds. The p K(i) values closely matched their p A2 values with three exceptions. The p K(i) values of proxyfan, FUB 138, and FUB 153 exceeded their respective p A(2) values by about 1 log unit. To reveal a potential partial agonism, the effect of the three drugs on (1) the electrically evoked tritium overflow and (2) [35S]GTPgammaS binding in mouse cortex preparations was determined. Proxyfan proved to be a partial agonist in both models (with intrinsic activities of 0.2 and 0.3, respectively) whereas FUB 138 and FUB 153 were devoid of agonistic effects. In conclusion, replacement of imidazole by piperidine or pyrrolidine affects the antagonist potencies of six H3-receptor antagonists in a very different manner. The piperidine analogue of FUB 181 (with a p A2 value as high as 7.7) may represent a lead for the development of non-imidazole H3-receptor antagonists. The discrepancy between the p K(i) and p A2 values may be accounted for by partial agonism in the case of proxyfan but can, at present, not be satisfactorily explained with respect to FUB 138 and FUB 153.

Topics: Animals; Dose-Response Relationship, Drug; Histamine Antagonists; Imidazoles; In Vitro Techniques; Male; Mice; Piperidines; Protein Binding; Receptors, Histamine H3

o,o'-Diphenyleneiodonium cations (DPI) convert relatively harmless radiation-produced electrons into efficient DNA cleaving agents. The cleavage products are unaltered DNA bases, 5-methylenefuranone (5-MF), and a complete set of 3' and 5'-phosphorylated DNA fragments. The production of alkali-labile sites is a minor factor in the process. Based on the production of 5-MF, it is concluded that DNA cleavage by DPI cations involves (but may not be limited to) the C1' chemistry. The loss of 3-aminoDPI (ADPI) cations bound to highly polymerized calf thymus DNA appears to be due to a short-chain reaction with an apparent length of up to 2.1 ADPI cations consumed for each radiation-produced electron. The suggested chain reaction mechanism includes the one-electron oxidation of DNA radicals (including the C1' sugar radical) by ADPI cations bound to the same duplex. The yields of DNA loss in complexes formed by ADPI with short synthetic duplexes indicate that there is more than a 60% probability of DNA damage after one-electron reduction of ADPI.

Topics: Animals; Cations; Cattle; Cobalt Radioisotopes; DNA; DNA Damage; Electrons; Enzyme Inhibitors; Furans; Gamma Rays; Kinetics; Models, Chemical; Onium Compounds; Piperidines

1. The aim of this study was to find taurinergic compounds that do not interact with brain GABA ergic systems. 2. Washed synaptic membranes (SM) from whole rabbit brain were able to bind [(3)H]muscimol. Saturation experiments of the binding of [(3)H]GABA to GABA(B) receptors showed that SM possess two binding components; twice Triton X-100-treated SM contained 0.048 mmol endogenous taurine/kg protein and bound [(3)H]taurine in a saturable manner (K(d)=249.0+/-6.3 nM and B(max)=3.4+/-1.0 pmol mg(-1) prot). 3. Among the 19 structural analogues of taurine, 6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (TAG), 2-aminoethylarsonic (AEA), 2-hydroxyethanesulfonic (ISE) and (+/-)cis-2-aminocyclohexane sulfonic acids (CAHS) displaced [(3)H]taurine binding (K(i)=0.13, 0.13, 13.5 and 4.0 micro M, respectively). These analogues did not interact with GABA(A) and GABA(B) receptors and did not affect taurine- and GABA-uptake systems and GABA-transaminase activity. 4. 3-Aminopropanesulfonic acid (OMO), beta-alanine, pyridine-3-sulfonic acid, N,N,N-trimethyltaurine (TMT), 2-(guanidino)ethanesulfonic acid (GES), ethanolamine-O-sulphate, N,N-dimethyltaurine (DMT), taurine and (+/-)piperidine-3-sulfonic acid (PSA) inhibited [(3)H]muscimol binding to GABA(A) receptors with different affinities (K(i)=0.013, 7.9, 24.6, 47.5, 52.0, 91.0, 47.5, 118.1 and 166.3 micro M, respectively). Taurine, 2-aminoethylphosphonic acid, DMT, TMT and OMO inhibited the binding of [(3)H]GABA to GABA(B) receptors with K(i)'s in the micro M range (0.8, 3.5, 4.4, 11.3 and 5.0, respectively). GES inhibited taurine uptake (IC(50)=3.72 micro M) and PSA GABA transaminase activity (IC(50)=103.0 micro M). 5. In conclusion, AEA, TAG, ISE and CAHS fulfill the criteria for taurinergic agents.

Topics: 4-Aminobutyrate Transaminase; Animals; Binding Sites; Brain; Drug Interactions; gamma-Aminobutyric Acid; Isomerism; Molecular Structure; Muscimol; Piperidines; Rabbits; Receptors, GABA-A; Receptors, GABA-B; Receptors, Neurotransmitter; Structure-Activity Relationship; Synaptic Membranes; Synaptosomes; Taurine; Tritium

Pseudomonas putida O1G3 catalyzes the degradation of pyrrolidine and piperidine. This strain can use these compounds as the sole source of carbon, nitrogen, and energy. When the cyclic amines were used as the growth substrates, the synthesis of a soluble heme amine mono-oxygenase was induced in this bacteria. This observation was confirmed by spectrophotometric analysis and specific inhibitor. This mono-oxygenase is a NADH-dependent enzyme and catalyzes the cleavage of the C-N bond of the pyrrolidine and piperidine ring by a mechanism similar to a N dealkylation. This reaction could be followed by ring cleavage to form gamma-aminobutyraldehyde oxidized to gamma-aminobutyrate. Further investigations to purify the heme-containing mono-oxygenase are in progress.

Topics: Amines; Biodegradation, Environmental; Cell Extracts; Culture Media; Cytochrome P-450 Enzyme System; gamma-Aminobutyric Acid; Mixed Function Oxygenases; Models, Molecular; Piperidines; Potassium Cyanide; Pseudomonas putida; Pyrrolidines; Soil Microbiology; Spectrophotometry

Two external spaces of an inorganic tennis ball are a novel type of metal-centered hydrophobic pocket where two hydrophobic trans-(+/-)-1,2-diaminocyclohexane groups stand perpendicularly to and around the metal coordination plane. The space recognizes pyridine over piperidine, and a novel supramolecule was obtained using such pyridine recognition properties.

Topics: Copper; Cyclohexylamines; Hydrophobic and Hydrophilic Interactions; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Organometallic Compounds; Picolines; Piperidines; Platinum; Pyridines

The sequence dependence of base-catalysed aspartmide formation during Fmoc-based SPPS was systematically studied employing the peptide models H-Val-Lys-Asp-Xaa-Tyr-Ile-OH. The extent of formation of aspartimide and related by-products was determined by RP-HPLC. Considerable amounts of by-products were formed in the case of Xaa = Asp(OtBu), Arg(Pbf), Asn(Mtt), Cys(Acm) and unprotected Thr. Aspartimide formation could be diminished by incorporation of Asp(OMpe) or by employing milder methods for Fmoc cleavage, e.g. hexamethyleneimine/N-methylpyrrolidine/HOBt/NMP/DMSO 4:50:4:71:71 (v/v/w/v/v).

Topics: Amino Acids; Aspartic Acid; Bridged Bicyclo Compounds, Heterocyclic; Chromatography, High Pressure Liquid; Fluorenes; Peptide Biosynthesis; Peptides; Piperidines

A paradigm for the structure-pharmacological activity relationship of bifunctional platinum antitumor drugs is that the trans isomer of antitumor cisplatin (transplatin) is clinically ineffective. To this end, however, several new complexes of the trans structure have been identified that exhibit cytotoxicity in tumor cells that is even better than that of the analogous cis isomers. We reported recently (Kasparkova, J., Marini, V., Najajreh, Y., Gibson, D., and Brabec, V. (2003) Biochemistry 42, 6321-6332) that the replacement of one ammine ligand by the heterocyclic ligand, such as piperidine, piperazine, or 4-picoline in the molecule of transplatin resulted in a radical enhancement of its cytotoxicity. We examined oligodeoxyribonucleotide duplexes bearing a site-specific cross-link of the transplatin analogue containing the piperidine ligand by biochemical methods. The results indicate that in contrast to transplatin, trans-(PtCl2(NH3)(piperidine)) forms stable 1,3-intrastrand cross-links in double-helical DNA that distort DNA and are not readily removed from DNA by nucleotide excision repair system. Hence, the intrastrand cross-links of trans-(PtCl2(NH3)(piperidine)) could persist for a sufficiently long time, potentiating its toxicity toward tumor cells. trans-(PtCl2(NH3)(piperidine)) also forms in DNA minor interstrand cross-links that are similar to those of transplatin so that these adducts appear less likely candidates for genotoxic lesion responsible for antitumor effects of trans-(PtCl2(NH3)(piperidine)). Hence, the role of structurally unique intrastrand cross-links in the anti-tumor effects of transplatin analogues in which one ammine group is replaced by a heterocyclic ligand may predominate.

Topics: Animals; Antineoplastic Agents; Base Sequence; CHO Cells; Cisplatin; Cricetinae; Cross-Linking Reagents; DNA; DNA Adducts; DNA Polymerase I; Dose-Response Relationship, Drug; HeLa Cells; HIV Reverse Transcriptase; Humans; Hydroxyl Radical; Ligands; Models, Chemical; Models, Theoretical; Molecular Sequence Data; Oligonucleotides; Piperidines; Platinum; Time Factors

DNA three-way junctions (TWJ) are branched molecules having three 'arms'. We studied long-distance radical cation migration in these assemblies by incorporating anthraquinone (AQ) groups linked by a covalent tether to one strand of one arm of the TWJ. Excitation of the AQ at 350 nm results in one-electron oxidation of the DNA, which generates a base radical cation. This leads to relatively inefficient (compared with duplex DNA) strand cleavage at guanines following piperidine treatment of the irradiated samples. When the AQ is linked to the 5'-terminus of arm III by a flexible tether, gel electrophoretic analysis shows that strand cleavage occurs at the guanines in all three arms. We also investigated a TWJ in which the anthraquinone is specifically intercalated in arm III. In this case, a different pattern of strand cleavage is detected. We conclude that there are at least two mechanisms for long-distance radical cation migration in TWJs: (i) by inefficient charge hopping through the junction; (ii) by a through-space, cross-arm interaction when the AQ is on a flexible tether.

Topics: Anthraquinones; Base Sequence; Cations; DNA; Free Radicals; Ion Transport; Molecular Structure; Oxidation-Reduction; Photochemistry; Piperidines

The influence of buffer pH on the electrophoretic behavior of 13 structurally related phenothiazines and determination of pK(a) values by capillary zone electrophoresis (CZE) were investigated. The results indicate that phenothiazines with a piperazine substituent behave quite differently from those with substituents having an aliphatic side chain or a piperidine moiety over the pH range studied. To separate these phenothiazines, it is preferable to select buffer pH in the range of 2.5-3.5. The pK(a) values of phenothiazines with three different types of substituents attached at the 10-position of the phenothiazine ring were determined. The determination of pK(a) values of phenothiazines allows us to rationalize the influence of buffer pH on the migration behavior of these compounds in CZE.

Topics: Buffers; Cyclodextrins; Electrophoresis, Capillary; Hydrogen-Ion Concentration; Phenothiazines; Piperazine; Piperazines; Piperidines; Promethazine; Stereoisomerism

Methods for the preparation of mixed tetra-amide esters 1 and 2, the partial amide ester 3, and tri- and P,P-diamides 4 and 5 from monophosphorus spieces 12, 8 and 9, respectively, were developed. Compounds 8 and 9 were obtained from phosphorus trichloride via MeOPCl2, which was treated with 2 eq. and 4 eq. of piperidine, followed by water or acetyl chloride, respectively. Tetrasubstituted amide bisphosphonates 1 and 2 were selectively dealkylated with lithium or silyl halide to achieve target compounds 3-5. Piperidine was found to be a good desilylation reagent. Quantum mechanical calculations illustrate why derivative 2 was produced in low yield. The usefulness of compounds 1, 3 and 4 as prodrugs of etidronate was determined in aqueous buffer and human serum.

Topics: Alkylation; Amides; Chemistry, Organic; Chlorides; Etidronic Acid; Magnetic Resonance Spectroscopy; Models, Chemical; Phosphorus Compounds; Piperidines

Replacement of the ammine group in antitumor cisplatin by a heterocyclic ligand (piperidine, piperazine, or 4-picoline) results in reduction of cytotoxicity in human ovarian cancer cells. DNA is generally believed to be a major pharmacological target of antitumor platinum complexes. Therefore, we examined conformation of oligodeoxyribonucleotide duplexes containing a cross-link of cis-[PtCl(2)(NH(3))(piperidine)], their recognition by high mobility group proteins, and nucleotide excision repair; that is, some of the processes that may mediate antitumor effects of platinum drugs. The replacement does not affect the DNA binding mode including conformational alterations and excision of the cross-links. The results suggest that in certain cancer cells the lower cytotoxicity of cis-[PtCl(2)(NH(3))(piperidine)] might be partially associated with reduced affinity of the high mobility group proteins to the major intrastrand cross-links of this analogue relative to the same adducts of cisplatin. Besides this and a number of other biochemical factors, the reduced intracellular accumulation with subsequent effects on the level of DNA platination in the cells may also contribute to the reduced cytotoxicity of cis-[PtCl(2)(NH(3))(piperidine)]. The results support the view that the concept based on the design of the complexes structurally derived from cisplatin that do not present an altered DNA binding mode may be less effective in the search for new platinum drugs that would overcome cisplatin resistance.

Topics: Antineoplastic Agents; Base Sequence; Binding Sites; Cisplatin; Cross-Linking Reagents; DNA; DNA Adducts; DNA Repair; Female; High Mobility Group Proteins; Humans; Ligands; Oligodeoxyribonucleotides; Ovarian Neoplasms; Piperidines; Platinum Compounds; Sequence Analysis, DNA; Spain; Tumor Cells, Cultured

Tetrahydropyrrolo[3,2-c]pyridines and tetrahydropyrido[4,3-b]indoles undergo piperidine ring opening under the action of dimethyl acetylene dicarboxylate in alcohols or in aqueous dioxane, providing beta-(alk)oxy-substituted pyrroles (indoles) in moderate to high yields.

Topics: Acetylene; Alcohols; Carboxylic Acids; Dioxanes; Indoles; Molecular Structure; Piperidines; Pyridines; Pyrroles; Solvents

Topics: Anti-Bacterial Agents; Biomimetics; Crystallography, X-Ray; Molecular Conformation; Piperidines; Thiostrepton

Stereochemistry plays a major role in the selectivity toward zinc ion over copper(II) of some tripodal ligands with a central piperidine scaffold, one of which acts as a fluorescent zinc sensor with nanomolar sensitivity.

Topics: Copper; Ligands; Molecular Conformation; Nanotechnology; Piperidines; Sensitivity and Specificity; Spectrometry, Fluorescence; Zinc

Biodegradability of secondary amines (pyrrolidine, piperidine, piperazine, morpholine, and thiomorpholine) under anaerobic conditions was examined in microbial consortia from six different environmental sites. The consortia degraded pyrrolidine and piperidine under denitrifying conditions. Enrichment cultures were established by repeatedly sub-culturing the consortia on pyrrolidine or piperidine in the presence of nitrate. The enrichments strictly required nitrate for the anaerobic degradation and utilized pyrrolidine or piperidine as a carbon, nitrogen, and energy source for their anaerobic growths. The anaerobic degradation of pyrrolidine and piperidine reduced nitrate to nitrogen gas, indicating that these anaerobic degradations were coupled with a respiratory nitrate reduction.

Topics: Bacteria, Anaerobic; Biodegradation, Environmental; Calcium Channel Blockers; Environmental Pollutants; Gases; Nitrates; Oxidation-Reduction; Piperidines; Pyrrolidines

Piperidine is a 1-ring heterocyclic compound formed from the polyamine cadaverine in the human intestine. Because heterocyclic compounds are routinely used in the promotion of antimicrobial treatment strategies, it was considered whether piperidine could be used against infection with enteric pathogens. This study demonstrates that piperidine treatment prevented the invasion of Salmonella typhimurium into model intestinal epithelium by nearly 95%. In vivo studies also revealed that it increased mouse survival and reduced S. typhimurium translocation into and colonization of various organs and tissues. Initial evaluations demonstrated that piperidine reduced the S. typhimurium-induced polymorphonuclear leukocyte transepithelial migration response in vitro by inhibiting activation of protein kinase C. Piperidine did not affect the ability of S. typhimurium to elicit interleukin-8 secretion by epithelial cells or to activate extracellular-regulated kinase signal transduction pathways. These results show that piperidine does not exhibit paninhibitory activity and suggest that piperidine may be useful in down-regulating active inflammation at mucosal surfaces.

Topics: Animals; Cadaverine; Cell Migration Inhibition; Cell Polarity; Cells, Cultured; Chemotaxis, Leukocyte; Epithelial Cells; Humans; Interleukin-8; Male; Mice; Mice, Inbred BALB C; Neutrophils; Phosphorylation; Piperidines; Protein Kinase C; Salmonella typhimurium

The natural abundance 15N-NMR chemical shifts of selected aliphatic amines, 2-substituted pyridine type compounds, bialicyclic tertiary amines have been measured as a function of the nature of the solvent. In the case of cyclic aliphatic amines, like piperidine, morpholine, piperazine, thiomorpholine, the nitrogen is more shielded in concentrated solution compared to that in dilute solution whereas in the hydrogen bonding and protonating solvents there is a prominent deshielding. 2-Substituted pyridines studied can be further divided into four sub groups. The site of hydrogen bonding and protonation in 2-amino, 2-hydroxy and 2-mercapto pyridines have been conclusively proved from the 15N-NMR chemical shifts and the well-known tautomeric forms of the above compounds. Similarly in the case of 2-(2-thienyl)pyridine and 2-(3-thienyl)pyridine, the site of donation has been proved as the nitrogen of the pyridine ring in both the compounds. In a similar manner, the site of hydrogen bonding and protonation in two individual compounds 2-anilinopyridine and 2-(2-pyridyl)benzimidazole have also been established. Among the bialicyclic amines, 1,2-diazabicyclo[2.2.2]octane (DABCO) behaved differently from the other two compounds. In both 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), it was possible to show that N1-nitrogen in both the compounds is the site of donation. The effect of the second donor site on the 15N-NMR chemical shift, the site of donation in the selected compounds and some typical compounds reported in literature have been presented and discussed.

Topics: Amines; Heterocyclic Compounds; Hydrogen Bonding; Magnetic Resonance Spectroscopy; Morpholines; Nitrogen Isotopes; Piperazine; Piperazines; Piperidines; Solvents

Methotrexate (MTX), an antineoplastic agent, demonstrates phototoxicity. The mechanism of damage to biomacromolecules induced by photoirradiated MTX was examined using 32P-labeled DNA fragments obtained from a human gene. Photoirradiated MTX caused DNA cleavage specifically at the underlined G in 5'-GG and 5'-GGG sequences in double-stranded DNA only when the DNA fragments were treated with piperidine, which suggests that DNA cleavage was caused by base modification with little or no strand breakage. With denatured single-stranded DNA the damage occurred at most guanine residues. The amount of formation of 8-hydroxy-2'-deoxyguanosine (8-oxodGuo), an oxidative product of 2'-deoxyguanosine, in double-stranded DNA exceeded that in single-stranded DNA. These results suggest that photoirradiated MTX participates in 8-oxodGuo formation at the underlined G in 5'-GG and 5'-GGG sequences in double-stranded DNA through electron transfer, and then 8-oxodGuo undergoes further oxidation into piperidine-labile products. Fluorescence measurement, high-pressure liquid chromatography and mass spectrometry have demonstrated that photoexcited MTX is hydrolyzed into 2,4-diamino-6-(hydroxymethyl)pteridine (DHP). DNA damage induced by DHP was observed in a similar manner as was the damage induced by MTX. The extent of DNA damage and the formation of 8-oxodGuo by DHP were much larger than those induced by MTX. The kinetic analysis, based on the time course of DNA oxidation by photoirradiated MTX, suggests that DNA damage is caused by photoexcited DHP rather than by photoexcited MTX. In conclusion, photoexcited MTX undergoes hydrolysis through intramolecular electron transfer, resulting in the formation of DHP, which exhibits a phototoxic effect caused by oxidation of biomacromolecules through photoinduced electron transfer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Chromatography, High Pressure Liquid; Deoxyguanosine; DNA; DNA Damage; Electron Transport; Humans; Hydrolysis; Methotrexate; Molecular Structure; Phosphorus Radioisotopes; Photolysis; Piperidines; Poly G; Pteridines; Spectrometry, Fluorescence

Carcinogenic benzo[a]pyrene (BP) is generally considered to show genotoxicity by forming DNA adducts of its metabolite, BP-7,8-diol-9,10-epoxide. We investigated oxidative DNA damage and its sequence specificity induced by BP-7,8-dione, another metabolite of BP, using (32)P-5'-end-labeled DNA. Formamidopyrimidine-DNA glycosylase treatment induced cleavage sites mainly at G residues of 5'-TG-3' sequence and at poly(C) sequences, in DNA incubated with BP-7,8-dione in the presence of NADH and Cu(II), whereas piperidine treatment induced cleavage sites at T mainly of 5'-TG-3'. BP-7,8-dione strongly damaged the G and C of the ACG sequence complementary to codon 273 of the p53 gene. Catalase and a Cu(I)-specific chelator attenuated the DNA damage, indicating the involvement of H(2)O(2) and Cu(I). BP-7,8-dione with NADH and Cu(II) also increased 8-oxo-7,8-dihydro-2'-deoxyguanosine formation. We conclude that oxidative DNA damage, especially double base lesions, may participate in the expression of carcinogenicity of BP in addition to DNA adduct formation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Animals; Benzopyrenes; Binding Sites; Carcinogens; Cattle; Copper; Cyclin-Dependent Kinase Inhibitor p16; Deoxyguanosine; DNA; DNA Damage; DNA-Formamidopyrimidine Glycosylase; Free Radical Scavengers; Genes, p53; Genes, ras; Humans; N-Glycosyl Hydrolases; NAD; Oxidation-Reduction; Piperidines

Derivatives of N-(1-phenethyl-4-piperidyl)propanamides incorporating guanidinium and 2-aminoimidazolinium groups have been prepared by a synthetic approach involving first introduction of a spacer between the piperidine and the functional group by reductive amination of piperidinone. The formation of each of these functional groups was carried out using N-N'-di(tert-butoxycarbonyl)thiourea and 2-methylthioimidazolinium iodide, respectively. These structures have been designed to incorporate two pharmacologic goals into one entity. Radioligand binding assays have been used to study their affinity for opioid (mu, delta and kappa) and I2-imidazoline receptors. Two of them, 10 and 16, showed high affinity for mu opioid receptors and functionally they had moderate analgesic properties in the hot plate and writhing tests. The in vitro studies on guinea pig ileum (GPI) indicated that both compounds are mu opioid agonists. In what concerns I2-imidazoline receptor activity, these derivatives showed low affinity around 6 to 7 times less than idazoxan.

