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PubMed2005

Piperidone derivative from Dalbergia sympathetica.

An alcoholic extract of Dalbergia sympathetica, on column chromatography, yielded a compound which analyzed for C(6)H(11)NO(3) (M(+) 145). The IR spectrum of the compound showed the presence of carbonyl and hydroxyl groups. PMR, (13)C and DEPT NMR spectral studies of the compound showed the presence of one N-methyl, two methine and two methylene groups. A quaternary carbon signal at delta 172.88 ppm was assigned to C-2 carbonyl of the compound. From all the above observations and also from the HMQC 2D NMR spectrum, the compound was identified as 3, 6-dihydroxy-N-methyl-2-piperidone. This is the first report of the natural occurrence of this compound from plant sources.

Carbon Isotopes↗
PubMed2006

Comments on 'Piperidone derivative from Dalbergia sympathetica'.

Alcoholic extraction of Dalbergia sympathetica leaves yielded N-methyl-trans-4-hydroxy-L-proline and not 3,6-dihydroxy-N-methyl-2-piperidone, as previously reported. This is shown by the identity of the 1H and 13C NMR data of the isolated compound with those of N-methyl-trans-4-hydroxy-L-proline.

Carbon Isotopes↗
PubMed1978

3-Amino-2-piperidone in the urine of patients with hyperornithinemia.

3-Amino-2-piperidone, a delta-lactam of ornithine, has been detected in the urine of a number of patients with hyperornithinemia. The distinctive yellow colour formed with a ninhydrin-cadmium reagent should help in the detection of hyperornithinemia by urinary chromatography.

Adolescent↗
PubMed1996

Imidazole derivatives of pyrrolidonic and piperidonic as potential inhibitors of human placental aromatase in vitro.

Inhibitory activities towards human Placental aromatase of novel pyrrolidinone and piperidinone drugs were investigated and compared with those of aminoglutethimide (AG) in vitro. All compounds showing a stronger inhibitory effect than this of AG had the following common structural feature: an imidazole side-chain in C-3 position, with a substituted or non-substituted aromatic ring in the C-2 position and an aliphatic chain (n-butyl or n-octyl) or a phenyl moiety on the nitrogen of the pyrrolidone or piperidone ring. When the C-3 side-chain did not bear any imidazole ring, no activity was observed. Respective Ki values for the competitive inhibition exerted by the more potent inhibitors 10, 11, 13 and 21 with androstenedione as substrate were 19.2, 20.3, 16.8 and 15.4 microM, respectively (Ki AG= 77.0 microM).

Aminoglutethimide↗
PubMed2005

Structure-activity relationships of 1-alkyl-5-(3,4-dichlorophenyl)-5-{2-[3-(substituted)-1-azetidinyl]-ethyl}-2-piperidones. Part 2: Improving oral absorption.

A series of piperidone analogues of 1b-q, seeking replacements for the polar sulfamide moiety in clinical candidate UK-224,671 1a, possessing reduced H-bonding potential as a strategy to improve oral absorption, were prepared. These studies led to the successful identification of 1n, which demonstrated equivalent pharmacology and metabolic stability to 1a, and greatly improved oral absorption as assessed in rat PK studies.

Administration, Oral↗
PubMed1983

Gramicidin S synthetase. Stability of reactive thioester intermediates and formation of 3-amino-2-piperidone.

The reactive thioester complexes of gramicidin S synthetase with substrate amino acids and intermediate peptides are slowly hydrolyzed in neutral buffer solutions under mild conditions. Fully active enzyme is recovered. These processes are strongly accelerated by certain thiol protective agents. In the presence of 1 mM dithioerythritol the half-life times of these hydrolysis reactions are in the range of 1-90 h at 3 degrees C. The thioester complex of gramicidin S synthetase 2 (GS2, the heavy enzyme) with the tripeptide DPhe-Pro-Val is distinguished by the highest stability of all these intermediates. A different decomposition pattern is observed for the thioester complex of GS2 with LOrn. Here 3-amino-2-piperidone (cyclo-LOrn) is formed in a rapid cyclization reaction. This product specifically blocks the activation center of GS2 for LOrn at the thioester binding site. All other activation reactions of gramicidin S synthetase are unaffected. A procedure for a specific labelling of the reaction centers of the multienzyme is outlined.

Amino Acid Isomerases↗
PubMed1998

A study of baker's yeast reduction of piperidone-carboxylates.

