title: Synthesis, characterization, and receptor interaction profiles of enantiomeric bile acids.
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.
authors.affiliation: Department of Molecular Biology and Pharmacology, Washington University in St. Louis School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Bryson W
authors.initials: BW
authors.lastname: Katona
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Cummins
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Ferguson
authors.forename: Tingting
authors.initials: T
authors.lastname: Li
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Schmidt
authors.forename: David J
authors.initials: DJ
authors.lastname: Mangelsdorf
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Covey
mesh_terms: D002460:Cell Line; D002635:Chenodeoxycholic Acid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000819:agonists; D006801:Humans; D008095:Lithocholic Acid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008823:Micelles; D008958:Models, Molecular; D000077297:Pregnane X Receptor; D018167:Receptors, Calcitriol / Q000819:agonists; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists; D011987:Receptors, Steroid / Q000819:agonists; D013237:Stereoisomerism; D014157:Transcription Factors / Q000819:agonists; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002635:Chenodeoxycholic Acid; D004268:DNA-Binding Proteins; D008095:Lithocholic Acid; D008823:Micelles; D000077297:Pregnane X Receptor; D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D011987:Receptors, Steroid; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C473772:GPBAR1 protein, human