Topics: Amides; Analgesics; Animals; Drug Evaluation, Preclinical; Guanidine; Guinea Pigs; Imidazoles; Imidazoline Receptors; In Vitro Techniques; Ligands; Male; Mice; Piperidines; Radioligand Assay; Receptors, Drug; Receptors, Opioid, mu; Sensation; Structure-Activity Relationship

Hypohalites (OCl-, OBr-) are formed at inflammation sites as antimicrobial agents. OCl- is also used for the disinfection of water supplies and the association of drinking chlorinated water with cancer risk is pointed out. In this study, OCl- itself induced 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) formation, while OBr- damaged DNA only when glutathione (GSH) was added. OCl- caused oxidative DNA damage more efficiently than OBr-/GSH. In experiment with 32P-labeled DNA fragments, OCl- strongly caused piperidine-labile sites at guanine residues than piperidine-inert 8-oxodG, whereas OBr-/GSH caused no piperidine-labile sites. Endogenous OCl- may play a role in genotoxicity close to the site of inflammation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Bromates; Carcinogens; Cattle; Cell Line; Deoxyguanosine; Dimethyl Sulfoxide; DNA; DNA Damage; Electron Spin Resonance Spectroscopy; Genes, p53; Genes, ras; Genes, Tumor Suppressor; Glutathione; Humans; Inflammation; Neoplasms; Oxidation-Reduction; Phosphorus Isotopes; Piperidines; Sodium Hypochlorite

The (Z)-hex-1,5-diyne-3-ene reactive core common to the enediyne antitumor antibiotics undergoes a Bergman cyclization after proper activation to afford reactive diradical intermediates that are responsible for initiating DNA cleavage. Direct modification of the enediyne core has been proposed as a method to permit cancer cell-specific triggering of the diradical-generating cyclization. For example, 3-aza-3-ene-1,5-diynes undergo an aza-Bergman cyclization to afford the fleeting 2,5-didehydropyridine diradicals. While protonation of these aza-enediynes can afford products of diradical trapping, the hydrolytic instability of the 3-aza-3-ene-1,5-diyne moiety prevents its use in pH-triggered DNA cleaving anticancer agents. Recently, more hydrolytically stable systems incorporating the 4-aza-3-ene-1,6-diyne moiety were developed. We report here studies of the 4-aza-3-ene-1,6-diyne-containing benzimidazolium salt AZB002 [1-methyl-2-(phenylethynyl)-3-(3-phenylprop-2-ynyl)-3H-benzimidazolium tetrafluoroborate] and two structurally related heterocycles that lack the aza-enediyne functionality, AZB016 [1,3-dimethyl-2-(phenylethynyl)-3H-benzimidazolium triflate] and AZB004 [3-methyl-2-(phenylethynyl)benzothiazolium triflate]. The interaction of these compounds with supercoiled DNA, a double-stranded DNA fragment, and a short DNA duplex oligonucleotide was investigated. There are three distinct DNA interactions exhibited by AZB002: a frank strand scission leading to the relaxation of supercoiled DNA and formation of at least two different DNA adducts, one of which leads to cytosine-specific cleavage after piperidine/heat treatment. In contrast, analogues lacking the aza-enediyne functionality either fail to interact with DNA (AZB016) or cleave DNA at guanine residues, presumably through alkylation of the N-7 position (AZB004). We also investigated the cytotoxicity of AZB002 and the related heterocyclic compounds AZB004 and AZB016 and find that only the DNA interactive compounds AZB002 and AZB004 display significant cytotoxicity. In particular, AZB002 is cytotoxic against a wide range of cancer cell lines.

Topics: Alkynes; Antineoplastic Agents; Aza Compounds; Benzimidazoles; Benzothiazoles; Cytosine; DNA Adducts; DNA, Superhelical; Growth Inhibitors; Heterocyclic Compounds, 2-Ring; Hot Temperature; Humans; Hydrogen-Ion Concentration; Hydrolysis; Piperidines; Thiazoles; Tumor Cells, Cultured; U937 Cells

Our objective was to evaluate piperidine alkaloids as potential resistance factors in Sitka spruce, Picea sitchensis (Bong.) Carr, at risk to attack by white pine weevils, Pissodes strobi (Peck). We sampled 72 seedlings in each of two replicated field trials in the Oregon Coast Range. The seedlings were grown from open-pollinated seeds of putatively "resistant" or "susceptible" off-site parental sources. Alkaloid concentrations in bark and foliage were measured in previously unattacked trees at the time of weevil host selection. Leader mortality was evaluated in the fall to gauge actual resistance in the sample trees. Five families had < or = 25% topkill and seven sustained >50% topkill. Alkaloid concentrations differed significantly among families, but the major alkaloids did not appear to be functionally linked with topkill or useful indicators of resistance. However, our study design did not address all potential resistance mechanisms. Therefore, before concluding that Sitka spruce alkaloids have no influence on white pine weevils, complementary laboratory and field experiments are needed.

Topics: Alkaloids; Animals; Coleoptera; Pest Control, Biological; Picea; Piperidines

Interference assays identify specific residues in the DNA binding site that, when modified, interfere with binding of the protein. The protocols use end-labeled DNA probes that are modified at an average of one site per molecule of probe. These probes are incubated with the protein of interest, and protein-DNA complexes are separated from free probe by the mobility shift assay. A DNA probe that is modified at a position that interferes with binding will not be retarded in this assay; thus, the specific protein-DNA complex is depleted for DNA that contains modifications on bases important for binding. After gel purification, the bound and unbound DNA are specifically cleaved at the modified residues and the resulting products analyzed by electrophoresis on polyacrylamide sequencing gels and autoradiography. In the methylation interference protocol presented here, probes are generated by methylating guanines (at the N-7 position) and adenines (at the N-3 position) with DMS; these methylated bases are cleaved specifically by piperidine. In the uracil interference protocol, probes are generated by PCR amplification in the presence of a mixture of TTP and dUTP, thereby producing products in which thymine residues are replaced by deoxyuracil residues (which contains hydrogen in place of the thymine 5-methyl group). Uracil bases are specifically cleaved by uracil-N-glycosylase to generate apyrimidinic sites that are susceptible to piperidine. These procedures provide complementary information about the nucleotides involved in protein-DNA interactions.

Topics: Animals; Autoradiography; Binding Sites; DNA; DNA Methylation; DNA Probes; DNA-Binding Proteins; Electrophoresis, Polyacrylamide Gel; Electrophoretic Mobility Shift Assay; Humans; Piperidines; Polymerase Chain Reaction; Protein Binding; Uracil; Uracil-DNA Glycosidase

The use of nickel and cobalt reagents is presented for characterizing the solvent exposure of guanine residues in DNA and RNA. These reagents promote guanine oxidation in the presence of a peracid such as monopersulfate, and the extent of reaction indicates the steric and electronic environment surrounding the N7 and aromatic face of this residue. Since oxidation does not itself perturb target structure or induce strand scission, it is coupled with fragmentation by treatment with piperidine (for smaller polynucleotides) or termination of primer extension (for larger polynucleotides).

Topics: Biochemistry; Cobalt; DNA; Guanine; Indicators and Reagents; Nickel; Nucleic Acids; Oxidation-Reduction; Piperidines

Chemical modification provides an inexpensive and rapid method for characterizing the structure of DNA and its association with drugs and proteins. Numerous conformation-specific probes are available, but most investigations rely on only the most common and readily available of these. The major groove of DNA is typically characterized by reaction with dimethyl sulfate, diethyl pyrocarbonate, potassium permanganate, osmium tetroxide, and, quite recently, bromide with monoperoxysulfate. This commentary discusses the specificity of these reagents and their applications in protection, interference, and missing contact experiments.

Topics: Base Pairing; Base Sequence; Biochemistry; DNA; DNA Methylation; DNA Probes; G-Quadruplexes; Hot Temperature; Indicators and Reagents; Molecular Sequence Data; Nucleic Acid Conformation; Oxidation-Reduction; Piperidines; Proteins

We determined the adduct maps of S(N)1 and S(N)2 alkylating agents in cultured human cells (in vivo) and in vitro to probe DNA-protein interactions along sequences of the promoter and exon 1 of the Fragile-X mental retardation 1 (FMR1) gene. Using ligation-mediated polymerase chain reaction (LMPCR), we compared the piperidine-sensitive alkylpurines sites generated by treating cultured cells (in vivo) and naked DNA (in vitro) with S(N)1 (N-methyl-N-nitrosourea, N-nitroso(acetoxymethyl)methylamine and 1-methyl-3-nitro-1-nitrosoguanidine) and S(N)2 alkylating agents (dimethyl sulfate (DMS), methane sulfonic acid methyl ester, iodo methane, diethyl sulfate, methane sulfonic acid ethyl ester and iodo ethane). The FMR1 promoter has four sites where DNA-protein interactions are observed. In these regions, the S(N)1 methylating agent reactions produced only hypo-reactive sites. In contrast, iodoalkane S(N)2 alkylating agents (MeI and EtI) reactions generated only hyper-reactive sites. Although there are hyper-reactive sites for the other S(N)2 reagents, the hyper-reactive site at +14 on the FMR1 map is more pronounced for the sulfate and sulfonate-derived alkylating agents than for the iodoalkanes. However, DMS modification in the presence of methyl sulfone, a compound that does not alkylate DNA, eliminates the hyper-reactive site observed at +14. This suggests that the electron-rich oxygen atoms of the sulfate and sulfonate-derived S(N)2 alkylating agent structure position the alkylating moiety to the neighboring N-7-guanine position to favor alkyl transfer to the guanine. Using KMnO(4) to probe for single-strand DNA, an unpaired cytosine base was detected at the 5'-side of the hyper- reactive guanine base at position +14, consistent with the formation of a local DNA single-strand bulge. In conclusion, we show that the sequence context-dependent formation of alkylpurines is determined by the chemical nature of the alkylating agent, the DNA sequence context, chromatin structure, and the presence of other non-reactive molecules that can inhibit alkylation.

Topics: Alkylating Agents; Alkylation; Base Sequence; Cell Line, Transformed; Chromatin; Dimethyl Sulfoxide; DNA; DNA Damage; DNA Footprinting; DNA Methylation; Exons; Fragile X Mental Retardation Protein; Guanine; Humans; Lymphocytes; Molecular Conformation; Molecular Sequence Data; Nerve Tissue Proteins; Piperidines; Potassium Permanganate; Promoter Regions, Genetic; Purines; RNA-Binding Proteins; Sulfones; Sulfuric Acid Esters

The repressor proteins BlaI and MecI bind similarly to the bla operator implicated in the regulation of beta-lactamase synthesis in Staphylococcus aureus. BlaI binds to two separate dyads but neither copper-phenanthroline footprinting nor dimethyl sulphate (DMS) methylation protection assays produced any evidence of a change in the geometry of the DNA between the two dyads. It is concluded that BlaI molecules bound at the dyads probably do not cause bending or looping of the intervening DNA. DMS protection assays of BlaI binding to the bla operator in vitro and in vivo gave similar results so that it is tentatively concluded that the in vitro results are an accurate reflection of the in vivo situation. Deletion of the dyad nearest to the blaZ gene resulted in decreased synthesis of the chloramphenicol acetyltransferase reporter protein synthesized from the blaZ promoter/translation initiator. Explanations for this are considered.

Topics: Bacterial Proteins; Base Sequence; beta-Lactamases; Chloramphenicol O-Acetyltransferase; Deoxyribonuclease I; DNA; DNA Footprinting; DNA-Binding Proteins; Electrophoresis, Polyacrylamide Gel; Gene Expression Regulation, Bacterial; Genes, Reporter; Molecular Sequence Data; Nucleic Acid Conformation; Operator Regions, Genetic; Phenanthrolines; Piperidines; Plasmids; Promoter Regions, Genetic; Repressor Proteins; Sequence Deletion; Staphylococcus aureus; Sulfuric Acid Esters; Time Factors

Long range oxidative damage as a result of charge transport is shown to occur through single crossover junctions assembled from four semi-complementary strands of DNA. When a rhodium complex is tethered to one of the arms of the four-way junction assembly, thereby restricting its intercalation into the pi-stack, photo-induced oxidative damage occurs to varying degrees at all guanine doublets in the assembly, though direct strand scission only occurs at the predicted site of intercalation. In studies where the Mg(2+) concentration was varied, so as to perturb base stacking at the junction, charge transport was found to be enhanced but not to be strongly localized to the arms that preferentially stack on each other. These data suggest that the conformations of four-way junctions can be relatively mobile. Certainly, in four-way junctions charge transport is less discriminate than in the more rigidly stacked DNA double crossover assemblies.

Topics: 2,2'-Dipyridyl; Base Pairing; Base Sequence; Cations, Divalent; Crossing Over, Genetic; DNA; DNA Damage; Electron Transport; Guanine; Intercalating Agents; Magnesium; Models, Molecular; Nucleic Acid Conformation; Oligodeoxyribonucleotides; Organometallic Compounds; Oxidants; Photolysis; Piperidines; Rhodium

Argatroban was synthesized in seven steps from 4-methylpiperidine. The condensation of (+/-)-trans-benzyl 4-methylpipecolic acid ester with N(alpha)-Boc-N(omega)-nitro-L-arginine led to two diastereomers that were separated. One of them is the precursor of argatroban.

Topics: Antithrombins; Arginine; Enzyme Inhibitors; Pipecolic Acids; Piperidines; Sensitivity and Specificity; Sulfonamides

A series of small molecules derived from MK-0677, a potent synthetic GHS, mimicking the N-terminal Gly-Ser-O-(n-octanoyl)-L-Ser-Phe segment of ghrelin was synthesized and tested in a binding and in a functional assay measuring intracellular calcium elevation in HEK-293 cells expressing hGHSR1a. Replacement of Phe in this tetrapeptide with a spiro(indoline-3,4'-piperidine) group, Gly-Ser with 2-aminoisobutyric acid, and O-(n-octanoyl)-L-Ser with O-benzyl-D-Ser provided synthetic GHS agonists with similar functional potency as ghrelin.

Topics: Binding Sites; Calcium; Cells, Cultured; Ghrelin; Humans; Indoles; Inhibitory Concentration 50; Luminescence; Molecular Mimicry; Peptide Hormones; Peptides; Piperidines; Protein Binding; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Receptors, Ghrelin; Spiro Compounds

In Escherichia coli, endonuclease III (endo III) repairs the oxidation products of 8-OHGua. However, the corresponding repair enzymes in eukaryotes have not been identified. Here we report that 8-hydroxyguanine (8-OHGua) is highly sensitive to further oxidation. We also show that Ntg2, a functional homolog of endo III in Saccharomyces cerevisiae, is capable of nicking the irradiated duplex DNA containing 8-OHGua. Moreover, Ntg2 formed a stable complex with the DNA upon incubation with NaBH(4). In contrast, Ntg1, another functional homolog of endo III, showed no such activities. These findings indicate that Ntg2 is, at least in part, responsible for repairing the oxidation products of 8-OHGua in eukaryotic cells.

Topics: Borohydrides; Deoxyadenosines; Deoxycytidine; Deoxyguanosine; DNA; DNA-(Apurinic or Apyrimidinic Site) Lyase; DNA-Formamidopyrimidine Glycosylase; Dose-Response Relationship, Radiation; Escherichia coli Proteins; Gamma Rays; Guanine; Hydrogen Peroxide; Hydroxyl Radical; Iron; Macromolecular Substances; N-Glycosyl Hydrolases; Oxidation-Reduction; Piperidines; Protein Binding; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Substrate Specificity; Thymidine

Topics: Binding Sites; Cross-Linking Reagents; Deoxyguanosine; DNA; DNA Adducts; Doxorubicin; Electrophoresis, Polyacrylamide Gel; Ethidium; Gas Chromatography-Mass Spectrometry; Hydrolysis; In Vitro Techniques; Nucleic Acid Denaturation; Pharmaceutical Preparations; Piperidines; Spectrometry, Fluorescence

Ligation-Mediated Polymerase Chain Reaction (LMPCR) is the most sensitive sequencing technique available to map single-stranded DNA breaks at the nucleotide level of resolution using genomic DNA. LMPCR has been adapted to map DNA damage and reveal DNA-protein interactions inside living cells. However, the sequence context (GC content), the global break frequency and the current combination of DNA polymerases used in LMPCR affect the quality of the results. In this study, we developed and optimized an LMPCR protocol adapted for Pyrococcus furiosus exo(-) DNA polymerase (Pfu exo(-)). The relative efficiency of Pfu exo(-) was compared to T7-modified DNA polymerase (Sequenase 2.0) at the primer extension step and to Thermus aquaticus DNA polymerase (Taq) at the PCR amplification step of LMPCR. At all break frequencies tested, Pfu exo(-) proved to be more efficient than Sequenase 2.0. During both primer extension and PCR amplification steps, the ratio of DNA molecules per unit of DNA polymerase was the main determinant of the efficiency of Pfu exo(-), while the efficiency of Taq was less affected by this ratio. Substitution of NaCl for KCl in the PCR reaction buffer of Taq strikingly improved the efficiency of the DNA polymerase. Pfu exo(-) was clearly more efficient than Taq to specifically amplify extremely GC-rich genomic DNA sequences. Our results show that a combination of Pfu exo(-) at the primer extension step and Taq at the PCR amplification step is ideal for in vivo DNA analysis and DNA damage mapping using LMPCR.

Topics: Base Sequence; Chromosome Breakage; DNA; DNA Damage; DNA Ligases; DNA Primers; DNA-Directed DNA Polymerase; GC Rich Sequence; Genome, Human; Humans; Lymphocytes; Male; Nucleic Acid Conformation; Nucleic Acid Denaturation; Osmolar Concentration; Physical Chromosome Mapping; Piperidines; Polymerase Chain Reaction; Pyrococcus furiosus; Salts; Taq Polymerase; Temperature; Thermodynamics

mu-Conotoxin GIIIA, a peptide toxin isolated from the marine snail Conus geographus, preferentially blocks skeletal muscle sodium channels in vertebrates. In this study, analogs of mu-conotoxin GIIIA in which essential Arg-13 was replaced with arginine analogs consisting of a piperidyl framework to regulate length and direction of the side chain were synthesized. Synthesized analogs exhibited similar CD and NMR spectra to that of GIIIA, suggesting a three-dimensional structure identical to that of the native toxin. The biological activities of piperidyl analogs were decreased or lost despite the small change in the side chain of Arg-13. The investigated structure-activity relationships in inhibiting electrically stimulated muscle contraction suggest that the guanidinium group at amino acid position 13 interacts best when spaced with three to four carbons and placed in a vertical direction from the peptide loop. Thus, the position of the guanidinium group at Arg-13 of GIIIA must be located in a certain range for its strong interaction with the channel protein.

Topics: Amino Acid Sequence; Animals; Arginine; Circular Dichroism; Conotoxins; Male; Molecular Sequence Data; Muscle Contraction; Nuclear Magnetic Resonance, Biomolecular; Piperidines; Rats; Rats, Wistar; Sodium Channel Blockers

The synthesis of novel 4beta-aryl-1-methyl-3alpha-(3-substituted-1,2,4-oxadiazol-5-yl)piperidines, bioisosteres of ester (+)-1, is described. The synthesized oxadiazoles were evaluated for their affinity to the DAT and their ability to inhibit monoamine reuptake at the DAT, NET, and 5HTT. The results show that affinity to the DAT and ability to inhibit the reuptake at the DAT, NET, and 5HTT is a function of the size of the substituent in the oxadiazole ring. (+)-(3R,4S)-4beta-(4-Chlorophenyl)-1-methyl-3alpha-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine [(+)-2a], which is structurally and pharmacologically most similar to the ester (+)-1 in this series, showed at least a 2-fold longer duration of action when compared to ester (+)-1.

Topics: Carrier Proteins; Cocaine; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; Membrane Glycoproteins; Membrane Transport Proteins; Nerve Tissue Proteins; Oxadiazoles; Piperidines; Structure-Activity Relationship

Structure-activity relationship studies directed toward the optimization of (2S)-2-(3-chlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[4-(substituted)piperidin-1-yl]butanes as CCR5 antagonists resulted in the synthesis of the spiro-indanone derivative 8c (IC50=5 nM). These and previous results are summarized in a proposed pharmacophore model for this class of CCR5 antagonist.

Topics: Animals; Anti-HIV Agents; Butanes; CCR5 Receptor Antagonists; Cells, Cultured; Chemokine CCL4; Cricetinae; Humans; Inhibitory Concentration 50; Macrophage Inflammatory Proteins; Models, Biological; Models, Molecular; Neutrophils; Piperidines; Structure-Activity Relationship

An enantiomeric synthesis of six piperidine and pyrrolidine alkaloids, (S)-nornicotine 1, (S)-nicotine 2, (S)-anatabine 3, (S)-N-methylanatabine 4, (S)-anabasine 5, and (S)-N-methylanabasine 6, known as natural products in tobacco, was established from a common chiral homoallylic (S)-3-(1-azido-but-3-enyl)-pyridine 15. An intramolecular hydroboration-cycloalkylation of the homoallylic azide intermediate 15 served as the key step in the pyrrolidine ring formation. A ring closing metathesis reaction (RCM) of a diethylenic amine intermediate (S)-allyl-(1-pyridin-3-yl-but-3-enyl)-carbamic acid benzyl ester 20 served as the key step in the piperidine ring formation. From the commercially available 3-pyridinecarboxaldehyde 13, a short and convenient enantiomeric synthesis of tobacco alkaloids is described: (S)-nornicotine 1 (5 steps, with an overall yield of 70%), (S)-nicotine 2 (6 steps, 65%), (S)-anatabine 3 (8 steps, 30%), (S)-N-methylanatabine 4 (8 steps, 25%), (S)-anabasine 5 (8 steps, 35%), and (S)-N-methylanabasine 6 (8 steps, 25%).