The stereoselective baker's yeast reduction of various N-protected piperidone-carboxylic acids have been studied, and the enantioselectivity was found to be widely dependent on whether fermenting or non-fermenting conditions were employed. Thus reaction of N-tert-butoxycarbonyl-4-oxopiperidine-3-carboxylic acid ethyl ester (6) with fermenting baker's yeast gave almost racemic N-tert-butoxycarbonyl-4-hydroxypiperidine-3-carboxylic acid ethyl ester (7), however, with complete diastereoselectivity. Reduction of 6 with non-fermenting yeast gave 7 with a 24-41% enantiomeric excess. Similarly, reduction of N-tert-butoxycarbonyl-3-oxopiperidine-4-carboxylic acid ethyl ester (17) with fermenting baker's yeast gave racemic N-tert-butoxycarbonyl-3-hydroxypiperidine-4-carboxylic acid ethyl ester [(+/-)-18] diastereoselectively. A convenient method for determining the enantiomeric excess of the hydroxypiperidine carboxylic acids derivatives was found in the reaction with Sanger's reagent followed by HPLC on a chiral column.

Carboxylic Acids↗
PubMed1992

Evaluation of some N-acyl analogues of 3,5-bis(arylidene)-4-piperidones for cytotoxic activity.

The synthesis of fourteen N-acyl derivatives of two 3,5-bis(arylidene)-4-piperidones was accomplished and these compounds were evaluated against L1210 leukemia cells in vitro. With one exception, the compounds had IC50 values of less than 10 microM and six of them had IC50 figures in the 0.2-0.6 microM range which were comparable to a reference drug melphalan. Twelve of the sixteen compounds showed specificity for human leukemia cell lines in the NCI in vitro screen. Studies using 1H NMR spectroscopy revealed that solutions of three N-acetylated compounds underwent deamination and possibly other reactions, the deaminated product itself being unstable in the solvent used.

Animals↗
PubMed1992

3,5-Bis-arylidene-1-methyl-4-piperidone methohalides and related compounds with activity against L 1210 cells and DNA binding properties.

A series of 3,5-bis-arylidene-1-methyl-4-piperidone methohalides 2 and two related analogues in general demonstrated activity against L 1210 leukemia cells in vitro and bound to a synthetic DNA, poly[d(AT)]. Plots of various physicochemical constants of the aromatic substituents in series 2 versus the IC50 figures revealed correlations between the aryl MR and pi values but not the sigma constants. The delta Tm values of six members of series 2 were correlated with the MR figures of the aryl substituents but not the sigma nor pi values of the aromatic atoms and groups. Some suggestions for future molecular modification with a view to increasing cytotoxicity are presented.

Animals↗
PubMed2006

1-N-(Arylmaleamoyl)-3,5-bis(phenylmethylene)4-piperidones: a novel class of antimycobacterial agents.

Various acyl groups possessing markedly divergent topography were placed on the nitrogen atom of the antimycobacterial agent 3,5-bis(phenylmethylene)-4-piperidone (1). Some of the N-maleamoyl analogues of 1 displayed antitubercular properties thereby affording an insight into the structural requirements for interactions at a putative auxiliary binding site in the bacterium.

Antitubercular Agents↗
PubMed1990

3,5-Bis-benzylidene-4-piperidones and related compounds with high activity towards P388 leukemia cells.

3,5-Bis(benzylidene)-4-piperidones and related compounds were prepared and found to have between 100 and 9700 times the activity of N,N'-bis(2-chloroethyl)-N-nitrosourea towards P388 leukemia cells. The shapes of six of these molecules--determined by X-ray crystallography--were compared, but no correlation between the stereochemistry of the molecules or their electronic properties and cytotoxicity was apparent. Molecular modification of the compounds by forming two mono-benzylidene compounds, a related acyclic derivative and an N-acyl compound resulted in diminished but retained high cytotoxicity. Two representative compounds lowered glutathione levels of liver following their intraperitoneal injection into mice. Two quaternary ammonium compounds were shown to bind in the minor groove of DNA, while four related non-quaternary ammonium derivatives did not demonstrate this property. We conclude that the modes of action of these highly cytotoxic compounds include alkylation of cellular thiols and DNA binding, but interference with other biochemical processes is also probably involved.

Animals↗
PubMedDate not supplied

Synthesis of 3-(4,4-dimethyl-2-piperidon-6-yl)methyl-2-pyrazoline derivatives.

The results of studies of condensation of 1-(4,4-dimethyl-2-piperidon-6-yl)-4-phenyl-3-buten-2-one and its derivatives substituted in the benzene ring (R = 4-CH3 and R = 4-Cl) with hydrazine and its methyl or phenyl derivative are described. Compounds 2a, 2c and 2g were tested for their possible action on the central nervous system. Two drugs: 2c and 2g decreased locomotor activity. None of the examined compounds inhibited the reserpine-induced hypothermia, 5-HT syndrome and convulsions induced by pentetrazole in mice. Compound 2c injected only intraperitoneally depressed the number of the writhing episodes induced by p-phenylbenzoquinone.

5-Hydroxytryptophan↗
PubMed1980

[Synthesis of antiproteolytically active 3,5-bis(4-amidinobenzyl)- and 3,5-bis(4-amidinobenzylidene)piperidone-(4) derivatives (author's transl)].

