title: Bile acids and their oxo derivatives: Potential inhibitors of carbonic anhydrase I and II, androgen receptor antagonists and CYP3A4 substrates.
abstract: Some biological properties of bile acids and their oxo derivatives have not been sufficiently investigated, although the interest in bile acids as signaling molecules is rising. The aim of this work was to evaluate physico-chemical parametar b (slope) that represents the lipophilicity of the examined molecules and to investigate interactions of bile acids with carbonic anhydrase I, II, androgen receptor and CYP450s. Thirteen candidates were investigated using normal-phase thin-layer chromatography in two solvent systems. Retention parameters were used in further quantitative structure-activity relationship analysis and docking studies to predict interactions and binding affinities of examined molecules with enzymes and receptors. Prediction of activity on androgen receptor showed that compounds 3α-hydroxy-12-oxo-5β-cholanoic and 3α-hydroxy-7-oxo-5β-cholanoic acid have stronger antiandrogen activity than natural bile acids. The inhibitory potential for carbonic anhydrase I and II was tested and it was concluded that molecules 3α-hydroxy-12-oxo-5β-cholanoic, 3α-hydroxy-7-oxo-5β-cholanoic, 3,7,12-trioxo-5β-cholanoic acid and hyodeoxycholic acid show the best results. Substrate behavior for CYP3A4 was confirmed for all investigated compounds. Oxo derivatives of bile acids show stronger interactions with enzymes and receptors as classical bile acids and lower membranolytic activity compared with them. These significant observations could be valuable in consideration of oxo derivatives as building blocks in medicinal chemistry.
authors.affiliation: Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Serbia.
authors.forename: Jovana
authors.initials: J
authors.lastname: Trifunović
authors.affiliation: Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Serbia.
authors.forename: Vladan
authors.initials: V
authors.lastname: Borčić
authors.affiliation: Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Serbia.
authors.forename: Momir
authors.initials: M
authors.lastname: Mikov
mesh_terms: D059002:Androgen Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000737:chemistry / Q000494:pharmacology*; D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors*; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors*; D002793:Cholic Acids / Q000737:chemistry / Q000494:pharmacology; D002855:Chromatography, Thin Layer / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: C000620473:3alpha-hydroxy-12-oxo-5beta-cholanoic acid; C000620472:3alpha-hydroxy-7-oxo-5beta-cholanoic acid; D059002:Androgen Receptor Antagonists; D001647:Bile Acids and Salts; D002793:Cholic Acids; D004791:Enzyme Inhibitors; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II
keywords: QSAR; antiandrogen; bile acids; carbon anhydrase; oxo bile acids