Topics: Alkaloids; Magnetic Resonance Spectroscopy; Molecular Conformation; Nicotiana; Piperidines; Plants, Toxic; Pyrrolidines

Triplex-forming oligonucleotides (TFOs) are being investigated as highly specific DNA binding agents to inhibit the expression of clinically relevant genes. So far, they have been shown to inhibit transcription from the HER-2/neu gene in vitro, whereas their use in vivo has been studied to a limited extent. This study uses a TFO-chlorambucil (chl) conjugate capable of forming site-specific covalent guanine adducts within the HER-2/neu promoter. We demonstrate that nucleotide excision repair (NER) represents a mechanism of cellular resistance to TFO-directed DNA alkylation. In vitro repair assays demonstrate that triplex-directed chl-guanine adducts are substrates for repair by NER competent cell extracts but not XP12BE cell extracts deficient in NER. The degree of repair is estimated by a ligation-mediated polymerase chain reaction with a pre-formed triplex in a plasmid transfected into repair competent cells, indicating that approximately 25% of the guanine adducts are removed after 24 h. These data indicate that guanine adducts from TFO-directed alkylation are a substrate for NER and that DNA repair is a significant barrier to the intracellular persistence of target gene binding by TFOs.

Topics: Alkylation; DNA; DNA Adducts; DNA Damage; DNA Ligases; DNA Repair; Genes, erbB-2; Guanidine; HeLa Cells; Humans; Mutagenesis, Site-Directed; Oligodeoxyribonucleotides; Piperidines; Polymerase Chain Reaction; Promoter Regions, Genetic; Substrate Specificity; Transfection

Two DTPA derivatives (PIP-DTPA and AZEP-DTPA) as potential contrast enhancement agents in MRI are synthesized. The T1 and T2 relaxivities of their corresponding Gd(III) complexes are reported. At clinically relevant field strengths, the relaxivities of the complexes are comparable to that of the contrast agent, Gd(DTPA) which is in clinical use. The serum stability of the (153)Gd-labeled complexes is assessed by measuring the release of (153)Gd from the ligands. The radiolabeled Gd chelates are found to be kinetically stable in human serum for up to at least 14 days without any measurable loss of radioactivity.

Topics: Contrast Media; Gadolinium; Gadolinium DTPA; Heterocyclic Compounds; Magnetic Resonance Imaging; Nuclear Magnetic Resonance, Biomolecular; Pentetic Acid; Piperidines; Radioisotopes

Topics: Catalysis; Ions; Models, Chemical; Nitriles; Oligosaccharides; Piperidines; Spectrometry, Mass, Electrospray Ionization; Time Factors

beta-Elemene and its derivatives were hopeful new antitumor drugs. A method for determination of elemenyl piperidine salt in water has been developed with capillary gas chromatography. The samples were neutralized by sodium carbonate and extracted by n-heptane. n-Octadecane was used as the internal standard. The linear range was from 10 g/L to 100 g/L, with a correlation coefficient of 0.9998. The average recovery of the method was 99.96% and the RSD was 0.46% (n = 5). The coefficient of variation was less than 2%. The method is simple, rapid, accurate and can be applied to the determination of the nitrogen-containing compounds of beta-elemene.

Topics: Antineoplastic Agents, Phytogenic; Chromatography, Gas; Piperidines; Plant Extracts; Sesquiterpenes; Water

Piperidine alkaloids compose most of the venom of the red imported fire ant, Solenopsis invicta, and we examined how six of these alkaloids varied across worker size and age. In a colony sampled intensively, the relative abundance of each alkaloid was highly correlated with worker size with one exception, and ratios of saturated to unsaturated alkaloids were positively correlated with worker size. Similarly, both the abundance and ratios of alkaloids differed significantly between the small and large workers sampled from colonies across Texas, USA. Young and old workers produced less venom than ants of intermediate age (3-7 weeks), and ratios of saturated to unsaturated alkaloids increased significantly with worker age. The differences in venom composition correspond to the size- and age-based functional roles of workers.

Topics: Age Factors; Alkaloids; Animals; Ant Venoms; Ants; Piperidines

In DNA, the deamination of dAMP generates 2'-deoxy-inosine 5'-monophosphate (dIMP). Hypoxanthine (HX) residues are mutagenic since they give rise to A.T-->G.C transition. They are excised, although with different efficiencies, by an activity of the 3-methyl-adenine (3-meAde)-DNA glycosylases from Escherichia coli (AlkA protein), human cells (ANPG protein), rat cells (APDG protein) and yeast (MAG protein). Comparison of the kinetic constants for the excision of HX residues by the four enzymes shows that the E.coli and yeast enzymes are quite inefficient, whereas for the ANPG and the APDG proteins they repair the HX residues with an efficiency comparable to that of alkylated bases, which are believed to be the primary substrates of these DNA glycosylases. Since the use of various substrates to monitor the activity of HX-DNA glycosylases has generated conflicting results, the efficacy of the four 3-meAde-DNA glycosylases of different origin was compared using three different substrates. Moreover, using oligo-nucleotides containing a single dIMP residue, we investigated a putative sequence specificity of the enzymes involving the bases next to the HX residue. We found up to 2-5-fold difference in the rates of HX excision between the various sequences of the oligonucleotides studied. When the dIMP residue was placed opposite to each of the four bases, a preferential recognition of dI:T over dI:dG, dI:dC and dI:dA mismatches was observed for both human (ANPG) and E.coli (AlkA) proteins. At variance, the yeast MAG protein removed more efficiently HX from a dI:dG over dI:dC, dI:T and dI:dA mismatches.

Topics: Animals; Bacterial Proteins; Base Pair Mismatch; Base Sequence; DNA; DNA Glycosylases; Escherichia coli; Fungal Proteins; Humans; Hypoxanthine; Inosine Monophosphate; Kinetics; N-Glycosyl Hydrolases; Oligodeoxyribonucleotides; Piperidines; Rats; Saccharomyces cerevisiae; Substrate Specificity; Thermodynamics

Hydrazobenzene is carcinogenic to rats and mice and azobenzene is carcinogenic to rats. Hydrazobenzene is a metabolic intermediate of azobenzene. To clarify the mechanism of carcinogenesis by azobenzene and hydrazobenzene, we investigated DNA damage induced by hydrazobenzene, using 32P-5'-end-labeled DNA fragments obtained from the c-Ha-ras-1 protooncogene and the p53 tumor suppressor gene. Hydrazobenzene caused DNA damage in the presence of Cu(II). Piperidine treatment enhanced the DNA damage greatly, suggesting that hydrazobenzene caused base modification and liberation. However, azobenzene did not cause DNA damage even in the presence of Cu(II). Hydrazobenzene plus Cu(II) caused DNA damage frequently at thymine residues. Catalase and a Cu(I)-specific chelator inhibited Cu(II)-mediated DNA damage by hydrazobenzene. Typical *OH scavengers did not inhibit the DNA damage. The main active species is probably a metal oxygen complex, such as Cu(I)-OOH. Formation of 8-oxo-7, 8-dihydro-2'-deoxyguanosine was increased by hydrazobenzene in the presence of Cu(II). Oxygen consumption and UV-Visible spectroscopic measurements have shown that hydrazobenzene is autoxidized to azobenzene with H2O2 formation. It is considered that the metal-mediated DNA damage by hydrazobenzene through H2O2 generation may be relevant for the expression of carcinogenicity of azobenzene and hydrazobenzene.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Azo Compounds; Catalase; Cattle; Chelating Agents; Copper; Deoxyguanosine; DNA; DNA Damage; Free Radical Scavengers; Humans; Hydrogen Peroxide; Hydroxyl Radical; Oxidation-Reduction; Phenanthrolines; Phenylhydrazines; Piperidines

Free radical intermediates were detected by the electron paramagnetic resonance spin trapping technique upon protonation/deprotonation reactions of carotenoid and beta-ionone radical ions. The hyperfine coupling constants of their spin adducts obtained by spectral simulation indicate that carbon-centered radicals were trapped. The formation of these species was shown to be a result of chemical oxidation of neutral compounds by Fe(3+) or I(2) followed by deprotonation of the corresponding radical cations or addition of nucleophilic agents to them. Bulk electrolysis reduction of beta-ionone and carotenoids also leads to the formation of free radicals via protonation of the radical anions. Two different spin adducts were detected in the reaction of carotenoid polyenes with piperidine in the presence of 2-methyl-2-nitroso-propane (MNP). One is attributable to piperidine radicals (C(5)H(10)N*) trapped by MNP and the other was identified as trapped neutral carotenoid (beta-ionone) radical produced via protonation of the radical anion. Formation of these radical anions was confirmed by ultraviolet-visible spectroscopy. It was found that the ability of carotenoid radical anions/cations to produce neutral radicals via protonation/deprotonation is more pronounced for unsymmetrical carotenoids with terminal electron-withdrawing groups. This effect was confirmed by the radical cation deprotonation energy (H(D)) estimated by semiempirical calculations. The results indicate that the ability of carotenoid radical cations to deprotonate decreases in the sequence: beta-ionone > unsymmetrical carotenoids > symmetrical carotenoids. The minimum H(D) values were obtained for proton abstraction from the C(4) atom and the C(5)-methyl group of the cyclohexene ring. It was assumed that deprotonation reaction occurs preferentially at these positions.

Topics: Anions; beta Carotene; Canthaxanthin; Carotenoids; Cations; Electrochemistry; Electron Spin Resonance Spectroscopy; Free Radicals; Norisoprenoids; Piperidines; Protons; Spin Labels; Terpenes

Using morpholine as sole source of carbon, nitrogen and energy, strain HE5 (DSM 44238) was isolated from forest soil. The isolated strain was identified as a member of the subgroup of fast-growing Mycobacterium species as revealed by 16S rDNA analysis. An identity of 99.4% was obtained to Mycobacterium gilvum; however, the type strain was unable to utilize morpholine. A maximal growth rate of 0.17 h(-1) was observed at a morpholine concentration of 30 mM, 30 degrees C and pH 7.2. The substrate was tolerated at concentrations up to 100 mM. Besides morpholine, the strain utilized pyrrolidine, piperidine and proposed intermediates in morpholine metabolism such as glycolate, glyoxylate and ethanolamine. Degradation of morpholine, piperidine and pyrrolidine by resting or permeabilized cells was strictly dependent on the presence of oxygen. Addition of the cytochrome-P450-specific inhibitor metyrapone to the growth medium resulted in a significantly decreased growth rate if these cyclic amines were used as a substrate. Carbon monoxide difference spectra of crude extracts from cells grown on these substrates compared to spectra obtained for extracts of succinate-grown cells indicated that cytochrome P450 is specifically expressed during growth on the cyclic amines. These data indicated that a cytochrome-P450-dependent monooxygenase is involved in the degradation of the three cyclic amines.

Topics: Amines; Biodegradation, Environmental; Carbon Monoxide; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Ethanolamine; Glycolates; Glyoxylates; Hydrogen-Ion Concentration; Metyrapone; Molecular Sequence Data; Morpholines; Nontuberculous Mycobacteria; Piperidines; Pyrrolidines; Soil Microbiology; Spectrophotometry, Ultraviolet; Substrate Specificity; Succinic Acid; Temperature; Time Factors

The mutagenic effects of ultraviolet and solar irradiation are thought to be due to the formation of DNA photoproducts, most notably cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts ((6-4)PPs). Experimental systems for determining the levels and sequence dependence of photoproduct formation in DNA have often used high doses of short-wave (UVC) irradiation. We have re-assessed this issue by using DNA sequencing technologies and different doses of UVC as well as more physiologically relevant doses of solar irradiation emitted from a solar UV simulator. It has been questioned whether hot alkali treatment can detect (6-4)PPs at all sequence positions. With high UVC doses, the sequence distribution of (6-4)PPs was virtually identical when hot alkali or UV damage endonuclease (UVDE) were used for detection, which appears to validate both methods. The (6-4)PPs form at 5'-TpC and 5'CpC sequences but very low levels are seen at all other dipyrimidines including 5'-TpT. Contrary to expectation, we find that (6-4) photoproducts form at almost undetectable levels under conditions of irradiation for up to five hours with the solar UV simulator. The same treatment produces high levels of CPDs. In addition, DNA glycosylases, which recognize oxidized and ring-opened bases, did not produce significant cleavage of sunlight-irradiated DNA. From these data, we conclude that cyclobutane pyrimidine dimers are at least 20 to 40 times more frequent than any other DNA photoproduct when DNA or cells are irradiated with simulated sunlight.

Topics: Alkalies; Deoxyribonuclease (Pyrimidine Dimer); DNA Damage; DNA Mutational Analysis; Dose-Response Relationship, Radiation; Endodeoxyribonucleases; Fibroblasts; Genes, p53; Hot Temperature; Humans; Mutagenesis; Neurospora crassa; Oligodeoxyribonucleotides; Piperidines; Plasmids; Pyrimidine Dimers; Reproducibility of Results; Time Factors; Ultraviolet Rays

1-(2-Deoxy-beta-D-erythro-pentofuranosyl)-5-hydroxy-5-methylhydantoin (5-OH-5-Me-dHyd) (3) has been shown to be a major oxidation product of thymidine formed upon exposure of DNA to (*)OH-radical and excited photosensitizers. To investigate the biological and structural significance of the 5-OH-5-Me-dHyd residue to DNA, the latter modified 2'-deoxyribonucleoside was chemically prepared and then site-specifically incorporated into oligodeoxyribonucleotides. This was efficiently achieved using the phosphoramidite approach that involved mild deprotection conditions. The purity and the integrity of the modified synthetic DNA fragments were checked using different complementary techniques such as HPLC and polyacrylamide gel electrophoresis, together with electrospray ionization and MALDI-TOF mass spectrometry. The piperidine test applied to 5-OH-5-Me-dHyd containing oligonucleotides showed a weak instability of hydantoin nucleoside inserted into the oligonucleotide chain. Several enzymatic experiments aimed at determining the biochemical features of such a DNA lesion were carried out. Thus, processing of 5-OH-5-Me-dHyd by nuclease P(1), snake venom phosphodiesterase, and calf spleen phosphodiesterase was investigated. The specificity and the mechanism of excision of the lesion by several bacterial and yeast DNA N-glycosylases, namely, endonuclease III (endo III), endonuclease VIII (endo VIII), formamidopyrimidine DNA N-glycosylase (Fpg), Ntg1 protein (Ntg1), Ntg2 protein (Ntg2), and Ogg1 protein (yOgg1), were also determined. These repair studies clearly showed that all these enzymes, with the exception of the yOgg1 protein, are able to recognize and remove 5-hydroxy-5-methylhydantoin from the double-stranded DNA fragment. Finally, a 22-mer DNA oligomer bearing a 5-OH-5-Me-dHyd residue was used as a template to study the in vitro nucleotide incorporation opposite the damage by the Klenow fragment of Escherichia coli polymerase I, Taq DNA polymerase, and DNA polymerase beta. Thus, it may be concluded that the oxidized thymine residue is a strongly blocking lesion for the three studied DNA polymerases.

Topics: Deoxyribonucleases; DNA Repair; DNA Replication; DNA-Directed DNA Polymerase; Oligonucleotides; Organophosphorus Compounds; Piperidines

Synthetic oligodeoxynucleotides containing secondary oxidative lesions at guanine nucleobases have been prepared by the site-specific oxidation by ONOO(-) of oligomers containing 8-oxoguanine (8-oxo-G). The oligomers have been tested for their stability to the standard hot piperidine treatment that is commonly used to uncover oxidized DNA lesions. While DNA containing oxaluric acid and oxazolone was cleaved at the site of modification under hot piperidine conditions, the corresponding cyanuric acid and 8-oxo-G lesions were resistant to piperidine. The recognition of the oxidative lesions by formamidopyrimidine glycosylase (Fpg enzyme) was examined in double-stranded versions of the synthetic oligodeoxynucleotides. Fpg efficiently excised 8-oxo-G and oxaluric acid and to some extent oxazolone, but not cyanuric acid. These data suggest that some DNA lesions formed via ONOO(-) exposures (cyanuric acid) are not repaired by Fpg and are not uncovered by assays based on piperidine cleavage at the site of lesion. Our results indicate that cryptic secondary and tertiary oxidation products arising from 8-oxo-G may contribute to the overall mutational spectra arising from oxidative stress.

Topics: Chromatography, High Pressure Liquid; DNA; DNA Repair; DNA-Formamidopyrimidine Glycosylase; Guanine; N-Glycosyl Hydrolases; Nitrates; Oligonucleotides; Oxidants; Oxidation-Reduction; Piperidines; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Free hydroxyl radicals (free (.)OH), singlet oxygen ((1)O(2)), or (. )OH produced by DNA-copper-hydroperoxo complexes are possible DNA-damaging reactive oxygen species (ROS) in the reaction system containing copper, catechol, and DNA. para-Chlorobenzoic acid (pCBA) degradation studies revealed that CuCl(2) mixed with catechol produced free (.)OH. In the presence of DNA, however, inhibition of the pCBA degradation suggested that another ROS is responsible for the DNA degradation. Of a series of ROS scavengers investigated, only KI, NaN(3), and Na-formate-all of the salts tested-strongly inhibited the DNA degradation, suggesting that the ionic strength rather than the reactivity of the individual scavengers could be responsible for the observed inhibition. The ionic strength effect was confirmed by increasing the concentration of phosphate buffer, which is a poor (.)OH scavenger, and was interpreted as the result of destabilization of DNA-copper-hydroperoxo complexes. Piperidine-labile site patterns in DNA degraded by copper and catechol showed that the mixture of Cu(II) and catechol degrades DNA via the intermediate formation of a DNA-copper-hydroperoxo complex. Replacement of guanine by 7-deazaguanine did not retard the DNA degradation, suggesting that the DNA-copper-hydroperoxo complexes do not bind to the guanine N-7 as proposed in the literature.

Topics: Catechols; Copper; DNA; DNA Damage; Free Radical Scavengers; Guanine; Hydroxyl Radical; Osmolar Concentration; Piperidines; Reactive Oxygen Species

Topics: Alkylating Agents; Animals; Base Sequence; Deoxyribonuclease I; DNA; DNA Footprinting; DNA Glycosylases; Embryo, Mammalian; Fibroblasts; Genetic Techniques; Mice; Molecular Sequence Data; N-Glycosyl Hydrolases; Piperidines; Polymerase Chain Reaction; Promoter Regions, Genetic; Protein Binding; RNA, Long Noncoding; RNA, Untranslated; Sulfuric Acid Esters; Ultraviolet Rays

An electrospray ionization (ESI) compatible separation of phospholipids (PL), phosphatidylglycerol (PG), phosphatidylethanolamine (PE), and phosphatidylcholine (PC), was performed on a C18 column by reversed phase High Performance Liquid Chromatography (HPLC) with minimal ESI suppression. The mobile phase, used isocratically, consisted of methanol and water. ESI was used to efficiently transfer the ions present in solution to the gas phase for mass spectrometric (MS) detection. Formation of negative ions was reinforced by incorporating piperidine post column. Limits of detection (LOD) and limits of quantitation (LOQ) were experimentally determined to be 20 and 60 fmol/microl, respectively, when acquiring data in the selected ion monitoring (SIM) mode monitoring three ions with a single quadrupole MS. When acquiring data from m/z 110-900 in the scanning mode, the LOD and LOQ were experimentally determined to be 1 pmol/microl and 3 pmol/microl. When acquiring product ion spectra for m/z 747, the LOD and LOQ were experimentally determined to be 446 attomol/microl and 1.3 fmol/microl, respectively.

Topics: Animals; Anions; Bacteria; Brain Chemistry; Chromatography, High Pressure Liquid; Egg Yolk; Mass Spectrometry; Phospholipids; Piperidines

Previous work showed that the dorsal periaqueductal gray is involved in the inhibition of fear-potentiated startle. The present study investigated the effects of blockade and stimulation of Kainate/AMPA and GABA(A) receptors within the dorsal periaqueductal gray on expression and conditioned inhibition of fear-potentiated startle. Blockade of the Kainate/AMPA receptors enhanced whereas stimulation of the Kainate/AMPA receptors decreased expression of fear-potentiated startle. These effects do not reflect conditioned inhibition since this modulation was not changed by injections of Kainate/AMPA receptor agonists or antagonists into the dorsal periaqueductal gray. Stimulation and blockade of GABA(A) receptors within the dorsal periaqueductal gray neither affected expression of fear-potentiated startle nor its conditioned inhibition. The present results together with findings from the literature indicate that glutamate in the dorsal periaqueductal gray is a critical substrate for the expression and modulation of fear-related behaviours.

Topics: Acoustic Stimulation; Animals; Conditioning, Classical; Electroshock; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Fear; Kainic Acid; Light; Male; Microinjections; Periaqueductal Gray; Picrotoxin; Piperidines; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, GABA-A; Receptors, Kainic Acid; Reflex, Startle

Mechanisms of DNA oxidation by copper complexes of 3-Clip-Phen and its conjugate with a distamycin analogue, in the presence of a reductant and air, were studied. Characterisation of the production of 5-methylenefuranone (5-MF) and furfural, associated with the release of nucleobases, indicated that these copper complexes oxidised the C1' and C5' positions of 2-deoxyribose, respectively, which are accessible from the DNA minor groove. Oxidation at C1' was the major degradation route. Digestion of DNA oxidation products by P1 nuclease and bacterial alkaline phosphatase allowed characterisation of glycolic acid residues, indicating that these copper complexes also induced C4' oxidation. However, this pathway was not associated with base propenal release. The ability of the copper complex of the 3-Clip-Phen conjugate with the distamycin analogue to produce sequence-selective DNA cleavage allowed confirmation of these mechanisms of DNA oxidation by PAGE. Comparison of DNA cleavage activity showed that conjugation of 3-Clip-Phen with a DNA minor groove binder, like the distamycin analogue, decreased both its ability to perform C1' oxidation as well as the initial rate of the reaction, but this conjugate is still active after 5 h at 37 degrees C, making it an efficient DNA cleaver.

