Journal
BIOMEDICAL CHROMATOGRAPHY
Volume 31, Issue 5, Pages -Publisher
WILEY
DOI: 10.1002/bmc.3870
Keywords
antiandrogen; bile acids; carbon anhydrase; oxo bile acids; QSAR
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Funding
- Ministry of Science and Technological Development, Republic of Serbia [III 41012]
- Autonomous Province of Vojvodina [114-451-698/2015-02]
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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 3 alpha-hydroxy-12-oxo-5 beta-cholanoic and 3 alpha-hydroxy-7-oxo-5 beta-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 3 alpha-hydroxy-12-oxo-5 beta-cholanoic, 3 alpha-hydroxy-7-oxo-5 beta-cholanoic, 3,7,12-trioxo-5 beta-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.
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