piperidines and morpholine

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

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

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

Four 3-((hetera)cyclobutyl)azetidine-based isosteres of piperidine, piperazine, and morpholine were designed and synthesized on up to gram scale. The key step of the synthetic sequence included cyclization of N-protected 2-(azetidin-3-yl)propane-1,3-diol or the corresponding 1,3-dibromide. X-ray diffraction studies of the products obtained, followed by exit vector plot analysis of their molecular geometry, demonstrated their larger size and increased conformational flexibility as compared to the parent heterocycles and confirmed their potential utility as building blocks for lead optimization programs.

Topics: Azetidines; Cyclization; Drug Discovery; Morpholines; Piperazine; Piperidines

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

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

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

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

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

Morpholine-4-carboxylic acid {(S)-1-[4-cyano-1-(3-morpholin-4-yl-propyl)-piperidin-4-ylcarbamoyl]-4,4- dimethyl-hexyl}-amide, (1) is a potent reversible and selective cathepsin S inhibitor. Deuterium labeled (1) was prepared in four steps in 62% overall yield from [2H8]- morpholine and chiral acid (6). Carbon-14 labeled (1) was obtained in two steps using sodium [14C]-cyanide in a modified Strecker reaction followed by amide bond formation with acid (6) in 74% overall radiochemical yield. The phosphate salt of this compound was produced by treatment with phosphoric acid in methanol in 97% yield.

Topics: Carbon Radioisotopes; Cathepsins; Deuterium; Morpholines; Piperidines

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 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

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

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

Stress impairs hippocampal long-term potentiation (LTP), but it is unknown whether the stress evoked by opiate withdrawal has the same effect. Here the authors report that opiate withdrawal for 4 days does not influence basal synaptic transmission, but results in a greatly increased LTP in hippocampal CA1 area in anesthetized rats. Elevated-platform stress enabled a large LTP in rats withdrawn for only 18 h, but the glucocorticoid receptor antagonist RU38486 (twice per day for 3 days) prevented the large LTP on 4 days withdrawal. Moreover, 4 days withdrawal enhanced the NMDAR-mediated EPSCs, in which the NR2A-containing NMDAR-mediated EPSC was increased but the NR2B-containing NMDAR-mediated EPSC was decreased. These results suggest that adaptive changes of the NMDAR and glucocorticoid receptor functions during 4 days of opiate withdrawal may enable stress to facilitate hippocampal LTP, potentially contributing to the opiate withdrawal experience-dependent modifications of hippocampal functions.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Analysis of Variance; Animals; Dose-Response Relationship, Radiation; Drug Administration Schedule; Drug Interactions; Electric Stimulation; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Hippocampus; Hormone Antagonists; In Vitro Techniques; Long-Term Potentiation; Male; Mifepristone; Morpholines; Patch-Clamp Techniques; Phenols; Piperidines; Rats; Rats, Sprague-Dawley; Stress, Psychological; Substance Withdrawal Syndrome; Time Factors

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

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

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

In order to see if the biodegradative pathways for morpholine and thiomorpholine during degradation by Mycobacterium aurum MO1 could be generalized to other heterocyclic compounds, the degradation of piperidine by this strain was investigated by performing (1)H-nuclear magnetic resonance directly with the incubation medium. Ionspray mass spectrometry, performed without purification of the samples, was also used to confirm the structure of some metabolites during morpholine and thiomorpholine degradation. The results obtained with these two techniques suggested a general pathway for degradation of nitrogen heterocyclic compounds by M. aurum MO1. The first step of the degradative pathway is cleavage of the C---N bond; this leads formation of an intermediary amino acid, which is followed by deamination and oxidation of this amino acid into a diacid. Except in the case of thiodiglycolate obtained from thiomorpholine degradation, the dicarboxylates are completely mineralized by the bacterial cells. A comparison with previously published data showed that this pathway could be a general pathway for degradation by other strains of members of the genus Mycobacterium.

Topics: Biodegradation, Environmental; Culture Media; Magnetic Resonance Spectroscopy; Mass Spectrometry; Morpholines; Mycobacterium; Piperidines

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

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

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 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

Topics: Amides; Amines; Morpholines; Piperidines; Quinolines

Topics: Anthelmintics; Ethylenediamines; Fatty Acids; Morpholines; Piperazines; Piperidines; Salts

Topics: 2-Naphthylamine; Amides; Ergotamine; Morpholines; Naphthalenes; Piperidines; Sympatholytics