Topics: Animals; Bleomycin; Cattle; Chromatography, High Pressure Liquid; Copper; Distamycins; DNA; DNA Damage; Electrophoresis, Polyacrylamide Gel; Furaldehyde; Gas Chromatography-Mass Spectrometry; Glycolates; Iron; Malondialdehyde; Oxidants; Oxidation-Reduction; Phenanthrolines; Piperidines; Substrate Specificity; Zinostatin

New fibrates containing piperidine, 4-hydroxypiperidine, piperidin-3-ene, and piperazine moieties in the structures were synthesized and evaluated. Among the synthesized compounds, 2-[3-[1-(4-fluorobenzoyl)-piperidin-4yl]phenoxyl-2-methylpropanoic acid (9aA: AHL-157) showed very superior activities in decreasing triglyceride, cholesterol, and blood sugar compared to bezafibrate in mice and rats.

Topics: Animals; Disease Models, Animal; Hypercholesterolemia; Hypertriglyceridemia; Hypoglycemic Agents; Hypolipidemic Agents; Male; Mice; Mice, Inbred ICR; Piperazine; Piperazines; Piperidines; Propionates; Rats; Rats, Sprague-Dawley

A micellar solution containing phosphate buffer, anionic surfactant, and water-miscible organic solvent was employed as a migration solution for the separation and the quantification of eleven analytes by micellar electrokinetic chromatography (MEKC): the analytes examined were haloperidol, methylparaben, ethylparaben, n-propylparaben, iso-propylparaben, n-butylparaben, iso-butylparaben, sec-butylparaben, 4-(4-chlorophenyl)-4-hydroxypiperidine, 4-fluorobenzoic acid and 4-hydroxybenzoic acid. In order to provide good separation between micelle and haloperidol, which showed strongest interaction with the micelle among the analytes, surfactant concentrations and organic modifier percentages were studied with phosphate buffer at pH 7.0. All the analytes were successfully resolved when 10 mM sodium dodecylsulfate and 15% ethanol were contained in the migration solution; the time window was very wide in the range from 14.8 to 65.5 min. Optimized applied voltage at 30 kV and capillary temperature at 45 degrees C enable analyze all compounds in less than 17 min with the best resolution, the shorter migration time window, the highest precision and lowest detection limit.

Topics: Benzoates; Calibration; Chromatography, Micellar Electrokinetic Capillary; Haloperidol; Parabens; Piperidines

Piperidines are a relatively novel class of calcium channel blockers which act at a unique receptor site associated with the calcium channel alpha1 subunit. Calcium channel blocking affinities ranging from subnanomolar to several hundred micromolar have been reported in the literature, suggesting that piperidine block is highly sensitive to the cellular environment experienced by the channel. Here, I have investigated some of the cytoplasmic determinants of haloperidol block of N-type calcium channels expressed in human embryonic kidney cells. In perforated patch clamp recordings, haloperidol blocks N-type calcium channels with an inhibition constant of 120 microM. Upon internal dialysis with chloride containing pipette solution, the blocking affinity increases by 40-fold. This effect could be attributed in part to the presence of internal chloride ions, as replacement of intracellular chloride with methanesulfonate reduced haloperidol blocking affinity by almost one order of magnitude. Tonic inhibition of N-type channels by Gbetagamma subunits further enhanced the blocking effects of haloperidol, suggesting the possibility of direct effects of Gbetagamma binding on the local environment of the piperidine receptor site. Overall, depending on the cytoplasmic environment experienced by the channel, the blocking affinity of N-type calcium channels for haloperidol may vary by more than two orders of magnitude. Thus, absolute blocking affinities at the piperidine receptor site must be interpreted cautiously and in the context of the particular experimental setting.

Topics: Binding Sites; Biological Transport; Calcium Channel Blockers; Calcium Channels; Cell Line; GTP-Binding Proteins; Humans; Kidney; Piperidines

Several studies have shown that ionizing radiation generates a wide spectrum of lesions to DNA including base modifications, abasic sites, strand breaks, crosslinks and tandem base damage. One example of tandem base damage induced by @OH radical inX-irradiated DNA oligomers is N -(2-deoxy-beta-d- erythro -pentofuranosyl)-formylamine/8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo). In order to investigate the biological significance of such a tandem lesion, both 8-oxo-7,8-dihydroguanine and formylamine were introduced into synthetic oligonucleotides at vicinal positions using the solid phase phosphoramidite method. For this purpose, a new convenient method of synthesis of 8-oxodGuo was developed. The purity and integrity of the modified synthetic DNA fragments were assessed using different complementary techniques including HPLC, polyacrylamide gel electrophoresis, electrospray and MALDI-TOF mass spectrometry. The piperidine test applied to the double modified base-containing oligonucleotides revealed the high alkaline lability of formylamine in DNA. In addition, various enzymatic experiments aimed at determining biochemical features of such multiply damaged sites were carried out using the synthetic substrates. The pro-cessing of the vicinal lesions by nuclease P1, snake venom phosphodiesterase, calf spleen phospho-diesterase and repair enzymes including Escherichia coli endonuclease (endo) III and Fapy-glycosylase was studied and is reported.

Topics: Alkaline Phosphatase; Animals; Base Pairing; Cattle; Deoxyribonuclease (Pyrimidine Dimer); DNA Damage; DNA-Formamidopyrimidine Glycosylase; Endodeoxyribonucleases; Escherichia coli Proteins; Exonucleases; Guanine; N-Glycosyl Hydrolases; Oligodeoxyribonucleotides; Phosphodiesterase I; Phosphoric Diester Hydrolases; Piperidines; Single-Strand Specific DNA and RNA Endonucleases; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Nitrogen mustards such as mechlorethamine have previously been shown to covalently cross-link DNA through the N7 position of the two guanine bases of a d[GXC].d[GYC] duplex sequence, a so-called 1,3 G-G-cross-link, when X-Y = C-G or T-A. Here, we report the formation of a new mechlorethamine cross-link with the d[GXC].d[GYC] fragment when X-Y is a C-C mismatch pair. Mechlorethamine cross-links this fragment preferentially between the two mismatched cytosine bases, rather than between the guanine bases. The cross-link also forms when one or both of the guanine bases of the d[GCC].d[GCC] fragment are replaced by N7-deazaguanine, and, more generally, forms with any C-C mismatch, regardless of the flanking base pairs. Piperidine cleavage of the cross-link species containing the d[GCC].d[GCC] sequence gives DNA fragments consistent with alkylation at the mismatched cytosine bases. We also provide evidence that the cross-link reaction occurs between the N3 atoms of the two cytosine bases by showing that the formation of the C-C cross-link is pH dependent for both mechlorethamine and chlorambucil. Dimethyl sulfate (DMS) probing of the cross-linked d[GCC].d[GCC] fragment showed that the major groove of the guanine adjacent to the C-C mismatch is still accessible to DMS. In contrast, the known minor groove binder Hoechst 33258 inhibits the cross-link formation with a C-C mismatch pair flanked by A-T base pairs. These results suggest that the C-C mismatch is cross-linked by mechlorethamine in the minor groove. Since C-C pairs may be involved in unusual secondary structures formed by the trinucleotide repeat sequence d[CCG]n, and associated with triplet repeat expansion diseases, mechlorethamine may serve as a useful probe for these structures.

Topics: Alkylating Agents; Alkylation; Base Pair Mismatch; Bisbenzimidazole; Cross-Linking Reagents; DNA; Guanine; Hydrogen-Ion Concentration; Mechlorethamine; Nucleic Acid Conformation; Nucleic Acid Heteroduplexes; Piperidines; Sulfuric Acid Esters

The mechanism of DNA damage induced by metabolites of nitrobenzene was investigated in relation to the carcinogenicity and reproductive toxicity of nitrobenzene. Nitrosobenzene, a nitrobenzene metabolite, induced NADH plus Cu(II)-mediated DNA cleavage frequently at thymine and cytosine residues. Catalase and bathocuproine inhibited the DNA damage, suggesting the involvement of H2O2 and Cu(I). Typical free hydroxyl radical scavengers showed no inhibitory effects on DNA damage. Nitrosobenzene caused the formation of 8-oxo-7, 8-dihydro-2'-deoxyguanosine in calf thymus DNA in the presence of NADH and Cu(II). ESR spectroscopic study has confirmed that nitrosobenzene is reduced by NADH to the phenylhydronitroxide radical even in the absence of Cu(II). These results suggest that nitrosobenzene can be reduced non-enzymatically by NADH, and the redox cycle reaction resulted in oxidative DNA damage due to the copper-oxygen complex, derived from the reaction of Cu(I) with H2O2.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Catalase; Cations; Cattle; Chelating Agents; Chromatography, High Pressure Liquid; Copper; Cytosine; Deoxyguanosine; DNA; DNA Damage; Electron Spin Resonance Spectroscopy; Free Radical Scavengers; Guanine; Humans; Hydrogen Peroxide; Metals; Models, Chemical; NAD; Nitrobenzenes; Nitroso Compounds; Oxidation-Reduction; Piperidines; Thymine

The frequency of oxidative base damage, such as 8-hydroxyguanine (8-OH-Gua), was determined at the nucleotide level of resolution using the ligation-mediated PCR technique. Administration of a renal carcinogen, ferric nitrilotriacetate (Fe-NTA), is known to induce oxidative stress and subsequent formation of 8-OH-Gua in the rat kidney. Whole genomic DNA was isolated from the rat kidney after or without Fe-NTA treatment and then cleaved with hot piperidine. In order to assess the frequency of 8-OH-Gua formation, we chose three genes, the tumor suppressor gene p53, the heat shock protein 70 (HSP70-1) gene and the Na,K-ATPase alpha1 subunit gene. No alteration in the cleavage profile was observed in the p53 and HSP70 genes after Fe-NTA treatment. In the case of the p53 gene, a low incidence of point mutations has been observed in this carcinogenesis system. On the other hand, time-dependent alterations, corresponding to the time course of overall 8-OH-Gua formation and repair, were detected in the promoter region of the Na,K-ATPase alpha1 subunit gene. GpG and GpGpG in specific regions seem to be hotspots for the formation of 8-OH-Gua. These results were confirmed by formamidopyrimidine-DNA glycosylase-dependent DNA cleavage patterns. Thus, oxidative base damage, such as 8-OH-Gua, was not distributed uniformly along the whole genome, but seemed to be restricted to particular genes and regions.

Topics: Animals; Base Sequence; Carcinogens; DNA; DNA Damage; Ferric Compounds; Guanine; HSP70 Heat-Shock Proteins; Kidney; Male; Molecular Sequence Data; Nitrilotriacetic Acid; Piperidines; Protozoan Proteins; Rats; Rats, Wistar; Sodium-Potassium-Exchanging ATPase; Tumor Suppressor Protein p53

2-Amino-3-piperidin-4-yl-propionic acid containing peptidomimetics are potent protease inhibitors when combined with an appropriate keto-thiazole or keto-carboxylic acid moiety. A novel P1 residue in factor Xa and thrombin inhibitors has been found resulting in IC50 values as low as 0.048 microM, a factor of ten more potent than Argatroban. Starting with non-chiral synthetic routes, a new stereospecific route was developed as well as a new solid-phase method.

Topics: Blood Coagulation Factors; Carboxylic Acids; Factor Xa Inhibitors; Inhibitory Concentration 50; Kinetics; Models, Chemical; Piperidines; Platelet Glycoprotein GPIIb-IIIa Complex; Thiazoles; Thrombin

The syntheses of a number of different N-linked heterocyclic pyrazole replacements based on the structure 1 are described (compounds 3-12) as hD4 ligands. After further optimisation the best compound identified was 13 which has high affinity for hD4 (5.2 nM) and >300-fold selectivity for hD4 receptors over hD2 and hD3 receptors.

Topics: Animals; CHO Cells; Clozapine; Cricetinae; Humans; Kinetics; Piperidines; Receptors, Dopamine D2; Receptors, Dopamine D4; Serotonin Antagonists

Transposon mutagenesis of Mycobacterium smegmatis mc2155 enabled the isolation of a mutant strain (called LGM1) altered in the regulation of piperidine and pyrrolidine utilization. The complete nucleotide sequence of the gene inactivated in mutant LGM1 was determined from the wild-type strain. This gene (pipR) encoded a member of the GntR family of bacterial regulatory proteins. An insertion element (IS1096), previously described for M. smegmatis, was detected downstream of the gene pipR. Three additional open reading frames were found downstream of IS1096. The first open reading frame (pipA) appeared to encode a protein identified as a cytochrome P450 enzyme. This gene is the first member of a new family, CYP151. By a gene replacement experiment, it was demonstrated that the cytochrome P450 pipA gene is required for piperidine and pyrrolidine utilization in M. smegmatis mc2155. Genes homologous to pipA were detected by hybridization in several, previously isolated, morpholine-degrading mycobacterial strains. A gene encoding a putative [3Fe-4S] ferredoxin (orf1) and a truncated gene encoding a putative glutamine synthetase (orf2') were found downstream of pipA.

Topics: Amino Acid Sequence; Bacterial Proteins; Base Sequence; Blotting, Southern; Cloning, Molecular; Cytochrome P-450 Enzyme System; DNA Transposable Elements; DNA-Binding Proteins; Escherichia coli Proteins; Genes, Bacterial; Glucose; Kinetics; Molecular Sequence Data; Mutagenesis, Insertional; Mycobacterium smegmatis; Open Reading Frames; Piperidines; Pyrrolidines; Repressor Proteins; Sequence Analysis, DNA; Sequence Homology; Transcription Factors

Nine bacterial strains that grew on morpholine and pyrrolidine as sole carbon, nitrogen, and energy sources were isolated from three different environments with no known morpholine contamination. One of these strains could also degrade piperidine. These bacteria were identified as Mycobacterium strains. A phylogenetic analysis based on the partial 16S rDNA sequences indicated that the isolated strains clustered within the fast growing group of mycobacteria. When the above-mentioned cyclic amines were used as growth substrates, the synthesis of a soluble cytochrome P450 was induced in all these bacteria. Other laboratory strains, Mycobacterium fortuitum and Mycobacterium smegmatis mc(2)155, were tested for their abilities to degrade morpholine. Neither of them degraded morpholine but could use pyrrolidine and piperidine. The growth of M. fortuitum and M. smegmatis mc(2)155 on these compounds involved a soluble cytochrome P450, suggesting that mycobacterial strains are naturally able to use pyrrolidine and have developed a similar enzymatic pathway to metabolize this amine.

Topics: Base Sequence; Biodegradation, Environmental; Cytochrome P-450 Enzyme System; Enzyme Induction; Molecular Sequence Data; Morpholines; Mycobacterium; Phylogeny; Piperidines; Pyrrolidines; RNA, Bacterial; RNA, Ribosomal, 16S; Soil Microbiology

1-(2-Deoxy-beta-D-erythro-pentofuranosyl)cyanuric acid (cyanuric acid nucleoside, dY) (1) has been shown to be formed upon exposure of DNA components to ionizing radiation and excited photosensitizers. To investigate the biological and structural significance of dY residue in DNA, the latter modified 2'-deoxynucleoside was chemically prepared and then site-specifically incorporated into oligodeoxyribonucleotides (ODNs). This was achieved in good yields using the phosphoramidite approach. For this purpose, a convenient glycosylation method involving 3,5-protected 2-deoxyribofuranoside chloride and cyanuric acid (2,4,6-trihydroxy-1,3,5-triazine) was devised. The anomeric mixture of modified 2'-deoxyribonucleosides (1/2 alpha/beta) was resolved by silica gel purification of the 5'-O-dimethoxytritylated derivatives, and then, phosphitylation afforded the desired beta-phosphoramidite monomer (5). After solid-phase condensation and final deprotection, the purity and the integrity of the modified synthetic DNA fragments were checked using different complementary techniques such as HPLC and polyacrylamide gel electrophoresis, together with electrospray ionization and MALDI-TOF mass spectrometry. The presence of cyanuric acid nucleoside in a 14-mer was found to have destabilizing effects on the double-stranded DNA fragment as inferred from melting temperature measurements. The piperidine test applied to dY-containing ODNs supported the high stability of cyanuric acid nucleoside inserted into the oligonucleotide chain. Several enzymatic experiments aimed at determining the biological features of such a DNA lesion were carried out. Thus, processing of dY by nuclease P(1), snake venom phosphodiesterase (SVPDE), calf spleen phosphodiesterase (CSPDE), and repair enzymes, including Escherichia coli endonuclease III (endo III) and Fapy glycosylase (Fpg), was investigated. Finally, a 22-mer ODN bearing a cyanuric acid residue was used as a template to study the in vitro nucleotide incorporation opposite the damage by the Klenow fragment of E. coli polymerase I.

Topics: Deoxyribonuclease (Pyrimidine Dimer); DNA; DNA Polymerase I; DNA-Formamidopyrimidine Glycosylase; Endodeoxyribonucleases; Escherichia coli Proteins; Guanine; Mass Spectrometry; N-Glycosyl Hydrolases; Nucleic Acid Denaturation; Nucleic Acid Hybridization; Nucleosides; Oligodeoxyribonucleotides; Piperidines; Triazines

Novel 3-(2-cycloalkyl and cycloalkenyl-3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazo lo [1,5-a]-pyridines were synthesized and evaluated for their adenosine A1 receptor binding activities. In this series, FR166124 (3) was found to be the most potent and selective adenosine A1 receptor antagonist, and the double bond of the cyclohexenyl acetic acid group was essential for selectivity of A1 receptor binding. Furthermore, the solubility in water of the sodium salt of FR 166124 was high.

Topics: Antihypertensive Agents; Inhibitory Concentration 50; Molecular Structure; Piperidines; Purinergic P1 Receptor Antagonists; Pyrazoles; Pyridines; Receptors, Purinergic P1; Solubility; Structure-Activity Relationship; Water; Xanthines

Substituted 1,2,4-oxadiazoles were synthesized in good yields on solid supports under basic conditions at room temperature.

Topics: Chemistry, Organic; Chromatography, High Pressure Liquid; Oxadiazoles; Piperidines; Solvents; Temperature

Following the discovery of the first dual antagonist of platelet-activating factor (PAF) and histamine, 1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin- 11-ylidene)piperidine, Sch 37370, 1, a related series of structures, exemplified by (+/-)-1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]-cyclohepta[1,2-b] pyridin-11-yl)piperazine, Sch 40338, 2, were prepared. Interestingly, the compounds exhibited a parallel structure antiallergy activity relationship, suggesting that the two series may adopt a common conformation at the PAF receptor. Conformational analysis led to a proposal for this bioactive conformation accessible to both series. The synthesis of novel conformationally constrained analogues that might mimic the proposed bioactive conformation of these compounds, and the evaluation of their in vitro antiallergy activity form the subject matter of this report.

Topics: Animals; Anti-Allergic Agents; Crystallography, X-Ray; Drug Design; Drug Evaluation, Preclinical; Guinea Pigs; Histamine Antagonists; Humans; Inhibitory Concentration 50; Isoquinolines; Loratadine; Mice; Models, Molecular; Molecular Conformation; Molecular Mimicry; Piperazines; Piperidines; Platelet Activating Factor; Platelet Aggregation; Platelet Aggregation Inhibitors; Pyridines; Rats; Receptors, Histamine H1; Stereoisomerism; Structure-Activity Relationship

The formal C1'-oxidation product, 2-deoxyribonolactone, is formed as a result of DNA damage induced via a variety of agents, including gamma-radiolysis and the enediyne antitumor antibiotics. This alkaline labile lesion may also be an intermediate during DNA damage induced by copper-phenanthroline. Oligo-nucleotides containing this lesion at a defined site were formed via aerobic photolysis of oligonucleotides containing a photolabile ketone, and were characterized by gel electrophoresis and electrospray mass spectrometry (ESI-MS). Treatment of oligo-nucleotides containing the lesion with secondary amines produces strand breaks consisting of 3'-phosphate termini, and products which migrate more slowly in polyacrylamide gels. MALDI-TOF mass spectrometry analysis indicates that the slower moving products are formal adducts of the beta-elimination product resulting from 2-deoxyribonolactone and one molecule of amine. The addition of beta-mercapto-ethanol to the reaction mixture produces thiol adducts as well. The stability of these adducts suggests that they cannot be the labile species characterized by gel electrophoresis in copper-phenanthroline-mediated strand scission. The characterization of these adducts by mass spectrometry also provides, by analogy, affirmation of proposals regarding the reactivity of nucleophiles with the beta-elimination product of abasic sites. Finally, the effects of this lesion and the various adducts on DNA repair enzymes are unknown, but their facile generation from oligonucleotides containing a photolabile ketone suggests that such issues could be addressed.

