piperidines and 1-piperideine

Unsymmetrical 1,2,5,6-tetrahydropyridine-3-carboxylates were obtained for the first time from a five-component Fe

Topics: Bismuth; Catalysis; Combinatorial Chemistry Techniques; Dendrimers; Magnetite Nanoparticles; Models, Molecular; Piperidines; Stereoisomerism; Triazines

The cyclization of oxidosqualene to lanosterol, catalyzed by the enzyme oxidosqualene cyclase (OSC), goes through a number of carbocationic high energy intermediates (HEI), and mimicking these intermediates is a promising approach for the development of OSC inhibitors. 3-Arylpiperidines (or tetrahydropyridines) were designed as steroidomimetic rings A + C equivalents containing two protonable amino groups for mimicking both the pro-C4 HEI and the pro-C20 HEI of the OSC-mediated cyclization cascade. Inhibitory activity is strongly dependent on the nature of the lipophilic substituent representing an equivalent of the sterol side chain. Here aromatic residues (substituted benzyl, cinnamyl, naphthylmethyl) were found to be most suitable. Docking experiments on a first optimized 3-arylpiperidine compound led to an isomeric 4-arylpiperidine with submicromolar activity on human OSC. This inhibitor reduced total cholesterol biosynthesis in a cellular assay with an IC50 value of 0.26 μM.

Topics: Anticholesteremic Agents; Cell Line; Cholesterol; Enzyme Inhibitors; Humans; Intramolecular Transferases; Molecular Docking Simulation; Piperidines; Structure-Activity Relationship

In continuation of previous efforts to investigate the biological potency of tetrahydropyridinol derivatives, the present study synthesized three target compounds: N-(bromoacetyl)-3-carboxyethyl-2,6-diphenyl-4-O-(pentafluorobenzoyl)-Δ3-tetra-hydropyridine (5a), N-(chloroacetyl)-3-carboxyethyl-2,6-diphenyl-4-O-(pentafluorobenzoyl)-Δ3-tetrahydropyridine (5b) and N-(2-bromopropanoyl)-3-carboxyethyl-2,6-diphenyl-4-O-(pentafluorobenzoyl)-Δ3-tetrahydropyridine (5c), and examined their anticancer potency. Experiments were performed using the Sk-Hep1 and Hep3B human hepatocellular carcinoma cell lines and MDA-MB-231 breast adenocarcinoma cell line. Among the three compounds, 5a and 5b were comparably and significantly cytotoxic to the Sk-Hep1, Hep3B and MDA-MB-231 cells. The highest level of cytotoxicity was detected in theSk-Hep1 cells with half maximal inhibitory concentrations for compounds 5a and 5b at 12 and 6 µM, respectively. These two compounds induced cell cycle arrest in the Sk-Hep1 and MDA-MB-231 cells through the downregulation of β-catenin and upregulation of glycogen synthase kinase-3β and E-cadherin. By contrast, 5a and 5b induced G1 arrest in the Hep3B cells by modulating the p21 and p27 cell cycle regulatory molecules and cyclin-dependent kinase 2. In addition, 5a and 5b significantly inhibited the invasion of Sk-Hep1 and MDA-MB-231 cells. These results suggested that the 5a and 5b compounds induce cell cycle arrest by suppressing Wnt/β-catenin signaling in highly invasive Sk-Hep1 and MDA-MB-231 cells, and by inducing p53 independent cell cycle arrest in Hep3B cells.

Topics: Antineoplastic Agents; Apoptosis; beta Catenin; Breast; Breast Neoplasms; Carcinoma, Hepatocellular; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Liver; Liver Neoplasms; Neoplasm Invasiveness; Piperidines; Wnt Signaling Pathway

A simple method for the photometric estimation of 1-piperideine, produced by the action of copper amino oxidases on cadaverine, is described. A discussion on the formation of 1-piperideine from lysine in acidic medium is also reported, together with some observations on the nature of acid 1-piperideine-ninhydrin condensation product.

Topics: Amine Oxidase (Copper-Containing); Cadaverine; Hydrogen-Ion Concentration; Indicators and Reagents; Kinetics; Lysine; Ninhydrin; Oxidation-Reduction; Piperidines; Pyridines; Spectrophotometry

The biological N-oxidation of piperidine, a pharmacologically active biogenic amine of mammals and human beings, was studied in vitro. After incubation of piperidine-HCl in a fortified rat liver microsomal preparation (9000 x g supernatant) at 37 degrees C for 30 min, 2 metabolites were detected. They were identified as N-hydroxy piperidine and 2, 3, 4, 5-tetrahydro-pyridine-1-oxide as evidenced by TLC, GLC, HPLC, GC-MS and MS.

Topics: Animals; Biotransformation; Microsomes, Liver; Piperidines; Pyridines; Rats; Rats, Inbred Strains

Intraperitoneal injection of the cyclic imine 1-piperideine in mice resulted in measurable quantities of 5-aminopentanoic acid in brain. 5-Aminopentanoic acid is a methylene homologue of gamma-aminobutyric acid (GABA) that is a weak GABA agonist. 5-Aminopentanoic acid formed in the periphery was ruled out as the source of brain 5-aminopentanoic acid based on the absence of detection in brain following injection of 100 mg/kg of 5-aminopentanoic acid. Deuterium-labeled 1-piperideine was prepared by exchange in deuterated phosphate buffer. Injection of [3.3-2H2]1-piperideine yielded [2.2-2H2]5-aminopentanoic acid in brain. The results are consistent with uptake of 1-piperideine into brain and oxidation of the precursor to 5-aminopentanoic acid. Inhibition of GABA catabolism by pretreatment with aminooxyacetic acid increased brain concentrations of 5-aminopentanoic acid formed from 1-piperideine, suggesting that 5-aminopentanoic acid is an in vivo substrate of 4-aminobutyrate:2-oxoglutarate aminotransferase.

Topics: Amino Acids; Amino Acids, Neutral; Aminooxyacetic Acid; Animals; Brain Chemistry; Chemical Phenomena; Chemistry; gamma-Aminobutyric Acid; Male; Mice; Mice, Inbred ICR; Piperidines; Pyridines

1-Piperideine, 5-aminopentanoic acid, and its lactam, 2-piperidone, were identified as metabolites of cadaverine in 10,000 g mouse liver supernatants to which diamine oxidase had been added. Both metabolites were also found when the cadaverine metabolite 1-piperideine was incubated with the preparation which suggested that 1-piperideine is an intermediate in the formation of 5-aminopentanoic acid and 2-piperidone. Identification of the metabolites was based on gas chromatography-mass spectrometric analysis in comparison to authentic standards. Mouse brain homogenates converted 1-piperideine to 5-aminopentanoic acid. The results suggest that the metabolic fate of cadaverine may provide precursors of pharmacologically active analogues of GABA.

Topics: Amine Oxidase (Copper-Containing); Amino Acids; Amino Acids, Neutral; Animals; Cadaverine; Diamines; gamma-Aminobutyric Acid; Gas Chromatography-Mass Spectrometry; Liver; Male; Mice; Mice, Inbred ICR; Piperidines; Piperidones; Pyridines