piperidines and pyrrolidine

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

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

Parasites of the Plasmodium genus are unable to produce purine nucleotides de novo and depend completely on the salvage pathway. This fact makes plasmodial hypoxanthine-guanine-(xanthine) phosphoribosyltransferase [HG(X)PRT] a valuable target for development of antimalarial agents. A series of nucleotide analogues was designed, synthesized and evaluated as potential inhibitors of Plasmodium falciparum HGXPRT, P. vivax HGPRT and human HGPRT. These novel nucleoside phosphonates have a pyrrolidine, piperidine or piperazine ring incorporated into the linker connecting the purine base to a phosphonate group(s) and exhibited a broad range of K

Topics: Antimalarials; Cell Line; Cell Survival; Drug Evaluation, Preclinical; Drug Resistance; Enzyme Inhibitors; Erythrocytes; Humans; Nucleotides; Pentosyltransferases; Piperazine; Piperidines; Plasmodium falciparum; Plasmodium vivax; Prodrugs; Protozoan Proteins; Pyrrolidines; Structure-Activity Relationship

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

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

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

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

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

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

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

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

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

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

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

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

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

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

A series of 3,4,6-triaryl-2-pyranones, new class of anti-breast cancer agents, have been synthesized as a structural variants of cyclic triphenylethylenes by replacing the fused benzene ring with pendant phenyl ring to mimic the phenolic A ring of estradiol. Nine of these newly synthesized pyranones exhibited significant anti-proliferative activity in both ER+ve and ER-ve breast cancer cell lines. Four active non-cytotoxic compounds 5c, 5d, 5g and 5h showed specific and selective cytotoxicity and two compounds 5d and 5h induced significant DNA fragmentation in both MCF-7 and MDA-MB-231 cell lines. Based on RBA studies, the molecules probably act in an ER-independent mechanism. The involved pathway was observed as caspase-dependant apoptosis in MCF-7 cells. However, the particular caspases involved and the possible cellular target through which this series of compounds mediate cell death are not known.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Female; Humans; Models, Molecular; Molecular Structure; Piperidines; Pyrones; Pyrrolidines

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

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

[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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 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

Topics: Base Sequence; Chemical Phenomena; Chemistry; DNA; Piperidines; Pyrrolidines

Imino acid and related alicyclic amine concentrations in blood and urine of mammals including humans were concurrently determined by a selected ion monitoring technique. Nanomole levels of proline and pipecolic acid, and pyrrolidine and piperidine as well, were found in human urine. Proline levels but not pipecolic acid levels were higher in blood of humans than in urine. Pyrrolidine and piperidine levels in blood of humans were picomole levels and much lower than those in urine. Similar tendencies were also recognized when these 4 compounds were analyzed using animal blood and urine, although the levels were generally higher in animals than in humans. Significantly high concentrations of the imino acids and the amines were found also in animal semen.

Topics: Amines; Animals; Body Fluids; Female; Gas Chromatography-Mass Spectrometry; Humans; Imino Acids; Male; Pipecolic Acids; Piperidines; Proline; Pyrrolidines; Rabbits; Rats; Rats, Inbred Strains

Topics: Alkanes; Amines; Chemistry, Pharmaceutical; Cyclohexanes; Piperidines; Pyrrolidines; Pyrrolidinones; Research

Topics: Chromatography; Piperidines; Pyrroles; Pyrrolidines; Research; Spectrophotometry

Topics: Alkaloids; Amines; Piperidines; Pyrroles; Pyrrolidines

Topics: Alkaloids; Amines; Oxidoreductases; Piperidines; Pyrroles; Pyrrolidines

Topics: Autonomic Agents; Cholinergic Agents; Humans; Piperidines; Pyrrolidines

Topics: Oxidoreductases; Piperidines; Plants; Pyrroles; Pyrrolidines

Topics: Animals; Dogs; Piperidines; Pyrroles; Pyrrolidines; Quinidine