Topics: Ammonia; DNA Adducts; DNA Damage; DNA Repair; DNA, Single-Stranded; Ethylenediamines; Mercaptoethanol; Oligodeoxyribonucleotides; Piperidines; Sugar Acids; Water

We have previously described compound 1a as a high-affinity subtype selective alpha(1a) antagonist. In vitro and in vivo evaluation of compound 1a showed its major metabolite to be a mu-opioid agonist, 4-methoxycarbonyl-4-phenylpiperidine (3). Several dihydropyrimidinone analogues were synthesized with the goal of either minimizing the formation of 3 by modification of the linker or finding alternative piperidine moieties which when cleaved as a consequence of metabolism would not give rise to mu-opioid activity. Modification of the linker gave several compounds with good alpha(1a) binding affinity (K(i) = < 1 nM) and selectivity (>300-fold over alpha(1b) and alpha(1d)). In vitro analysis in the microsomal assay revealed these modifications did not significantly affect N-dealkylation and the formation of the piperidine 3. The second approach, however, yielded several piperidine replacements for 3, which did not show significant mu-opioid activity. Several of these compounds maintained good affinity at the alpha(1a) adrenoceptor and selectivity over alpha(1b) and alpha(1d). For example, the piperidine fragments of (+)-73 and (+)-83, viz. 4-cyano-4-phenylpiperidine and 4-methyl-4-phenylpiperidine, were essentially inactive at the mu-opioid receptor (IC(50) > 30 microM vs 3 microM for 3). Compounds (+)-73 and (+)-83 were subjected to detailed in vitro and in vivo characterization. Both these compounds, in addition to their excellent selectivity (>880-fold) over alpha(1b) and alpha(1d), also showed good selectivity over several other recombinant human G-protein coupled receptors. Compounds (+)-73 and (+)-83 showed good functional potency in isolated human prostate tissues, with K(b)s comparable to their in vitro alpha(1a) binding data. In addition, compound (+)-73 also exhibited good uroselectivity (DBP K(b)/IUP K(b) > 20-fold) in the in vivo experiments in dogs, similar to 1a.

Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Biological Availability; Blood Pressure; Dogs; Drug Design; Drug Evaluation, Preclinical; GTP-Binding Proteins; Half-Life; Humans; In Vitro Techniques; Male; Microsomes; Piperidines; Prostate; Pyrimidinones; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1; Receptors, Opioid, mu; Recombinant Proteins; Stereoisomerism; Structure-Activity Relationship; Urethra

The acceptor character of iron violurate complex was studied by examining the electronic, vibrational and 1H-nmr spectra of the charge transfer molecular complexes formed between the iron violurate as pi-acceptor and some amines as n-donors. Elemental analysis and spectral results establishes 1:2 stoichiometry of the adducts. The study has been conducted at different temperatures. Values of delta G degree, delta H degree and delta S degree have been calculated from the self-consistent values of the formation constants (KCT). Ionization potentials of the donors have been calculated and the solvent effect on the KCT values is discussed. The antibacterial and antifungal effects of the molecular complexes were studied.

Topics: Amines; Anti-Infective Agents; Antifungal Agents; Barbiturates; Diethylamines; Drug Evaluation, Preclinical; Ethylamines; Piperidines; Solvents; Spectrophotometry, Ultraviolet; Structure-Activity Relationship; Thermodynamics; Vibration

A Mycobacterium strain (RP1) was isolated from a contaminated activated sludge collected in a wastewater treatment unit of a chemical plant. It was capable of utilizing morpholine and other heterocyclic compounds, such as pyrrolidine and piperidine, as the sole source of carbon, nitrogen, and energy. The use of in situ 1H nuclear magnetic resonance (1H NMR) spectroscopy allowed the determination of two intermediates in the biodegradative pathway, 2-(2-aminoethoxy)acetate and glycolate. The inhibitory effects of metyrapone on the degradative abilities of strain RP1 indicated the involvement of a cytochrome P-450 in the biodegradation of morpholine. This observation was confirmed by spectrophotometric analysis and 1H NMR. Reduced cell extracts from morpholine-grown cultures, but not succinate-grown cultures, gave rise to a carbon monoxide difference spectrum with a peak near 450 nm, which indicated the presence of a soluble cytochrome P-450. 1H NMR allowed the direct analysis of the incubation medium containing metyrapone, a specific inhibitor of cytochrome P-450. The inhibition of morpholine degradation was dependent on the morpholine/metyrapone ratio. The heme-containing monooxygenase was also detected in pyrrolidine- and piperidine-grown cultures. The abilities of different compounds to support strain growth or the induction of a soluble cytochrome P-450 were assayed. The results suggest that this enzyme catalyzes the cleavage of the C-N bond of the morpholine ring.

Topics: Acetates; Biodegradation, Environmental; Carbon Monoxide; Cytochrome P-450 Enzyme System; Ethanolamine; Ethylamines; Glycolates; Hydrogen; Industrial Waste; Magnetic Resonance Spectroscopy; Metyrapone; Morpholines; Mycobacterium; Piperidines; Pyrrolidines; Sewage; Succinic Acid

An investigation of the stability of the Dde protecting group for amines, used in solid-phase peptide synthesis, shows that an unprotected epsilon-NH2 group of lysine can acquire the Dde protection from another epsilon-NH2 group or from an alpha-NH2 group. An unprotected alpha-NH2, however, cannot remove Dde from an epsilon-NH2 function. This migration takes place during Fmoc removal from the epsilon-NH2 with piperidine and/or during the subsequent washing steps. The Dde migration is also possible in neat dimethylformamide by a direct nucleophilic attack of the free epsilon-NH2 group. Addition of piperidine to the reaction medium accelerates the side reaction, probably because of the formation of an unstable piperidine-Dde adduct. Dde migration can be prevented if the 9-fluorenylmethyloxycarbonyl is cleaved with 1,8-diazabicyclo[5.4.0]undec-7-ene for a short reaction time (2%, 3 x 3 min). Finally, this rearrangement is shown to occur both as an intra- and intermolecular reaction between peptides on the same resin bead.

Topics: Amino Acid Sequence; Amino Acids; Chromatography, High Pressure Liquid; Dimethylformamide; Drug Stability; Fluorenes; Lysine; Mass Spectrometry; Molecular Structure; Peptides; Piperidines

A cyclic peptide that spans the major antigenic determinant of the human immunodeficiency virus (HIV) glycoprotein 41 (gp41) has been synthesized according to various strategies. For immunodiagnostic applications, biotin was added at the N-terminus of the peptide and aminohexanoic acid was used as a spacer. Polymer-supported oxidations were carried out in a variety of ways with thallium (III) trifluoroacetate. The biotinylcyclic peptide was released from the support using trimethylsilyl trifluoromethane sulfonate and various scavengers. The efficacy of these different cyclization and cleavage procedures was compared. Side reactions were studied, and a simple and efficient procedure was set up to monitor peptide cyclization by mass spectrometry. In a second series of syntheses the disulfide bridge was replaced by an amide bond. For this purpose, an aspartic acid derivative and a diaminopropionic acid were introduced during the synthesis in place of the two cysteine residues in the parent sequence. On-resin cyclization was performed and led to a major side-product identified as a piperidide. This undesired base-mediated side reaction was prevented when, instead of piperidine, 1,8-diazabicyclo-[5.4.0]undec-7-ene was used for fluorenylmethyl ester deprotection. Reactivity of these peptides with different patients' sera and with a monoclonal antibody directed against the whole gp41 was tested using an enzyme-linked immunosorbent assay.

Topics: Antibodies, Monoclonal; Biochemistry; Biotin; Dimethylformamide; Disulfides; Enzyme-Linked Immunosorbent Assay; Epitopes; HIV Envelope Protein gp41; HIV Infections; Humans; Lactams; Peptides; Piperidines

The effects of oral administration of 4-benzhydryloxy-1-[3-(1H-tetrazol-5-yl)-propyl]piperidine (HQL-79), a newly synthesized antiallergic drug, in various experimental allergic and asthmatic models were investigated. HQL-79 markedly inhibited immediate hypersensitivity reactions such as passive cutaneous anaphylaxis in rats, antigen-induced bronchoconstriction and nasal vascular permeability in actively sensitized guinea pigs, like epinastine and ketotifen did. Airway eosinophilia in repeatedly antigen-exposed guinea pigs was suppressed by chronic administration of HQL-79 for 2 weeks. In another experiment, the antigen-induced late asthmatic response (LAR) in metyrapone-treated guinea pigs was also ameliorated by chronic treatment with HQL-79. Moreover, HQL-79 partially inhibited the toluene diisocyanate-induced delayed-type hypersensitivity (DTH) reaction in mice when administered chronically during the immunization period. The corticosteroid dexamethasone inhibited the airway inflammatory responses in guinea pigs and the DTH in mice. These results indicate that HQL-79 has potent inhibitory effects on the immediate hypersensitivity reactions, and when administered chronically, it also inhibits airway eosinophilia, LAR and DTH, similarly to corticosteroids.

Topics: Animals; Anti-Allergic Agents; Anti-Asthmatic Agents; Antigens; Bronchoconstriction; Capillary Permeability; Dibenzazepines; Disease Models, Animal; Dose-Response Relationship, Drug; Guinea Pigs; Histamine H1 Antagonists; Hypersensitivity, Delayed; Imidazoles; Ketotifen; Leukocytes; Male; Mice; Mice, Inbred ICR; Nasal Mucosa; Passive Cutaneous Anaphylaxis; Piperidines; Rats; Rats, Wistar; Respiratory Hypersensitivity

The effects of 4-benzhydryloxy-1-[3-(1H-tetrazol-5-yl)-propyl]piperidine (HQL-79), a newly developed antiallergic drug, on various chemical mediators and on chemical mediator release were investigated. Orally administered HQL-79 strongly inhibited the histamine-induced skin reaction in rats, and histamine- and 5-hydroxytryptamine (5-HT)-induced bronchoconstriction in guinea pigs. HQL-79 inhibited antigen-induced release of leukotriene (LT) B4, LTC4, histamine and prostaglandin (PG) D2 from the chopped lung tissues of actively sensitized guinea pigs. On the other hand, release of PGE2, one of the bronchoprotective prostanoids, was significantly enhanced by HQL-79. In an in vivo experiment, chronic administration of HQL-79 clearly reduced PGD2 contents and enhanced PGE2 contents in the lungs of repeatedly antigen-exposed guinea pigs. In biochemical studies, HQL-79 inhibited mouse spleen PGD synthase in a concentration-dependent manner. None of the antiallergics such as epinastine, terfenadine, oxatomide and cetirizine inhibited the PGD synthase. HQL-79 did not affect PGE synthase in sheep vesicular gland microsomes. These results suggest that antiallergic and antiasthmatic effects of HQL-79 could be ascribed to antihistaminic- and anti-5-HT effects, chemical mediator release inhibition, PGE2-release enhancement and PGD synthase inhibition. It is considered, in particular, that the differential modulation of PGD2 and PGE2 production is a conspicuous pharmacological feature of HQL-79.

Topics: Animals; Anti-Allergic Agents; Anti-Asthmatic Agents; Antigens; Capillary Permeability; Dibenzazepines; Dinoprostone; Dose-Response Relationship, Drug; Free Radical Scavengers; Guinea Pigs; Histamine; Histamine H1 Antagonists; Histamine Release; Ileum; Imidazoles; In Vitro Techniques; Intramolecular Oxidoreductases; Ketotifen; Leukotriene B4; Leukotriene C4; Lipocalins; Lung; Male; Mice; Mice, Inbred ICR; Muscle Contraction; Piperidines; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; Respiratory Hypersensitivity; Serotonin; Sheep; Skin Physiological Phenomena; Trachea

An optimized automated PNA synthesis protocol is reported. Under optimal conditions the product yield of a test 17-mer PNA is approximately 90%. The average coupling yield is 99.4%. The synthesis strategy is Boc/Z and the deprotected amine is neutralized in situ. The monomers are added in molar excess to HATU and pre-activated for 60 s before delivery to the resin. The concentration of the activated monomers is 0.08 M during the couplings. Heteroselective solvation provides the highest coupling yields. Acetic anhydride is used as capping reagent followed by a piperidine wash. The protocol has been developed in a 5 mumol scale but is easily scaled up to 10-50 mumol scale syntheses on the automated synthesizer (ABI 433A).

Topics: Biopolymers; Chromatography, High Pressure Liquid; Glycine; Nucleic Acids; Peptides; Piperidines; Purines; Pyrimidinones; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

In an effort to discover novel nonpeptide glycoprotein IIb/IIIa (GPIIb/IIIa, alpha IIb/beta 3) inhibitors, we investigated RGD mimetics featuring a 3-substituted benzoic acid as the core, benzamidine as the basic moiety, and a series of beta- and alpha-substituted beta-alanine derivatives as aspartic acid surrogates. It was found that the use of beta-methyl beta-alanine slightly improved the anti-aggregant potency in human platelet-rich plasma over the unsubstituted beta-alanine compound, while beta-substitution with a trifluoromethyl group resulted in considerable loss in activity. Significant enhancement (up to 100-fold) in potency was obtained when the beta-alanine was replaced with N2-substituted 1-2,3-diaminopropionic acid derivatives. Among the three types of alpha-substituents (carbamate, amide, and sulfonamide) investigated, no apparent preference was observed with respect to in vitro potency. However, alkyl groups were more favorable than arylalkyl groups (Cbz) in the carbamate analogues. We also investigated piperidine, piperazine, and N-formamidinopiperidine as replacements for the benzamidine moiety. The former two replacements led to a drop in potency while the latter replacement resulted in maintenance of activity as compared with the corresponding benzamidine analogue.

Topics: Alanine; Alkylation; Animals; Aspartic Acid; Benzamides; Benzamidines; Benzoates; Benzoic Acid; beta-Alanine; Carbamates; Esterases; Humans; Liver; Magnetic Resonance Spectroscopy; Oligopeptides; Piperazine; Piperazines; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Structure-Activity Relationship; Sulfonamides; Swine

The effects of local anesthetics were examined on a family of transiently expressed neuronal calcium channels. Fomocaine, a local anesthetic containing a morpholine ring, preferentially blocked alpha1E channels (Ki = 100 microM), and had a lower affinity (3- to 15-fold) for alpha1A, alpha1B, and alpha1C channels. Block was incompletely reversible, followed 1:1 kinetics, and did not affect steady-state inactivation properties. Fomocaine block was sensitive to the concentration of permeant ion and enhanced in the presence of external pore blockers, suggesting a site of action in the conducting pathway. Flecainide, which carries a piperidine ring, and the diphenylbutylpiperidine antipsychotic, penfluridol, caused qualitatively similar block, suggesting that morpholine rings are compatible with the piperidine receptor site. In contrast, procaine, which contains an alkyl chain, caused reversible low affinity block of the different calcium channels (Kd values between 2 and 5 mM) and was least effective on alpha1E and did not compete with fomocaine, suggesting that local anesthetics interact with at least two distinct receptor sites. Compared to coexpression with the Ca channel beta1b subunit, block at the piperidine receptor site was significantly weakened with the beta2a subunit suggesting that the nature of the beta subunit contributes to drug binding. Amino acid changes in the cytoplasmic linker between domains I and II resulted in decreased fomocaine and penfluridol blocking affinity. Furthermore, the blocking affinity observed with alpha1B, was conferred on alpha1A by substitution of the domain I-II linker of alpha1B into alpha1A. Taken together, the data suggest that beta subunit binding and the domain I-II linker contribute to the piperidine receptor site on neuronal calcium channels.

Topics: Animals; Calcium Channels; Dose-Response Relationship, Drug; Membrane Potentials; Molecular Structure; Neurons; Oocytes; Patch-Clamp Techniques; Phenyl Ethers; Piperidines; Procaine; Xenopus

An N-bromoacetyl electrophile attached to the 5'-phosphate group of a purine-rich oligonucleotide affords sequence-specific alkylation of duplex DNA (at 37 degrees C, pH 7.4) through the formation of a specific purine.purine.pyrimidine triple-helical complex. In a 645 bp restriction fragment containing three consecutive guanine bases adjacent to the 3'-end of an oligonucleotide binding site, the yield of single-strand cleavage after piperidine treatment is 80% at the guanine base directly adjacent to the binding site and 88% overall. In an 837 bp restriction fragment containing two adjacent inverted repeats of the third strand binding site and a single 3'-guanine base, yields of single-strand cleavage are 87% on each strand at the 3'-guanine base. Double-strand cleavage was obtained in 61% yield at a single site in a 6.6 kbp plasmid containing the 837 bp fragment. Extension of triple helix mediated DNA alkylation from the pyrimidine to purine motif formally extends the number of sites in duplex DNA that can be cleaved in a sequence-specific and nucleotide-specific manner in good yields.

Topics: Acetates; Alkylation; Binding Sites; DNA; DNA Restriction Enzymes; Electrophoresis, Polyacrylamide Gel; Kinetics; Magnetic Resonance Spectroscopy; Models, Molecular; Nucleic Acid Conformation; Oligodeoxyribonucleotides; Piperidines; Plasmids; Purines; Pyrimidines

Topics: Base Composition; Chemistry Techniques, Analytical; Cytosine; Electrophoresis, Polyacrylamide Gel; Globins; Hydrolysis; Hydroxylamine; Hydroxylamines; Nucleic Acid Hybridization; Osmium Tetroxide; Piperidines; Sequence Homology, Nucleic Acid; Thymidine

With the objectives of developing new protecting groups for the beta-carboxyl group of aspartic acid that are resistant to base-catalyzed aspartimide formation and of evaluating the importance of sterical factors in the design of such protecting groups, four new alkyl ester derivatives of aspartic acid were synthesized. The beta-3-pentyl, beta-4-heptyl, beta-2,6-dimethyl-4-heptyl and the recently described beta-2,4-dimethyl-3-pentyl esters of Boc-aspartic acid were incorporated into model peptides, and the resin-bound protected peptides were treated with 20% piperidine for 10 h. The levels of aspartimide-related side products were compared with the previously reported beta-cyclohexyl, beta-menthyl and beta-2-adamantyl esters of aspartic acid. The results show that bulky, acyclic, aliphatic protecting groups (in particular the 2,4-dimethyl-3-pentyl ester) are significantly more resistant to base-catalyzed aspartimide formation than comparably rigid cyclic alkyl esters that under the same reaction conditions form several-fold more aspartimide-related side products. Using elevated temperatures to overcome difficult couplings leads to the formation of significant amounts of aspartimide when aspartic acid is protected with the cyclohexyl group, but the 2,4-dimethyl-3-pentyl protecting group offers excellent protection under these conditions. The use of the 2,4-dimethyl-3-pentyl protecting group will allow the use of orthogonally removable base-labile protecting groups in Boc chemistry and suggests a design of protecting groups for other nucleophile-sensitive trifunctional amino acids in both Boc and Fmoc chemistry.

Topics: Aspartic Acid; Chromatography, High Pressure Liquid; Esters; Oligopeptides; Piperidines; Temperature; Time Factors

Topics: Animals; Base Sequence; Cattle; Cloning, Molecular; DNA Footprinting; DNA Probes; DNA-Binding Proteins; DNA, Mitochondrial; Genome; Indicators and Reagents; Methylation; Mitochondria; Molecular Sequence Data; Piperidines; Regulatory Sequences, Nucleic Acid; Restriction Mapping; Sulfuric Acid Esters

BOP-Cl was found to be an efficient coupling reagent for the introduction of thiopeptide bonds on imino acid residues (Pro, Sar). Boc-amino monothioacids were coupled at moderate temperature (0 degree C-RT) with fair yields and with retained optical purity. The mechanism of the coupling reaction is discussed.

Topics: Amino Acids; Cross-Linking Reagents; Imines; Leucine; Models, Chemical; Organophosphorus Compounds; Oxazoles; Phosphorus; Piperidines; Proline; Sulfhydryl Compounds; Thioamides

The major initial product of riboflavin- and methylene blue-mediated photosensitization of 2'-deoxyguanosine (dG) in oxygen-saturated aqueous solution has previously been identified as 2-amino-5-[(2-deoxy-beta-D-erythro-pentofuranosyl)amino] 4H-imidazol-4-one (dlz). At room temperature in aqueous solution dlz decomposes quantitatively to 2,2-diamino-4-[(2-deoxy-beta-D-erythro- pentofuranosyl)amino]-5(2H)-oxazolone (dZ). The data presented here show that the same guanine photooxidation products are generated following riboflavin- and methylene blue-mediated photosensitization of thymidylyl-(3',5')-2'-deoxyguanosine [d(TpG)]. As observed for the monomers, the initial product, thymidylyl-(3',5')-2-amino-5-[(2-deoxy- beta-D-erythro-pentofuranosyl)amino]-4H-imidazol-4-one [d(Tplz)], decomposes in aqueous solution at room temperature to thymidylyl-(3',5')-2,2-diamino-4- [(2-deoxy-beta-D-erythro-pentofuranosyl)amino]-5(2H)-oxazolone [d(TpZ)]. Both modified dinucleoside monophosphates have been isolated by HPLC and characterized by proton NMR spectrometry, fast atom bombardment mass spectrometry, chemical analyses and enzymatic digestions. Among the chemical and enzymatic properties of these modified dinucleoside monophosphates are: (i) d(Tplz) and d(TpZ) are alkali-labile; (ii) d(Tplz) reacts with methoxyamine, while d(TpZ) is unreactive; (iii) d(Tplz) is digested by snake venom phosphodiesterase, while d(TpZ) is unaffected; (iv) relative to d(TpG), d(TpZ) and d(Tplz) are slowly digested by spleen phosphodiesterase; (v) d(Tplz) and d(TpZ) can be 5'-phosphorylated by T4 polynucleotide kinase. The first observation suggests that dlz and dZ may be responsible for some of the strand breaks detected following hot piperidine treatment of DNA exposed to photosensitizers.

Topics: Bacteriophage T4; Chemical Phenomena; Chemistry, Physical; Chromatography, High Pressure Liquid; Dinucleoside Phosphates; Hot Temperature; Hydrogen-Ion Concentration; Imidazoles; Kinetics; Magnetic Resonance Spectroscopy; Methoxamine; Methylene Blue; Oxazoles; Phosphodiesterase I; Phosphoric Diester Hydrolases; Phosphorylation; Photochemistry; Piperidines; Polynucleotide 5'-Hydroxyl-Kinase; Riboflavin; Spectrometry, Mass, Fast Atom Bombardment; Thymidine

Three varieties of kola nut, Cola acuminata, C. nitida and Garcinia cola, of Nigerian origin, were analysed for their content of primary and secondary amines, and assessed for their relative methylating potential due to nitrosamide formation. Primary and secondary amines were determined as benzene sulfonamides by gas chromatography/thermal energy analysis (GC/TEA). Dimethylamine, methylamine, ethylamine and isopentylamine were detected in all kola nut varieties, while pyrrolidine, piperidine and isobutylamine were detected in one or more varieties. Estimated average total daily intake of aliphatic amines by a typical kola nut chewer varied from 260 to 1040 micrograms/day for secondary amines and from 2430 to 9710 micrograms/day for primary amines. Methylating activity of the nitrosated kola nuts, expressed as N-nitroso-N-methylurea equivalents, was also determined by GC/TEA. Methylating activity was significantly higher in kola nuts (170-490 micrograms/kg) than has ever been reported for a fresh plant product. These data suggest that the possible role of kola nut chewing in human cancer aetiology should be explored in countries where kola nuts are widely consumed as stimulants.