Because of the good inhibitory effects of some alpha, alpha'-bis (amidinobenzylidene)cycloalkanoes and of their hydrogenation products on serine proteinases, the authors prepared structurally analogous bisamidines of heterocycloalkanones. To obtain 3,5-bis(4-amidinobenzyl)-N-benzoylpiperidone-(4), N-benzoylpiperidone-(4) was condensed with 4-cyanobenzaldehyde in concentrated phosphoric acid. The resultant 3,5-bis(4-cyanobenzylidene)-N-benzoylpiperidone-(4) was reduced with zinc-glacial acetic acid, and the reduction product was converted into the respective bisamidine by means of the Pinner method. 3-(4-Cyanobenzylidene)-5-(4-aminocarbonylbenzylidene)-N-benzoylpiperidone-(4) was isolated as a by-product of the condensation of N-benzoylpiperidone-(4) with 4-cyanobenzaldehyde. To prepare 3,5-bis(4-amidinobenzylidene)-N-benzoylpiperidone-(4), N-benzoylpiperidone-(4) was condensed with 4-amidinobenzaldehyde hydrochloride in concentrated phosphoric acid. The resultant bis-dihydrogen phosphate was converted into the bis-hydrochloride by treatment with methanolic hydrochloric acid solution in the cold, and debenzoylated to 3,5-bis(4-amidinobenzylidene)piperidone-(4) trihydrochloride on heating with methanolic hydrochloric acid solution.

Amidines↗
PubMed1994

Cytotoxic evaluation of some N-acyl and N-acyloxy analogues of 3,5-bis(arylidene)-4-piperidones.

The preparation of thirteen N-acyl and N-acyloxy analogues of two 3,5-bis(arylidene)-4-piperidones were prepared as potential prodrugs of the parent ketones. Approximately half of the compounds demonstrated antileukemic properties when evaluated against murine L1210 lymphoid leukemia cells. Three of the derivatives were more active than or equipotent with the reference drug melphalan. All of the compounds were examined against approximately 55 human tumours representing eight different neoplastic diseases. Not only were most of the compounds more cytotoxic than melphalan but 60% of the derivatives displayed selective toxicity to leukemia. A stability study of six of the candidate prodrugs using 1H NMR spectroscopy revealed that while some decomposition in solution occurred, the parent amine was not liberated.

Animals↗
PubMed1978

ESR correlation times of 2,2,6,6-tetramethyl piperidone-N-oxyl (Tempone) in solutions of hemoglobin A and hemoglobin S.

Correlation times for the tumbling motion of the spin probe 2,2,6,6,-tetramethyl piperidone-N-oxyl (Tempone) were obtained in the presence of different concentrations of oxyhemoglobin A, oxyhemoglobin S, and deoxyhemoglobin S and compared to the viscosity of non-gelling hemoglobin solutions. Reorientational motion (or tumbling) of Tempone in gelled solutions of deoxyhemoglobin S is as great as that in non-gelled hemoglobins of the same total concentration. It is concluded that the gel does not exclusively partition Tempone into an aqueous phase of lower solute concentration after gel formation. The gel at room temperature is a highly mobile and dynamic structure on the microscopic level.

Electron Spin Resonance Spectroscopy↗
PubMed2001

A conformational and structure-activity relationship study of cytotoxic 3,5-bis(arylidene)-4-piperidones and related N-acryloyl analogues.

A series of 3,5-bis(arylidene)-4-piperidones 1 and related N-acryloyl analogues 2 were prepared as candidate cytotoxic agents with a view to discerning those structural features which contributed to bioactivity. A number of the compounds were markedly cytotoxic toward murine P388 and L1210 leukemic cells and also to human Molt 4/C8 and CEM neoplasms. Approximately 40% of the IC50 values generated were lower than the figures obtained for melphalan. In virtually all cases, the N-acyl compounds were significantly more bioactive than the analogues 1. In general, structure-activity relationships revealed that the cytotoxicity of series 1 was correlated positively with the size of the aryl substituents, while in series 2, a -sigma relationship was established. In particular, various angles and interatomic distances were obtained by molecular modeling, and the presence of an acryloyl group on the piperidyl nitrogen atom in series 2 affected the relative locations of the two aryl rings. This observation, along with some differences in distances between various atoms in series 1 and 2, may have contributed to the disparity in cytotoxicity between 1 and 2. The results obtained by X-ray crystallography of representative compounds were mainly in accordance with the observations noted by molecular modeling. Selected compounds interfered with the biosynthesis of DNA, RNA, and protein in murine L1210 cells, while others were shown to cause apoptosis in the human Jurkat leukemic cell line. This study has revealed the potential of these molecules for development as cytotoxic and anticancer agents.

Acrylates↗