pyrimidinones and monastrol

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Molecular Docking Simulation; Molecular Structure; Pyrimidines; Pyrimidinones; Structure-Activity Relationship; Thiones

Monastrol and its analog oxomonastrol differ by replacement of the sulfur atom present in monastrol to an oxygen atom in oxomonastrol. Monastrol inhibits the mitotic kinesin family member 11 (EG5), which has been studied for its potential use in cancer therapy. The aim of this study was to investigate the effect of monastrol and oxomonastrol on HepG2/C3A cells. Our results showed that monastrol induced DNA damage, reduced cell proliferation, and up-regulated the cytochrome P450 family 1 subfamily A member 1 (CYP1A1) mRNA levels. However, oxomonastrol was cytotoxic only at the highest concentrations used, without reducing cell proliferation and viability. Moreover, no genotoxic damage or alteration of levels of mRNA were found. Our results suggest that monastrol has greater antiproliferative activity compared to oxomonastrol, and this effect is probably related to the DNA damage induced by monastrol and its possible bioactivation demonstrated by the increase in CYP1A1 mRNA expression. Moreover, these effects appear to be related to the presence of the sulfur atom in its structure.

Topics: Apoptosis; Carcinoma, Hepatocellular; Cell Proliferation; Cell Survival; Comet Assay; Cytochrome P-450 CYP1A1; DNA Damage; Drug Screening Assays, Antitumor; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Kinetics; Liver Neoplasms; Pyrimidines; Pyrimidinones; RNA, Messenger; Spindle Apparatus; Thiones

A series of conformationally flexible and restricted dimers of monastrol as well as related dihydropyrimidones have been synthesized by employing one-pot Biginelli multicomponent reaction. These dimers have been evaluated for cytotoxic potency against selected human cancer cell lines and some of the compounds have exhibited more cytotoxic potency than the parent monastrol. Further, the DNA binding ability by thermal denaturation studies and antimicrobial activities of these compounds are also discussed.

Topics: Anti-Infective Agents; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Colonic Neoplasms; Differential Thermal Analysis; Dimerization; DNA; Drug Screening Assays, Antitumor; Female; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Inhibitory Concentration 50; Lung Neoplasms; Microbial Sensitivity Tests; Molecular Conformation; Pyrimidines; Pyrimidinones; Skin Neoplasms; Structure-Activity Relationship; Thiones

Gamma-aminobutyric acid type A receptors (GABA(A) receptors) are ligand-gated chloride channels that play a central role in signal transmission within the mammalian central nervous system. Compounds that modulate specific GABA(A) receptor subtypes containing the delta-subunit are scarce but would be valuable research tools and starting points for potential therapeutic agents. Here we report a class of dihydropyrimidinone (DHPM) heterocycles that preferentially potentiate peak currents of recombinant GABA(A) receptor subtypes containing the delta-subunit expressed in HEK293T cells. Using the three-component Biginelli reaction, 13 DHPMs with structural features similar to those of the barbiturate phenobarbital were synthesized; one DHPM used (monastrol) is commercially available. An up to approximately 3-fold increase in the current from recombinant alpha1beta2delta receptors was observed with the DHPM compound JM-II-43A or monastrol when co-applied with saturating GABA concentrations, similar to the current potentiation observed with the nonselective potentiating compounds phenobarbital and tracazolate. No agonist activity was observed for the DHPMs at the concentrations tested. A kinetic model was used in conjunction with dose-dependent measurements to calculate apparent dissociation constant values for JM-II-43A (400 muM) and monastrol (200 microM) at saturating GABA concentrations. We examined recombinant receptors composed of combinations of subunits alpha1, alpha4, alpha5, alpha6, beta2, beta3, gamma2L, and delta with JM-II-43A to demonstrate the preference for potentiation of delta-subunit-containing receptors. Lastly, reduced currents from receptors containing the mutated delta(E177A) subunit, described by Dibbens et al. [(2004) Hum. Mol. Genet. 13, 1315-1319] as a heritable susceptibility allele for generalized epilepsy with febrile seizures plus, are also potentiated by these DHPMs.

Topics: Alanine; Allosteric Regulation; Cell Line; Drug Synergism; Epilepsy; Genetic Variation; Glutamic Acid; Humans; Mutagenesis, Site-Directed; Protein Binding; Protein Isoforms; Protein Subunits; Pyrimidines; Pyrimidinones; Receptors, GABA-A; Thiones

The chiral discrimination ability of two recently prepared chiral stationary phases (CSP 1 and CSP 2), based on a leucine derived chiral selector, was tested for the enantiomers of dihydropyrimidone (DHPM) derivatives and compared with the commercially available Hyun-leucine CSP 3 and classical Pirkle-leucine CSP 4. By combining all of these CSPs, the enantiomers of all DHPM derivatives used in this study can be properly resolved. Particularly good enantioresolutions were achieved for thioureide derivatives, such as Monastrol. The results presented show that sulfur-aromatic interactions are meritorious for these very good separations.

Topics: Chemistry Techniques, Analytical; Chromatography; Chromatography, Liquid; Models, Chemical; Molecular Conformation; Pyrimidines; Pyrimidinones; Stereoisomerism; Sulfur; Thiones; Time Factors