Topics: Amines; Central Nervous System Stimulants; Chromatography, Gas; Methylation; Nigeria; Nitrosation; Nitroso Compounds; Piperidines; Plant Extracts; Plants, Medicinal; Pyrrolidines; Seeds

The effect of laser dyes, derivatives of 1,2-benzopyrone (coumarin), on the chemiluminescence (CL) accompanying Fe(2+)-induced lipid peroxidation (LPO) in liposomes prepared from egg yolk phospholipids has been investigated. It was found that quinolizin (9a,9,1-gh)-substituted coumarins enhanced CL at the stages of "fast" and "slow" flashes (abbreviated as FF and SF, respectively), which are known to accompany lipid hydroperoxide decomposition (FF) and chain LPO reaction development (SF). On the other hand, these compounds did not virtually change the shape of CL curve (in particular, lag phase duration) and accumulation of the LPO products reacting with 2-thiobarbituric acid (TBARS). The dependences of FF and SF amplitudes on the concentration of coumarins exhibited for some compounds an effect of saturation with subsequent decrease of CL at high concentrations of the dyes. The highest degree of CL amplification was reached with the compound 2,3,5,6-1H,4H-tetrahydro-9-(2'-benzoimidazolyl)-quinolizin- (9,9a,1-gh)coumarin (C-525), which enhanced CL at the stages of FF and SF by a factor 1600 at a dye concentration of 8 nmoles/mg of phospholipid. On the other hand, C-525 did not increase the intensity of CL associated with the decomposition of H2O2 by Fe2+ ions (Fenton's reaction). Apparently, these coumarin sensitizers may be used for selective enhancement of CL associated with LPO both in experimental and clinical investigations.

Topics: Coloring Agents; Coumarins; Free Radicals; Iron; Kinetics; Lasers; Lipid Metabolism; Liposomes; Luminescent Measurements; Piperidines; Pyrrolidines

Topics: Base Sequence; DNA; DNA-Binding Proteins; Ethylnitrosourea; Genetic Techniques; Guanine; Molecular Sequence Data; NF-kappa B; Phosphates; Piperidines; Sequence Analysis, DNA; Sodium Hydroxide

Reductively-activated mitomycin C (MC) presents a high specificity to the 5'-CG site and to a lesser extent the 5'-GG site. However, its affinity is different for each 5'-CG site. This was evidenced by using the 3'-5' exonuclease activity of T4 DNA polymerase on a short DNA fragment exposed to MC, which was gradually activated by several Na2S2O4 additions. The time-delayed appearance of some exonuclease digestion stop sites (corresponding to MC-monofunctional adducts) suggests that MC discriminates between very fine structural variations. The feature of the stop sites suggests a good fit of MC in the DNA groove, in the case of the major alkylation sites, but not in the case of a minor 5'-TG alkylation site. Furthermore, it is evidenced by the use of the chemical probe hydroxylamine (HA) that MC-monoalkylation of 5'-CG (or 5'-GG) does not induce notable local structural disturbance of the DNA double helix, as opposed to alkylation of the 5'-TG site of minor specificity, which leads to significant local DNA distortion. This suggests that the 'in vivo' effect of MC is related, not only to amount of alkylated sites (essentially 5'-CG sites), but also to possible local DNA deformations (at minor alkylation sites).

Topics: Alkylation; Base Sequence; Binding Sites; Cytosine; Deoxyribonuclease HindIII; DNA; DNA-Directed DNA Polymerase; Exodeoxyribonuclease V; Exodeoxyribonucleases; Hydroxylamine; Hydroxylamines; Mitomycin; Molecular Sequence Data; Piperidines; Viral Proteins

Furanoside derivatives having ethynylene group and related compounds were prepared. The reaction of these functionalized furanosides with oligodeoxy-ribonucleotide (21 mer, 5'-32P-GATAAGCTTGAAT TCATGGCC-3') and subsequent treatment with piperidine resulted in cleavage of the oligonucleotide.

Topics: Base Sequence; Hydrogen-Ion Concentration; Indicators and Reagents; Molecular Structure; Oligodeoxyribonucleotides; Pentoses; Piperidines

Type II topoisomerases are the targets of several classes of chemotherapeutic agents that stabilize an intermediate of the catalytic cycle with the enzyme covalently linked to cleaved DNA. We have used 3-azido-AMSA [4'-(3-azido-9-acridinylamino)methanesulfon-m-anisidide], a photo-activatible analog of the inhibitor m-AMSA [4'-(9-acridinylamino)methanesulfon-m-anisidide], to localize the inhibitor binding site in a cleavage complex consisting of an oligonucleotide substrate and the bacteriophage T4 type II DNA topoisomerase. Upon photoactivation, the inhibitor covalently attached to the substrate only in the presence of topoisomerase. Sites of inhibitor attachment were detected by primer-extension analysis and by piperidine-induced cleavage of the covalently modified substrate. 3-Azido-AMSA reacted with bases immediately adjacent to the two phosphodiester bonds cleaved by the enzyme. Therefore, topoisomerase creates or stabilizes preferential binding sites for the inhibitor precisely at the two sites of DNA cleavage.

Topics: Amsacrine; Azides; Base Sequence; Binding Sites; Cell-Free System; DNA Damage; DNA Topoisomerases, Type II; In Vitro Techniques; Molecular Sequence Data; Oligodeoxyribonucleotides; Photochemistry; Piperidines

The effects on the conformation of DNA produced by the monofunctional adducts of chloro-(diethylenetriamine)platinum(II) chloride or cis-diamminemonoaquamonochloroplatinum(II) have been investigated by means of the single-strand-specific probe chloroacetaldehyde (CAA). The denatured sites to which CAA was bound and that were induced in DNA by the monofunctional adducts of the platinum complexes were characterized by means of three experimental approaches. These include measurement of the fluorescence of a plasmid fragment treated with CAA, analysis of oligonucleotides treated with CAA and cleaved by piperidine, and termination of duplex transcription on a fragment of plasmid DNA treated with CAA. The results indicate that the denaturational change preferentially occurs in the base pair containing the monoadducted deoxyriboguanosine in the trinucleotide sequence Py-deoxyriboguanosine-Py (Py is a pyrimidine deoxyribonucleoside). It was suggested that this conformational alteration facilitates in DNA the formation of minor bifunctional adducts of cis-diamminedichloroplatinum(II).

Topics: Acetaldehyde; Base Composition; Base Sequence; Chromosome Mapping; Cisplatin; Deoxyribonucleases, Type II Site-Specific; DNA; Enzyme-Linked Immunosorbent Assay; Hydrogen Bonding; Molecular Sequence Data; Nucleic Acid Conformation; Nucleic Acid Denaturation; Piperidines; Spectrometry, Fluorescence; Transcription, Genetic

A method for DNA sequencing that combines limited chemical degradation of 3'-fluorescent-labeled DNA with densitometric analysis using an automatic sequencer is presented. The DNA sequence is determined in a single electrophoretic lane by monitoring the intensities of bands representing products of cleavage at the four bases obtained by solvolysis in hot aqueous piperidine (10%) followed by treatment with hot formamide. An application of the method for the detection of point mutations is reported.

Topics: Autoanalysis; Base Sequence; Computer Systems; Densitometry; DNA; Fluorescence; Formamides; Lasers; Molecular Sequence Data; Piperidines; Point Mutation

Topics: Acetates; Acetic Acid; Cacodylic Acid; Chemical Precipitation; Electrophoresis, Polyacrylamide Gel; Hydrazines; Piperidines; Sequence Analysis, DNA; Sulfuric Acid Esters

Neocarzinostatin chromophore (NCS chrom) was found to induce site-specific cleavage at the 3' side of a bulge in single-stranded DNA in the absence of thiol. This reaction involved the oxidative formation of a DNA fragment with a nucleoside 5'-aldehyde at its 5' terminus and generated an ultraviolet light-absorbing and fluorescent species of post-activated drug containing tritium abstracted from the carbon at the 5' position of the target nucleotide. The DNAs containing point mutations that disrupt the bulge were not cleavage substrates and did not generate this drug product. Thus, DNA is an active participant in its own destruction, and NCS chrom may be useful as a probe for bulged structures in nucleic acids.

Topics: Base Sequence; Biotransformation; DNA Damage; DNA, Single-Stranded; Enediynes; Molecular Sequence Data; Nucleic Acid Conformation; Oxidation-Reduction; Piperidines; Point Mutation; Sulfhydryl Compounds; Zinostatin

Topics: DEAE-Cellulose; DNA; Electrophoresis, Polyacrylamide Gel; Genetic Techniques; Membranes, Artificial; Piperidines

Topics: Autoradiography; Base Composition; DNA; DNA Probes; DNA, Recombinant; Electrophoresis, Polyacrylamide Gel; Hydroxylamine; Hydroxylamines; Indicators and Reagents; Mutagenesis; Mutation; Osmium Tetroxide; Phosphorus Radioisotopes; Piperidines; Polymerase Chain Reaction; Sulfur Radioisotopes

Deoxyoligonucleotide 49-mers containing a central cis-syn, trans-syn-I, (6-4), or Dewar photoproduct of TpT were constructed for use in repair and replication studies by ligation of shorter photoproduct-containing oligonucleotides. A (6-4) product-containing 6-mer was prepared in 3.4% yield by 254 nm irradiation of d(AATTAA) and converted in nearly quantitative yield to the Dewar isomer by irradiation with Pyrex- and Mylar-filtered medium-pressure mercury arc light. d(CGAATTAAGC) containing a site-specific cis-syn or trans-syn-I dimer was prepared via automated solid-phase DNA synthesis utilizing photoproduct building blocks. The photoproduct-containing 49-mers were characterized by their susceptibility to base cleavage and a number of enzymes routinely used to map the sites of DNA photoproduct formation. 1 M piperidine at 90 degrees C cleaved the Dewar product faster than the (6-4) product, but did not cleave the cyclobutane dimers. The 3'-->5' exonuclease activity of T4 DNA polymerase was completely blocked by all the lesions except the (6-4) product, which it slowly bypassed. T4 endonuclease V did not cleave the (6-4) or Dewar photoproduct, but unexpectedly cleaved the trans-syn-I dimer at most 1% the rate of the cis-syn dimer in double-stranded DNA. The trans-syn-I dimer was cleaved at a 50-fold higher rate in double- than in single-stranded DNA. Escherichia coli photolyase was found to be specific for the cis-syn dimer at low concentrations. Implications of this work to methodology for mapping and quantifying DNA photoproducts are also discussed.

Topics: Base Sequence; Chromatography, High Pressure Liquid; Dinucleoside Phosphates; DNA Damage; Isomerism; Kinetics; Magnetic Resonance Spectroscopy; Molecular Sequence Data; Oligodeoxyribonucleotides; Photolysis; Piperidines

The structural features that confer upon minoxidil the ability to suppress lysyl hydroxylase activity in human skin fibroblasts were investigated. Substitution of the amino group in position 2 or 6 of the pyrimidine ring with a methyl group had no significant effect on the inhibitory activity of minoxidil, whereas substitution of both amino groups with methyl groups resulted in a complete loss of inhibitory activity. Together, these observations indicate that only one of the two amino groups ortho to the nitroxide oxygen is essential for the enzyme-suppressing effect of minoxidil. Derivatives of minoxidil formed by hydroxylation at position 3 or 4 of the piperidine ring were as active as the parent compound in suppressing lysyl hydroxylase activity. However, replacement of the piperidinyl group in position 4 of the pyrimidine ring with a pyrrolidinyl, morpholinyl, or N-methylpiperazinyl group resulted in loss of inhibitory activity, demonstrating that the piperidinyl group para to the nitroxide oxygen is essential for the enzyme-suppressing effect of minoxidil. Removing the nitroxide oxygen from position 1 of the pyrimidine ring resulted in a partial loss of the specificity of minoxidil for suppression of lysyl hydroxylase activity. The results indicate that distinct structural elements determine the enzyme-suppressing effect and the antihypertensive effect of minoxidil.

Topics: Antihypertensive Agents; Cells, Cultured; Fibroblasts; Humans; Infant; Male; Minoxidil; Piperidines; Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; Procollagen-Proline Dioxygenase; Pyrimidines; Skin; Structure-Activity Relationship

The two findings indicate that 8-hydroxyguanine(8-OH-Gua) is a hot piperidine-sensitive lesion in DNA. These are cleavages of DNA containing 8-OH-Gua at the site of this residue and decomposition of 8-hydroxydeoxyguanosine when the DNA and nucleoside were treated in 1 M piperidine for 30 min at 90 degrees C. However, no cleavage was observed in DNA containing 8-hydroxyadenine or O6-methylguanine. 8-OH-Gua was found to be different from apurinic sites that are also alkali-labile lesions since the former was more resistant to alkali treatment. This property of 8-OH-Gua can be used as a check for the incorporation of this base into DNA after the synthesis of DNA containing 8-OH-Gua at a specific position or possibly can be one of the markers for the identification of 8-OH-Gua formed in DNA exposed to reactive oxygen species.

Topics: Base Sequence; DNA; DNA Damage; Guanine; Hot Temperature; Molecular Sequence Data; Oligodeoxyribonucleotides; Piperidines; Spectrophotometry, Ultraviolet

N-Nitroso compounds (NOCs) are known to be strong carcinogens in various animals including primates (Preussman and Stewart, (1984) N-Nitroso Compounds). Human exposure to these compounds can be by ingestion or inhalation of preformed NOCs or by endogenous nitrosation from naturally occurring precursors (Bartsch and Montesano, Carcinogenesis, 5 (1984) 1381-1393; Tannebaum (1979) Naturally Occuring Carcinogens, Mutagens and Modulators of Carcinogenesis; Shephard et al., Food Chem. Toxicol., 25 (1987) 91-108). Several factors present in the diet can modify levels of endogenously formed nitrosamines by acting as catalysts or inhibitors. Compounds in the human diet that alter nitrosamine formation would thus play an important role in carcinogenesis study. Earlier researchers have reported the nitrite scavenging nature of sulphydryl compounds (Williams, Chem. Soc. Rev., 15 (1983) 171-196). We therefore studied the modifying effect of sulphydryl compounds viz., cysteine (CE), cystine (CI), glutathione (GU), cysteamine (CEA), cystamine (CEI), cysteic acid (CIA) and thioglycolic acid (TGA) on the nitrosation of model amines viz., pyrrolidine (PYR), piperidine (NPIP) and morpholine (NMOR). Many of these compounds are present in the food we consume. The present work also describes the inhibitory effect of onion and garlic juices on the nitrosation reactions. Both onion and garlic are known to contain sulphur compounds (Block, Sci. Am., 252 (1985) 114-119). Most of these compounds behave as antinitrosating agents and their inhibitory activity towards formation of carcinogenic nitrosamines, under different conditions is described.

Topics: Allium; Anticarcinogenic Agents; Chromatography, Gas; Cystamine; Cysteamine; Cysteic Acid; Cysteine; Cystine; Diet; Garlic; Glutathione; Humans; Morpholines; Nitrosamines; Nitrosation; Piperidines; Plants, Medicinal; Pyrrolidines; Sulfhydryl Compounds; Thioglycolates

A series of nonpeptidic human renin inhibitors with a 4-methoxymethoxypiperidinylamide at the P4 position of the molecule exhibited slow tight binding to the enzyme. Replacement of the methoxymethoxy moiety on the piperidine ring with H, OH, methoxyethyl, propyloxy or n-butyl eliminated the effect. The inhibition was partially reversed by prolonged dialysis at 4 degrees C, arguing against formation of a covalent bond in the tightened complex.

Topics: Binding Sites; Enzyme Activation; Humans; Piperidines; Protein Binding; Renin; Structure-Activity Relationship

We have developed a method to determine rapidly the sequence specificity of DNA alkylation resulting from chemical treatment. The utility of this approach is demonstrated here in a study of the sequence specificity of alkylation by dimethylsulphate (DMS). The method is independent of the sequence chosen and makes use of the polymerase chain reaction (PCR) to generate a fluorescently labelled DNA target. In this study, a 302 bp segment of the Escherichia coli lacI gene was amplified and the product purified by liquid chromatography on a Mono Q column. This DNA was alkylated with DMS and treated with hot piperidine to produce single-strand breaks at sites of N7 alkylation. The distribution of the break points, and hence the position and extent of alkylation, were determined on an Applied Biosystems 370A automated DNA sequencer.

Topics: Alkylation; DNA; DNA Damage; Escherichia coli; Gene Amplification; Guanine; Lac Operon; Molecular Sequence Data; Oligonucleotides; Piperidines; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Sulfuric Acid Esters

Cleavage of 3'-end-labeled DNA in hot aqueous solutions of different amines is comparatively examined for overall rate of DNA scission as well as for potential differences in the preference of the various amines for cleavage at the different bases. Under comparable conditions (0.5 M amine, 0.3 M NaCl, 90 degrees C), piperidine, diethylamine, morpholine, and ethylenediamine produce the same set of labeled fragments, at approximately equal overall cleavage rates. The same set of fragments is also obtained with diisopropylamine, triethylamine, and 1,4-diazabicyclo[2.2.2]octane, but at markedly lower overall cleavage rates. Solvolysis in aqueous piperidine or aqueous diethylamine leads to DNA scission predominantly at A sites, followed by G and C sites, and least frequently at T sites. In contrast, morpholine, ethylenediamine, diisopropylamine, triethylamine, and diazabicyclo[2.2.2]octane cleave the DNA predominantly at G sites. Therefore, use of one of the latter amines allows clear distinction of G bands and C bands, which could not be distinguished by the criterion of band intensity in the original one-lane sequencing method based on cleavage in hot aqueous piperidine (B. Ambrose and R. Pless (1985) Biochemistry 24, 6194-6200). The effect of varying the salt concentration on the cleavage distribution obtained with various amines is also examined, and a rationale is given for the influence of salt concentration and amine basicity on the relative rate of cleavage at G sites.

Topics: Amines; Base Sequence; Diethylamines; DNA; Electrophoresis, Polyacrylamide Gel; Molecular Sequence Data; Piperidines; Plasmids; Solutions

Osmium tetroxide, 2,2'-bipyridine (Os,bipy) has been widely applied as a probe of the DNA structure. To obtain information about reactivity of DNA bases toward this probe synthetic homopolynucleotides poly(dT), poly(dC), poly(dG) and poly(dA) were treated with Os,bipy and the content of modified bases measured by stripping voltammetry and absorption spectrophotometry. After 20 hours' treatment strong modification of poly(dT) and poly(dC) and weak modification of poly(dG) were observed, while no modification was detected in poly(dA). At short incubation times under conditions close to those usually used in probing the DNA structure the extent of poly(dT) modification was more than 10 times higher than that of poly(dC). Thus, in single-stranded DNA Os,bipy reacts with T much greater than C and G. Due to the fast reaction of thymines with Os,bipy (and osmium tetroxide, pyridine) these chemicals can be applied in Maxam-Gilbert nucleotide sequencing as agents specific for thymines in single-stranded DNA.

Topics: 2,2'-Dipyridyl; Base Sequence; DNA; DNA, Single-Stranded; Electrophoresis, Polyacrylamide Gel; Osmium Tetroxide; Piperidines; Poly A; Poly C; Poly G; Poly T; Spectrophotometry, Atomic; Thymine

Oligopyrimidines covalently linked to ellipticine derivatives form duplex and triplex structures with target single-stranded oligopurine sequences. They also bind to duplex DNA at homopurine-homopyrimidine sequences where they form local triple helices. Irradiation at wavelengths longer than 300 nm of the complex formed by an oligonucleotide-ellipticine conjugate with its target sequence induced (i) cleavage of the target at bases located in close proximity to the dye and (ii) cross-linking of the target sequence to the derivatized oligonucleotide. Both cross-linking and cleavage reactions decreased when temperature increased with a half-transition corresponding to the dissociation of the oligonucleotide-ellipticine conjugate from its target nucleic acid, demonstrating that the observed photochemical effects are dependent on hybrid formation. When the target was a double-stranded DNA, photochemical reactions were observed on both strands of the duplex. Photo-induced cross-linking was more efficient than cleavage when the target was single-stranded; the reverse was observed when the target was duplex DNA.

Topics: Base Sequence; Cross-Linking Reagents; DNA; Ellipticines; Hydrogen-Ion Concentration; Macromolecular Substances; Molecular Sequence Data; Molecular Structure; Oligonucleotides; Photochemistry; Piperidines; Temperature; Ultraviolet Rays

The location of OsO4 bispyridine hyper- and hyporeactivity in a small deletion derivative of plasmid ColE1 (PTC12, 1727 bp) has been determined for approximately 70% of the molecule. Thymine bases in homopolymeric (dA)n.(dT)n tracts (n greater than or equal to 4) were always found to be resistant toward OsO4 modification. DNA supercoiling did not destabilize these tracts. The extent of OsO4 bispyridine reactivity of homopolymeric (dA)n.(dT)n tracts, where n = 3, was found to be dependent on the rate of base unpairing of the sequence immediately 5' and 3' to the tract. Repressed OsO4 reactivity of thymine bases in (dA)3.(dT)3 tracts was observed if immediately both 5' and 3' to the tract were stable DNA sequences composed of GC base pairs and/or a homopolymeric (dA)n.(dT)n tract (n greater than or equal to 4). Homopolymeric tracts of n = 3 not having adjacent sequences with repressed unpairing rates did not show reduced levels of OsO4 bispyridine reactivity. Alternating d(TA)n tracts (n greater than or equal to 2) were found to exhibit hyperreactivity with OsO4. The extent of this hyperreactivity was dependent on the length of the tract and superhelical torsional stress. The distribution and frequency of homopolymeric (dA)n.(dT)n (n greater than or equal to 4) tracts in Escherichia coli promoter sequences were examined, and the possible implications of these tracts on promoter function are discussed.

