Synthesis, characterization, and receptor interaction profiles of enantiomeric bile acids

Bryson W. Katona, Carolyn L. Cummins, Andrew D. Ferguson, Tingting Li, Daniel R. Schmidt, David J. Mangelsdorf, Douglas F. Covey

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Bile acids are endogenous steroid detergents with receptor-mediated physiologic actions including activation of the G-protein coupled receptor TGR5 and gene regulation mediated by nuclear receptors. In this study, we report the first synthesis of enantiomeric lithocholic acid (ent-LCA, ent-1) and chenodeoxycholic acid (ent-CDCA, ent-2) via ent-testosterone (3). ent-1 was synthesized in 21 total steps in 4.2% yield, whereas ent-2 was obtained in 23 total steps in 0.8% yield. Critical micelle concentrations of the enantiomeric bile acids were found to be identical to their natural counterparts. Furthermore, enantiomeric bile acids were also tested for their ability to modulate bile acid activated proteins: farnesoid X receptor, vitamin D receptor, pregnane X receptor, and TGR5. Interestingly, ent-1 and ent-2 showed differential interactions with these proteins as compared to their corresponding natural bile acids. These data highlight the potential for using enantioselectivity as a way to distinguish between receptor and nonreceptor-mediated functions of natural bile acids.

Original languageEnglish (US)
Pages (from-to)6048-6058
Number of pages11
JournalJournal of Medicinal Chemistry
Volume50
Issue number24
DOIs
Publication statusPublished - Nov 29 2007

    Fingerprint

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Katona, B. W., Cummins, C. L., Ferguson, A. D., Li, T., Schmidt, D. R., Mangelsdorf, D. J., & Covey, D. F. (2007). Synthesis, characterization, and receptor interaction profiles of enantiomeric bile acids. Journal of Medicinal Chemistry, 50(24), 6048-6058. https://doi.org/10.1021/jm0707931