Topics: Base Sequence; DNA, Bacterial; DNA, Superhelical; Electrophoresis, Agar Gel; Electrophoresis, Polyacrylamide Gel; Escherichia coli; Formates; Molecular Sequence Data; Osmium Tetroxide; Piperidines; Plasmids; Promoter Regions, Genetic

We have determined the effect of H-DNA formation on the distributions of two ultraviolet (UV) light induced photoproducts--cyclobutane dipyrimidines and mean value of 6-4 dipyrimidines. A region of DNA containing the sequence (dT-dC)18.(dA-dG)18 was treated under conditions that specifically yield the triple-stranded H-y3 or H-y5 DNA structure and then irradiated with UV. The positions of cyclobutane dipyrimidines and mean value of 6-4 dipyrimidines were determined by T4 endonuclease V cleavage and by hot piperidine cleavage, respectively. Formation of H-DNA structures greatly decreased the photoproduct yield in the (dT-dC)18.(dA-dG)18 region but not elsewhere in the DNA. Suppression of photoproduct formation is greater in half of the repeat, reflecting whether the DNA is in the H-y3 or H-y5 conformation. Within the repeat, the suppression was less in the middle and toward the ends. Models for the suppression of photoproduct formation in H-DNA and the possible utility of our findings are discussed.

Topics: Base Composition; Base Sequence; Cyclobutanes; DNA; Humans; Hydrolysis; Molecular Sequence Data; Nucleic Acid Conformation; Piperidines; Pyrimidine Dimers; Ultraviolet Rays

The effect of piperidine (Pip) on isolated Aplysia neurons was investigated using the voltage clamp and concentration clamp techniques in which neurons were perfused internally and externally with Na+,K+ free solution. Pip induced a Cl-current (ICl) in a dose-dependent manner for doses ranging from 10(-4) M to 10(-2) M. The dose-response curve gave an apparent dissociation constant of 8.4 x 10(-4) M and a Hill coefficient of 1.7. The current-voltage relationship was linear in the voltage range examined (-70 to +30 mV). The equilibrium potential for Pip induced current was close to the calculated equilibrium potential for chloride ions (ECl), (-10.7 mV). The activation phase of the ICl was characterized by a single exponential at all concentrations. The time constant of this phase decreased with increasing concentrations of Pip but did not depend on the membrane potential. The deactivation phase of the ICl proceeded on a single exponential curve at concentrations of Pip less than 5 x 10(-4) M, but on a double exponential at concentrations of 5 x 10(-4) M and higher. The deactivation time constant also decreased with increasing concentrations of Pip, but showed no potential dependence. Pip- and ACh-induced IClS were not blocked by 10(-4) M atropine. However, Pip-induced ICl was abolished with 10(-4) M d-tubocurarine (dTC), and the ACh-induced ICl was depressed by the same dose of dTC. These results suggest that Pip acts on at least two components of the nicotinic receptor-Cl channel complex in Aplysia neurons to elicit the ICl.

Topics: Animals; Aplysia; Chloride Channels; Chlorides; In Vitro Techniques; Kinetics; Membrane Proteins; Neurons; Piperidines; Seawater

This study demonstrates that the reaction of Fe(II)-EDTA and hydrogen peroxide with the single-stranded nucleic acids d(pT)70 and a 29-base sequence containing a mixture of bases results in substantial damage which is not directly detected by gel electrophoresis. Cleavage of the DNA sugar backbone is enhanced significantly after the samples are incubated at 90 degrees C in the presence of piperidine. The latter reaction is used in traditional Maxam-Gilbert DNA sequencing to detect base damage, and the current results are consistent with reaction of the hydroxyl radical with the bases in single-stranded DNA (although reaction with sugar may also produce adducts that are uncleaved but labile to cleavage by piperidine). We propose that hydroxyl radicals may react preferentially with the nucleic acid bases in ssDNA and that reaction of the sugars in dsDNA is dominant because the bases are sequestered within the double helix. These results have implications both for the study of single-stranded DNA binding protein binding sites and for the interpretation of experiments using the hydroxyl radical to probe DNA structure or to footprint double-stranded DNA binding protein binding sites.

Topics: Base Sequence; Binding Sites; DNA; DNA Damage; DNA, Single-Stranded; Edetic Acid; Ferrous Compounds; Free Radicals; Hydrogen Peroxide; Molecular Sequence Data; Nucleotide Mapping; Oligodeoxyribonucleotides; Piperidines; Temperature

A range of simple, natural chemicals almost unknown 20 years ago are now being used to advance research in cancer, AIDS, diabetes, immunology and plant-insect recognition. These alkaloids of the pyrrolidine, piperidine, pyrrolizidine and indolizidine classes resemble sugar molecules in the arrangement of hydroxyl substituents and are often potent and specific glycosidase inhibitors.

Topics: Alkaloids; Heterocyclic Compounds; Indolizines; Piperidines; Pyrrolidines; Pyrrolizidine Alkaloids

ACh-induced Cl- -current (ICl) is well known to desensitize with two components: an initial fast phase followed by a second, more slowly developing phase. In the present study, the influence of piperidine, a normal constituent in vertebrates and invertebrates, on ACh-induced ICl in isolated neurons of Aplysia was investigated by using the concentration clamp in combination with the voltage clamp technique. Pretreatment with piperidine in doses greater than 2 X 10(-4)M depressed the transient ACh-induced ICl but had little effect on the persistent ICl. Kinetic study of the desensitization phase of ACh-induced ICl showed that the slow time constant of the desensitization phase of ACh-induced ICl was not altered by pretreatment with piperidine. The present results indicate that piperidine can discriminate between the fast transient and slow persistent components of ACh-induced ICl in Aplysia neurons, and also suggest that two components of the desensitization phase of ACh-induced ICl function in an independent manner.

Topics: Acetylcholine; Animals; Aplysia; Chlorides; In Vitro Techniques; Membrane Potentials; Neurons; Piperidines

Oligonucleotide derivatives bearing hemin and deuterohemin groups were synthesized. The derivatives efficiently react with the complementary nucleotide sequence in ssDNA forming covalent adducts and piperidine-labile sites. In the case of the deuterohemin derivative, some direct cleavage of the target DNA occurs.

Topics: Base Sequence; Chemical Phenomena; Chemistry; Chromatography, High Pressure Liquid; DNA Damage; DNA, Single-Stranded; Heme; Hemin; Molecular Sequence Data; Oligodeoxyribonucleotides; Piperidines

DNA photosensitization by several furocoumarins (including 3-carbethoxypsoralen (3-CPs), 8-methoxypsoralen (8-MOP), 5-methoxypsoralen (5-MOP) and angelicin was investigated by using DNA sequencing methodology. 3-CPs induces photo-oxidation of guanine residues leading to alkali-labile sites in DNA (revealed by hot piperidine), whereas 8-MOP, 5-MOP and angelicin do not. There is a preferential photo-oxidation of G when located on the 5' side of GG doublets, likely to reflect a better accessibility of the G moiety in such a context. Mechanisms operating via both radicals (type I) and singlet oxygen (type II) are involved in the photo-oxidation of G residues by 3-CPs. Photo-oxidized G residues are produced independently of the formation of photoadducts, and scavengers of singlet oxygen or radicals do not inhibit photobinding of 3-CPs to DNA. This leads us to propose that covalent photoadducts arise from the intercalated excited sensitizer molecules, whereas G photo-oxidations are produced either by electron transfer reactions involving bound 3-CPs or by energy transfer to molecular oxygen, thereby producing singlet oxygen that subsequently reacts with guanine bases. Quantification of both types of DNA lesions indicated that in vitro photo-oxidized G residues are produced in DNA by 3-CPs plus ultraviolet light at least to the same extent as photoadducts, under our conditions. A calf thymus redoxyendonuclease, equivalent to the endonuclease III of Escherichia coli, specific for oxidative DNA damages, recognizes and cleaves DNA at sites of photo-oxidized G residues. The extent of the cleavage by this enzyme was close to that observed by hot piperidine and followed the amount of photo-oxidized G residues produced when the lifetime of excited oxygen species is modified. The redoxyendonuclease did not incise DNA treated with 8-MOP, 5-MOP or angelicin plus ultraviolet light. The exonuclease III and endonuclease IV of E. coli also involved in the repair of oxidative DNA damage, convert the replicative form I of 3-CPs-treated DNA to replicative form II. This suggests that the lesions recognized by these enzymes are apurinic-like lesions. In view of the low toxicity and mutagenicity of 3-CPs, DNA photo-oxidation products induced by the photodynamic effect of 3-CPs are likely to be efficiently taken care of by the DNA repair system(s). It is clear that 3-CPs photo-induces several classes of DNA damage, including oxidative damage.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Base Sequence; Deoxyribonuclease IV (Phage T4-Induced); DNA Damage; DNA-(Apurinic or Apyrimidinic Site) Lyase; Endodeoxyribonucleases; Escherichia coli; Escherichia coli Proteins; Exodeoxyribonucleases; Furocoumarins; Light; Molecular Sequence Data; Oxidation-Reduction; Oxygen; Piperidines

Two DNA duplexes of identical sequence and 35 nt in length were synthesized by an original and a highly improved version of phosphoramidite chemistry. By base composition analysis, DNA synthesized by improved chemistry (termed DMTS-imp) contained no detectable modified bases while DNA synthesized by the original chemistry (termed DMTS-std) had a large number of modifications. Under optimal reaction conditions, HhaI and RsaI cleaved the DMTS-std duplex to 76-77% completion and the DMTS-imp duplex to 96-99% completion. Restriction analysis and piperidine treatment yielded estimates of approximately 3.0% modified nucleotides in DMTS-std and approximately 1.0% in DMTS-imp. Overall, the improvements in chemistry increased the restriction efficiency of synthetic DNA up to 10-fold.

Topics: Adenine; Base Composition; Cloning, Molecular; DNA; DNA Modification Methylases; DNA Restriction Enzymes; Guanine; Oligodeoxyribonucleotides; Organophosphorus Compounds; Piperidines; Restriction Mapping; Substrate Specificity; Thymine

Osmium tetroxide and hydroxylamine (in combination with piperidine) have previously been shown to cleave mismatched T and C bases, respectively, in DNA.DNA heteroduplexes. In this work we report that mismatched T and C bases were similarly cleaved in DNA.RNA heteroduplexes of nucleic acids derived from different strains of dengue virus type 2. Further, some matched T or C bases one or two bases from mismatches were also chemically reactive and thus cleavable as detected by minor bands. Cleavages both at and near mismatches combined to generate a simply obtained pattern of difference between virus strains that could be used as a fingerprint of a given virus relative to another. The patterns obtained using viral RNA of one strain hybridized with the cDNA of another were similar for RNA prepared from purified virions and for total RNA extracted from infected cells. Use of probes of both senses should detect all differences. Two sequenced (NGC and PUO-218) and one unsequenced (D80-100) strains of virus were compared in these studies. The analyses allowed proof reading of the differences between NGC and PUO-218, ascertained from nucleotide sequencing, and demonstrated that D80-100 is more similar to PUO-218 than to NGC.

Topics: Base Composition; Base Sequence; Dengue Virus; DNA Probes; Hydroxylamine; Hydroxylamines; Molecular Sequence Data; Nucleic Acid Hybridization; Nucleotide Mapping; Osmium; Osmium Tetroxide; Piperidines; RNA, Viral

We describe a method that permits the study of the state of cytosine methylation and of in vivo protein-DNA interactions in higher eukaryotes. This powerful technique is applicable to any gene of interest at the single-copy level. To study DNA methylation, the total uncloned genomic DNA, digested with a restriction endonuclease is subjected to a cytosine-specific hydrazine reaction and chemical cleavage. The DNA fragments of interest are linearly amplified with Taq polymerase and a sequence-specific radioactivity labeled synthetic primer. Following amplification, the DNA fragments are separated on a sequencing gel that is directly autoradiographed. To study protein-DNA interactions in vivo, we use a similar method, except that the DNA of interest is isolated from cells treated either with dimethyl sulfate or UV light. The resolution power of this technique is demonstrated by two examples, which have been studied previously by the conventional methods of genomic sequencing and "footprinting."

Topics: 5-Methylcytosine; Animals; Chemical Phenomena; Chemistry; Chickens; Cytosine; DNA; DNA-Binding Proteins; Gene Amplification; Genes; Methylation; Piperidines; Promoter Regions, Genetic; Vitellogenins

Topics: Base Sequence; Chemical Phenomena; Chemistry; DNA; Piperidines; Pyrrolidines

One-lane DNA sequencing by solvolysis in hot aqueous piperidine solutions, originally described for 5'-32P-labeled DNA (B. Ambrose and R. Pless (1985) Biochemistry 24, 6194-6200), is extended to 3'-labeled fragments. A salt-free sample for electrophoresis can be obtained by using 1 M LiCl in the solvolysis mixture and removing this salt from the dried hydrolysate by washing with ethanol. Rate and distribution of DNA cleavage in hot aqueous piperidine, containing 0.3 M NaCl, are studied in dependence of temperature, solvent, amine concentration, and reaction time. An increase in temperature strongly accelerates overall DNA degradation, but leaves the distribution of cleavage essentially unchanged. When 50% aqueous ethanol is substituted for water as the reaction solvent, the overall cleavage is slower, and scission at G-sites is enhanced relative to cleavage at the other bases. A rise in the piperidine concentration strongly accelerates the reaction, except at very high amine concentration. Cleavage at A-, G-, and C-sites increases steadily with reaction time, while the T-cleavage observed takes place primarily at the very beginning of the solvolysis.

Topics: Autoradiography; Base Sequence; Chlorides; DNA; Hot Temperature; Hydrolysis; Lithium; Lithium Chloride; Piperidines; Sodium Chloride

We show that chloroacetaldehyde, a chemical compound known to be reactive with unpaired adenine and cytosine residues, reacts with adenine residues (syn conformation) but not with cytosine residues (anti conformation) within Z-DNA. These modified residues are sensitive to cleavage by piperidine, which allows mapping at the single nucleotide level.

Topics: Acetaldehyde; Base Sequence; DNA; Nucleotide Mapping; Piperidines

The factors influencing the binding of CC-1065 to DNA were examined using racemic analogs with varying chain lengths. The ability of these agents to bind DNA appeared to be related to cytotoxic potency, however this did not appear to be a direct quantitative correlation. Two enantiomers of a bis-indole analog of CC-1065 were studied for DNA binding and cytotoxic activity. The agent with the same stereochemical configuration as CC-1065 was a potent cytotoxin, but its enantiomer was essentially inactive. Both enantiomers showed significant binding to DNA, but the biologically less active isomer showed less overall binding. In all cases, the agents preferred AT-rich DNA, and all bound to similar regions in DNA as evidenced by positions of drug-initiated thermal breaks in single end-labelled fragments of phi X 174RF DNA. The overall similarity in site specificity for binding of the structurally diverse agents suggests that much of the specificity observed in binding of the agent to DNA lies in the DNA itself. Thus, it may be difficult to change minor groove specificity for agents of this type simply by designing structures that can encompass guanine or cytosine residues. Other modifications, such as changing the specificity of the alkylating moiety, may be required to achieve this goal.

Topics: Animals; Antineoplastic Agents; Base Sequence; Cell Survival; Circular Dichroism; DNA; DNA Damage; DNA, Superhelical; Duocarmycins; In Vitro Techniques; Indoles; Leucomycins; Leukemia L1210; Mercaptoethanol; Piperidines; Stereoisomerism; Structure-Activity Relationship

Apurinic sites were introduced to dGpdG, dGpdT, dTpdG and pdGpdG by HCl hydrolysis and the cleavage of the phosphodiester bond was measured in the monobase dinucleotides by HPLC. The half-lives of apdG and apdT (a = apurinic nucleotide) were 30 min and the half-life of papdG was 21 min in 66 mM Tris (pH 7.4) and 100 degrees C. The half-lives of dGpa and dTpa were 228 and 408 min, respectively. In these compounds the cleavage of the phosphodiester bond was not the main reaction pathway as little 3'-dGMP and 3'-TMP was isolated. The half-life of dGpa was similar to that of dGMP indicating that both compounds break down primarily by depurination. The results show that the phosphodiester bond is cleaved predominantly at the 3' side of the apurinic sugar. Sodium hydroxide and piperidine increased the rate of chain cleavage.

Topics: Chromatography, High Pressure Liquid; Deoxyguanine Nucleotides; Guanine; Half-Life; Hydrochloric Acid; Hydrolysis; Kinetics; Oligodeoxyribonucleotides; Piperidines; Purines; Sodium Hydroxide; Thymine; Thymine Nucleotides

Double-stranded DNA containing a d(pG)18.d(pC)18 sequence was shown to be selectively alkylated in the vicinity of this fragment using the 5'-p-(N-2-chloroethyl-N-methylamino)benzylamide of deoxyribooligocytidylate, CIRCH2NH(pdC)n (n = 9,15), in conditions favouring triple-stranded complex formation.

Topics: Alkylation; Base Sequence; DNA; Hydrogen-Ion Concentration; Molecular Sequence Data; Mustard Compounds; Piperidines; Poly C; Polydeoxyribonucleotides

Using unit recording and electrophoretic techniques, the action of piperidine on unit activity of the brain of the rat was studied. Piperidine excited 31%, and inhibited 4% of cortical cells tested. In the hippocampus and caudate nucleus, piperidine excited larger proportions of the cells tested. The actions of piperidine were blocked by tetraethylammonium but not by scopolamine.

Topics: Acetylcholine; Action Potentials; Animals; Caudate Nucleus; Cerebral Cortex; Hippocampus; Male; Piperidines; Rats; Rats, Inbred Strains; Scopolamine; Tetraethylammonium Compounds

Reaction of DNA with K2PdCl4 at pH 2.0 followed by a piperidine workup produces specific cleavage at adenine (A) residues. Product analysis revealed the K2PdCl4 reaction involves selective depurination at adenine, affording an excision reaction analogous to the other chemical DNA sequencing reactions. Adenine residues methylated at the exocyclic amine (N6) react with lower efficiency than unmethylated adenine in an identical sequence. This simple protocol specific for A may be a useful addition to current chemical sequencing reactions.

Topics: Adenine; Base Sequence; Chromatography, High Pressure Liquid; DNA; DNA, Bacterial; Palladium; Piperidines; Plasmids

We have shown that morpholine, a cyclic amine, exerts a selective inhibition of growth on melanocytic pigmented cell lines compared to nonpigmented cells. The ID50 of morpholine for the pigmented B-16 cell line HFH was 1200 micrograms/ml, compared to values greater than 2400 micrograms/ml for baby hamster kidney, Chinese hamster ovary and NP, an unpigmented primate cell line. Two other cyclic amines piperazine and piperidine, were similarly found to be selectively toxic to melanocytes. This selective toxicity could be synergistically enhanced by pretreatment of the cells with theophylline, a stimulator of tyrosinase activity, which indicates that the selective toxicity may be associated with melanin synthesis. Low passage HFH, high passage HFH and Syrian hamster melanoma RPMI 1846 cells that were pretreated with theophylline showed between 13 and 29% greater toxicity compared to controls treated with theophylline or morpholine alone. Unpigmented NP primate cells, Chinese hamster ovary and mouse fibroblast L929 remained unaffected. These cyclic amines join a list of other amines that have also been shown to be melanocytotoxic.

Topics: Animals; Cell Survival; Cells, Cultured; Cricetinae; Drug Synergism; Melanins; Melanoma; Mice; Morpholines; Pigmentation; Piperazine; Piperazines; Piperidines; Theophylline

The volatile, secondary amine piperidine is used in the Maxam-Gilbert chemical method of DNA sequencing to create strand breaks in DNA at sites of damaged bases. As such it is often used in generalized studies of DNA damage to identify 'alkali-labile lesions'. We confirm the mechanism proposed by Maxam and Gilbert (Maxam, A. and Gilbert, W. (1980) Methods Enzymol. 65, 499-560) by which aqueous piperidine creates strand breaks at sites of N7-guanine alkylations: alkaline conditions catalyze rupture of the C8-N9 bond, forming a formamido-pyrimidine structure which is displaced from the ribose moiety by piperidine. In keeping with this mechanism, the tertiary amine, N-methylpiperidine, does not catalyze the formation of strand breaks in alkylated DNA. Our data confirm the prediction that high pH in and of itself will not create strand breaks at sites of N7-alkylguanines.

Topics: Alkylation; DNA; DNA Damage; Electrophoresis, Polyacrylamide Gel; Guanine; Humans; Piperidines

The effect of piperidine and related alicyclic amines on central nicotinic and muscarinic cholinoceptors was investigated by measuring specific binding of [3H]nicotine and [3H]cismethyldioxolane (CD) in rat cerebral cortical membranes. Piperidine, pyrrolidine, 4-hydroxypiperidine and piperazine at concentrations of 1 microM-30 mM completed dose-dependently with [3H]nicotine and [3H]CD for the binding sites. Among these compounds, piperidine was the most potent competitor of brain [3H]nicotine binding sites. Piperidine and pyrrolidine showed a greater affinity for [3H]nicotine binding sites in the rat cerebral cortex than of [3H]CD binding sites. In contrast, 4-hydroxypiperidine and piperazine displayed approximately 10 times greater affinity for [3H]CD binding sites. Pipecolic acid had little effect on these cholinoceptor agonist binding sites. The inhibitory effect of brain [3H]nicotine binding by piperidine did not differ between brain regions or during development. In addition, there was little difference in the piperidine-induced inhibition of brain [3H]nicotine binding between species such as rat, mouse, guinea-pig and rabbit. Thus, the present study demonstrates a high affinity of piperidine for nicotinic cholinoceptors in the mammalian brain.

Topics: Amines; Animals; Animals, Newborn; Binding, Competitive; Brain; Guinea Pigs; In Vitro Techniques; Mice; Nicotine; Parasympathomimetics; Piperidines; Rabbits; Rats; Rats, Inbred Strains; Receptors, Muscarinic; Receptors, Nicotinic; Species Specificity

Treatment of 5'-end 32P-labeled oligodeoxyribonucleotides with 0.4 M aqueous piperidinium formate, pH 2, at 37 degrees C for 6 h, followed by treatment with 1 M aqueous piperidine at 90 degrees C for 6 h, produces, after electrophoresis through 27% polyacrylamide sequencing gels, one-dimensional distributions of radioactivity from which the base sequences can be deduced. The order of intensities for the bands signaling the various bases is G greater than A greater than C greater than T. The spacing from a given band to the next higher band in the ladder was base characteristic, the order of band spacings being G greater than T greater than or equal to A greater than C. In contrast to the one-cleavage one-lane DNA sequencing method reported earlier (B. J. B. Ambrose and R. C. Pless, 1985, Biochemistry 24, 6194-6200), which was based on treatment of end-labeled DNA with hot aqueous piperidine in the presence of sodium chloride, the present method produces a salt-free hydrolysate, thus minimizing electrophoretic irregularities in the fastest moving bands.

Topics: Autoradiography; Base Sequence; DNA; Electrophoresis, Polyacrylamide Gel; Oligodeoxyribonucleotides; Piperidines; Polydeoxyribonucleotides

By means of microiontophoresis, we have compared the actions of a putative sleep substance, piperidine, with other neurotransmitters in the rat anaesthetized with urethane. In the pons and midbrain, piperidine mimicked the actions of acetylcholine on more than 200 neurones. Piperidine- and acetylcholine-induced excitations were equally effectively antagonized by hexamethonium or atropine. In 32 neurones piperidine showed no affinity for the receptors for the excitatory amino acid agonists, quisqualate and N-methyl-D-aspartate, piperidine-evoked excitations being unaffected by the antagonists glutamate diethylester or 2-amino-5-phosphonovalerate. Similarly, piperidine-evoked excitations in 23 neurones were unaffected by alpha-methylnoradrenaline, suggesting that piperidine does not act at receptors for noradrenaline. Twenty per cent of neurones responsive to piperidine were inhibited. These inhibitions in 12 neurones were insensitive to either strychnine or bicuculline indicating that piperidine does not act on receptors for glycine or gamma-aminobutyric acid. In a further 68 neurones, neither hexamethonium (4 out of 59 cells) nor atropine (0 out of 9 cells) was effective in antagonizing the inhibitions evoked by piperidine or by acetylcholine. It is suggested that piperidine may exert its central hypnogenic effects by an action at cholinoceptors in brainstem areas involved in sleep regulation.

Topics: Acetylcholine; Amino Acids; Animals; Brain Stem; Female; gamma-Aminobutyric Acid; Hexamethonium Compounds; In Vitro Techniques; Iontophoresis; Male; Norepinephrine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Adrenergic; Receptors, Cholinergic; Sleep

Lysine and its metabolic intermediates were studied for their effect on pentylenetetrazol (PTZ)-induced seizures in mice. L-Lysine at dosages above 2 mmol/kg given i.p. significantly increased seizure protection and seizure latency (the time required to develop seizures after PTZ injection) with a peak effect dose at 10 mmol/kg. A pretreatment time of 15 min was required to significantly prolong seizure latency with a peak effect time of 45 min. D-Lysine at 10 mmol/kg i.p. afforded some seizure protection and significantly prolonged seizure latency but has a peak effect time of 15 min. When administered intracerebroventricularly, both L-lysine and piperidine at 0.1 mmol/kg prolonged seizure latency significantly, and increased seizure protection slightly. L-Pipecolic acid at the same dose given through the same route, however, shortened seizure latency significantly. L-alpha-Aminoadipic acid, on the other hand, had no significant effect. Lysine metabolites that prolonged seizure latency also increased seizure protection and decreased seizure death, and one that shortened seizure latency had the opposite effect. The anticonvulsant activity of lysine and its metabolites was explained on the basis of their connection with the GABAergic transmission.

Topics: 2-Aminoadipic Acid; Animals; Anticonvulsants; gamma-Aminobutyric Acid; Lysine; Male; Mice; Pentylenetetrazole; Pipecolic Acids; Piperidines; Seizures; Synaptic Transmission

When DNA is gamma-irradiated in aerated aqueous solution, strand breaks are produced during irradiation or the next few hours. Subsequent piperidine treatment gives rise to further DNA strand ruptures at alkali-labile sites. These different types of DNA chain breaks provoked by gamma-irradiation have been studied with oligonucleotides having defined sequences. The breaks selectively developed inside the DNA chain at alkali-labile sites by piperidine treatment appeared at lower doses preferentially at guanine positions and the order G greater than A greater than T greater than or equal to C was observed. The total contribution of the direct DNA chain ruptures, formed during irradiation and the next few hours, and those obtained by piperidine treatment was studied at doses ranging from 10 to 120 Gy. The chain breaks appeared preferentially at thymine positions and the order T greater than G greater than A greater than or equal to C was shown for the higher doses.

Topics: Bacteriophage phi X 174; Base Sequence; Cobalt Radioisotopes; DNA, Viral; Dose-Response Relationship, Radiation; Gamma Rays; Phosphorus Radioisotopes; Piperidines

Topics: Adenine; Benzyl Compounds; Chemical Phenomena; Chemistry; Formaldehyde; Kinetin; Magnetic Resonance Spectroscopy; Piperidines; Purines

The action of high-intensity ultraviolet pulse laser radiation on a 161 bp fragment of pBR 322 DNA (EcoRI-MspI fragment) was studied. At doses up to 5 X 10(18) photons/cm2 the N-glycosidic bond splitting is negligible. The action of hot piperidine on irradiated DNA leads to chain splitting at the residues, modified via biphotonic processes. The modification and, hence, splitting efficiencies depend on the type of base (G greater than T greater than A greater than C) and on its position in the sequence. Preferentially modified bases in the opposite strands of double-stranded DNA belong, mainly, to the same or adjacent base pairs. Residues in the Pribnow box are modified considerably less, than in the sequences, immediately upstream and downstream. This approach seems to be useful in footprinting of DNA secondary structure peculiarities and alterations, conjugated with the functional role and state of the respective fragment.

Topics: Base Sequence; DNA; Endodeoxyribonucleases; Glycosides; Lasers; Nucleic Acid Conformation; Piperidines; Plasmids; Pyrimidine Dimers; Ultraviolet Rays

The fluorescence of myoglobin, cytochromes b5 and c in the reversed aerosol OT (AOT) micelles in octane has been investigated. The fluorescence intensity of all the three hemoproteins is higher than that in aqueous solutions. The maxima and intensities of fluorescence in the AOT micelles depend on the [H2O]/[AOT] ratio and reflect the protein structure. Aliphatic alcohols and secondary amines (piperidine and morpholine) quench the cytochrome c fluorescence in the AOT micelles, whereas dipolar aprotic solvents (dimethylsulfoxide, dimethylformamide) significantly increase the intensity of cytochrome c fluorescence in the same micelles. The transformations of the proteins solubilized by the reversed micelles of a surfactant are discussed.

Topics: Animals; Colloids; Cytochrome b Group; Cytochrome c Group; Cytochromes b5; Dioctyl Sulfosuccinic Acid; Fluorescence; Horses; Micelles; Morpholines; Myoglobin; Octanes; Piperidines; Rabbits; Solutions; Surface-Active Agents; Whales

The breakage of double-strand (ds) DNA by 13-L-hydroperoxy-cis-9,trans-11-octadecadienoic acid (LAHPO) was investigated by agarose gel electrophoresis of supercoiled pBR322 DNA and the site of cleavage on the DNA molecule was determined by the method of DNA sequence analysis using 3'-end and 5'-end-labeled DNA fragments as substrates. LAHPO caused cleavage at the position of guanine nucleotide in dsDNA. LAHPO caused dsDNA breaks at specific sites, but linoleic acid (LA) and 13-L-hydroxy-cis-9,trans-11-octadecadienoic acid (LAHO) have no such effects on dsDNA. The active oxygen atom of the hydroperoxy group of LAHPO was perhaps responsible for the site-specific cleavage of dsDNA.

Topics: Animals; DNA, Superhelical; Drosophila melanogaster; Linoleic Acid; Linoleic Acids; Lipid Peroxides; Piperidines; Plasmids

Cadaverine and pipecolic acid metabolism was investigated in vitro in several organs of the mouse by measuring 14CO2 formation from labeled precursors. The liver showed the highest formation of 14CO2 from [1,5-14C]-cadaverine, whereas brain demonstrated a much lower formation. Anaerobiosis or inhibition of monoamineoxidase (MAO) activity significantly reduced 14CO2 formation in every organ, but inhibition of diamine oxidase (DAO) activity had no effect in brain and kidney. Piperidine was formed from cadaverine in vitro only in the large intestine and its content. This formation is probably of bacterial origin. Under a variety of experimental conditions we were unable to demonstrate any formation of piperidine in brain from cadaverine. Biosynthesis in vitro of [3H]-piperidine from D,L-[3H]-pipecolic acid was very low in brain and kidney. With the exception of brain and kidney, no other organs showed any formation of [3H]-piperidine. Neither MAO nor DAO inhibition influenced [3H]-piperidine formation in the large intestine with its content. Following 1 hr incubation at 37 degrees C under aerobic conditions, the levels of [14C]-pipecolic acid and [3H]-piperidine recovered from mouse brain homogenate did not indicate any significant degradation of these two substances. Our results suggest that under in vitro conditions, cadaverine is not a precursor of piperidine in brain, liver, heart, and kidney and that only very low levels of piperidine can be formed from pipecolic acid in brain. Outside the brain, formation of piperidine from pipecolic acid is detectable only in kidney and in the content of the large intestine. The latter is probably of bacterial origin. Our results do not support previous findings from other authors on an endogenous origin of piperidine in brain from cadaverine and pipecolic acid, and they suggest that a) cadaverine is not a precursor of piperidine in brain, b) the conversion of pipecolic acid into piperidine in the brain does not constitute a major metabolic pathway, and c) the main source of piperidine in the CNS may be of nonneural origin.

Topics: Animals; Brain; Cadaverine; Carbon Radioisotopes; Diamines; Intestine, Large; Kidney; Kinetics; Liver; Lysine; Mice; Myocardium; Organ Specificity; Pipecolic Acids; Piperidines

Topics: Air Pollutants, Occupational; Animals; Cats; Chemical Phenomena; Chemistry; Dogs; Guinea Pigs; Humans; Lethal Dose 50; Mice; Piperidines; Rabbits; Rats

Topics: Chemistry, Pharmaceutical; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Pharmaceutical Solutions; Piperidines; Research

Topics: Anesthesia; Anesthesia, Obstetrical; Antipsychotic Agents; Butyrophenones; Female; Haloperidol; Humans; Labor, Obstetric; Piperidines; Pregnancy

Topics: Alkanes; Amines; Chemistry, Pharmaceutical; Cyclohexanes; Piperidines; Pyrrolidines; Pyrrolidinones; Research

Topics: Drug Therapy; Geriatrics; Patients; Phenothiazines; Piperidines; Thioridazine; Toxicology

Topics: Acetates; Female; Humans; Labor, Obstetric; Muscle Relaxants, Central; Piperidines; Pregnancy

Topics: Alcohols; Chemistry, Pharmaceutical; Methanol; Piperidines; Pyridines; Research

Topics: Cardiovascular Agents; Muscle Relaxants, Central; Parasympatholytics; Pharmacology; Piperidines; Rats; Research

Topics: Antitussive Agents; Pharmacology; Piperidines; Rats; Research; Substance-Related Disorders; Toxicology

Topics: Anti-Allergic Agents; Calcium; Child; Histamine H1 Antagonists; Humans; Piperidines; Respiratory Hypersensitivity; Salts

Topics: Chemistry, Pharmaceutical; Pharmacology; Pharmacy; Piperidines; Pyridines; Quinuclidines; Research

Topics: Bemegride; Glutethimide; Hypnotics and Sedatives; Mice; Pentylenetetrazole; Pharmacology; Phenobarbital; Piperidines; Research; Seizures; Toxicology

Topics: Amino Acids; Biochemical Phenomena; Carbon Isotopes; Carboxylic Acids; Lysine; Metabolism; Pipecolic Acids; Piperidines; Radiometry; Rats; Research

Topics: Chromatography; Piperidines; Pyrroles; Pyrrolidines; Research; Spectrophotometry

Topics: Chemistry, Pharmaceutical; Heterocyclic Compounds; Nortropanes; Piperidines; Pyridines; Pyrroles; Quinolizidines; Quinolizines; Research; Tropanes

Topics: Aldosterone; Arginine Vasopressin; Cinnamates; Diuresis; Methacholine Chloride; Methacholine Compounds; Neurosecretion; Pharmacology; Piperidines; Rats; Research; Vasopressins

Topics: Anesthetics; Diagnosis, Differential; Hallucinogens; Humans; Neurotic Disorders; Phencyclidine; Piperidines; Psychopharmacology; Psychotic Disorders

Topics: Anesthetics; Brain Chemistry; Pharmacology; Phencyclidine; Piperidines; Psychoses, Substance-Induced; Psychotic Disorders; Toxicology

Topics: Alkaloids; Chromatography, Thin Layer; Hemlock; Piperidines

Topics: Atropine; Biliary Dyskinesia; Cholinergic Antagonists; Dyskinesias; Humans; Parasympatholytics; Piperidines

Topics: Animals; Carboxylic Acids; Lysine; Pipecolic Acids; Piperidines; Proteins; Rats

Topics: Carboxylic Acids; Piperidines; Research

Topics: Alkaloids; Amines; Piperidines; Pyrroles; Pyrrolidines

Topics: Analgesics; Analgesics, Non-Narcotic; Antipyretics; Cats; Guinea Pigs; Meperidine; Mice; Muscle, Smooth; Pharmacology; Piperidines; Pupil; Rabbits; Research; Toxicology

Topics: Antihypertensive Agents; Blood Pressure; Chemistry, Pharmaceutical; Dogs; Heterocyclic Compounds; Indazoles; Indoles; Mice; Pharmacology; Piperidines; Research; Seizures; Selective Serotonin Reuptake Inhibitors; Serotonin; Toxicology; Tryptamines

Topics: Brain; Brain Diseases; Humans; Piperidines; Propiophenones; Tolperisone

Topics: Phenethylamines; Piperidines; Thiazoles

Topics: Amines; Methenamine; Piperidines; Research; Salicylates

Topics: Bromides; Nitrogen; Piperidines

Topics: Carboxylic Acids; Meperidine; Piperidines

Topics: Ammonium Compounds; Anti-Allergic Agents; Antihypertensive Agents; Chemical Phenomena; Chemistry; Dogs; Pharmacology; Piperidines; Quaternary Ammonium Compounds; Research

Topics: Behavior; Brain; Humans; Piperidines

Topics: Anticonvulsants; Barbiturates; Hydantoins; Piperidines

Topics: Child; Electroencephalography; Humans; Hypnotics and Sedatives; Infant; Piperidines

Topics: Benzoin; Piperidines

Topics: Anesthetics; Hallucinogens; Humans; Mental Disorders; Phencyclidine; Piperidines

The behaviour of two new analgesics, benzethidine and furethidine, in a number of different tests has been compared with that of pethidine. Some differences in side-effects at equi-analgesic dosage were observed, particularly a reduction in histamine release.

Topics: Analgesics; Analgesics, Non-Narcotic; Analgesics, Opioid; Antipyretics; Meperidine; Piperidines

Topics: Amines; Heterocyclic Compounds; Hydrogen; Piperidines; Sympatholytics

Topics: Animals; Anura; Heart; Methenamine; Piperidines; Ranidae; Salicylates

Topics: Anesthetics; Anesthetics, Local; Phenylcarbamates; Piperidines; Propylene Glycols

Topics: Alkaloids; Amines; Oxidoreductases; Piperidines; Pyrroles; Pyrrolidines

Topics: Female; Humans; Labor, Obstetric; Meperidine; Piperidines; Pregnancy

Topics: Analgesics; Analgesics, Non-Narcotic; Antipyretics; Piperidines

Topics: Central Nervous System; Piperidines

Topics: Barbiturates; Humans; Hypnotics and Sedatives; Piperidines; Pyridines

Topics: Methenamine; Piperidines; Research; Salicylates

Topics: Humans; Methenamine; Piperidines; Research; Salicylates

Topics: Betaine; Piperidines; Sulfonic Acids

Topics: Histamine H1 Antagonists; Humans; Piperidines

Topics: Alkylation; Muscle Relaxants, Central; Parasympatholytics; Piperidines; Pyridines

Topics: Animals; Anura; Humans; Methane; Piperidines

Topics: Analgesics; Analgesics, Non-Narcotic; Animals; Antipyretics; Arteriosclerosis; Epinephrine; Piperidines; Rabbits

Topics: Analgesics; Analgesics, Non-Narcotic; Antipyretics; Endocrine Glands; Neurosecretory Systems; Piperidines

Topics: Antihypertensive Agents; Blood Pressure; Humans; Hypotension; Piperidines; Pyridines

Topics: Methylphenidate; Parasympatholytics; Parkinson Disease; Parkinsonian Disorders; Piperidines; Reserpine; Salts

Topics: Anti-Allergic Agents; Histamine H1 Antagonists; Piperidines

Topics: Anti-Allergic Agents; Benzhydryl Compounds; Piperidines; Pyridines

Topics: Hypnotics and Sedatives; Narcotics; Piperidines

Topics: Hypnotics and Sedatives; Piperidines

Topics: Fibrinogen; Piperidines; Sulfur

Topics: Barbiturates; Humans; Hypnotics and Sedatives; Piperidines; Piperidones

Topics: Amides; Amines; Morpholines; Piperidines; Quinolines

Topics: Hypnotics and Sedatives; Mental Disorders; Piperidines; Psychiatry; Psychotherapy

Topics: Chlorpromazine; Humans; Piperidines; Sleep Wake Disorders

Topics: Acetates; Anesthesia; Anesthesiology; Piperidines

Topics: Autonomic Agents; Cholinergic Agents; Humans; Piperidines; Pyrrolidines

Topics: Oxidoreductases; Piperidines; Plants; Pyrroles; Pyrrolidines

Topics: Carbon; Carbonic Acid; Curare; Muscle Relaxants, Central; Piperidines; Pyridines; Salts

Topics: Anti-Allergic Agents; Hypnotics and Sedatives; Piperidines

Topics: Anthelmintics; Ethylenediamines; Fatty Acids; Morpholines; Piperazines; Piperidines; Salts

Topics: Anesthesia; Basal Metabolism; Hibernation; Humans; Meperidine; Piperidines

Topics: Anti-Allergic Agents; Calcium; Histamine H1 Antagonists; Humans; Piperidines

Topics: Anti-Allergic Agents; Hypnotics and Sedatives; Piperidines; Piperidones

Topics: Hypnotics and Sedatives; Piperidines; Piperidones

Topics: Hypnotics and Sedatives; Piperidines; Pyridines

Topics: Piperidines

Topics: Humans; Piperidines

Topics: Hydrogenation; Piperidines

Topics: Anti-Allergic Agents; Central Nervous System Stimulants; Humans; Piperidines

Topics: Cholinergic Antagonists; Parasympatholytics; Piperidines

Topics: Piperidines

Topics: Acetates; Esters; Parasympatholytics; Piperidines

Topics: Cell Nucleus; Piperidines; Strychnine

Topics: Cell Nucleus; Piperidines; Seizures; Strychnine

Topics: Acetylcholine; Histamine; Histamine Agents; Humans; Methacholine Chloride; Pharmaceutical Preparations; Piperidines; Skin

Topics: Picolinic Acids; Piperidines; Pyridines

Topics: Piperidines

Topics: Analgesics; Biphenyl Compounds; Humans; Meperidine; Methadone; Parasympatholytics; Piperidines

Topics: Alkaloids; Piperidines

Topics: Photometry; Piperidines

Topics: Animals; Cadaverine; Lysine; Piperidines; Rabbits

Topics: Histamine Antagonists; Piperidines

Topics: Humans; Piperidines; Rhinitis; Rhinitis, Allergic, Seasonal; Rhinitis, Vasomotor

Topics: Alphaprodine; Female; Humans; Labor, Obstetric; Piperidines; Pregnancy

Topics: Humans; Hypnosis; Piperidines; Pyridones

Topics: Anti-Allergic Agents; Dicarboxylic Acids; Piperidines

Topics: Piperidines

Topics: Animals; Filariasis; Loa; Microfilariae; Piperidines

Topics: Piperazines; Piperidines

Topics: Piperidines

Topics: Piperidines; Pyridines

Topics: Morphine; Piperidines; Tetrahydronaphthalenes

Topics: Gastrointestinal Tract; Humans; Ketones; Piperidines

Topics: Animals; Dogs; Piperidines; Pyrroles; Pyrrolidines; Quinidine

Topics: Aldehydes; Piperidines; Piperidones

Topics: Humans; Piperidines

Topics: Anesthesia; Anesthesiology; Anesthetics, Local; Piperidines

Topics: Analgesics; Piperidines

Topics: Analgesics; Anti-Allergic Agents; Humans; Piperidines

Topics: Piperidines

Topics: Cough; Humans; Hypnotics and Sedatives; Piperidines

Topics: Piperidines

Topics: Piperidines

Topics: Piperidines

Topics: Piperidines

Topics: Piperidines

Topics: Anesthesia, Spinal; Humans; Piperidines

Topics: Anesthesia, Local; Anesthetics, Local; Piperidines

Topics: 4-Aminobenzoic Acid; Acids; Morpholines; para-Aminobenzoates; Piperidines

Topics: Alkylation; Piperidines; Piperidones

Topics: Nicotinic Acids; Piperidines; Piperidones

Topics: Humans; Piperidines

Topics: Humans; Lewy Bodies; Phthalimides; Piperidines

Topics: Parasympatholytics; Piperidines; Spasm

Topics: Adrenal Glands; Epinephrine; Neostigmine; Piperidines; Tissue Extracts

Topics: Animals; Body Fluids; Humans; Piperidines; Urine

Topics: Blood Pressure; Blood Pressure Determination; Hypertension; Piperidines

Topics: Meperidine; Piperidines

Topics: Diuresis; Humans; Meperidine; Morphine; Piperidines