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

MEDI 469

Bryson W. Katona1, Carolyn L. Cummins2, Andrew D. Ferguson3, David J. Mangelsdorf2, and Douglas F. Covey1. (1) Department of Molecular Biology and Pharmacology, Washington University in St. Louis School of Medicine, Box 8103, 660 S. Euclid Ave., St. Louis, MO 63110, (2) Howard Hughes Medical Institute and Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park, Dallas, TX 75390, (3) Department of Biochemistry, University of Texas Southwestern Medical Center, 6001 Forest Park, Dallas, TX 75390
Bile acids are endogenous steroid detergents that modulate gene expression through interactions with nuclear receptors, which can lead to changes in the synthesis and metabolism of these steroids. Specific modulation of nuclear receptors could also have important therapeutic potential. In this study we report the first total synthesis of the enantiomers of lithocholic acid (LCA) and chenodeoxycholic acid (CDCA). ent-LCA was synthesized in 21 total steps with a 4.2% yield whereas ent-CDCA was obtained in 23 steps with a 0.8% yield. Furthermore, the critical micelle concentrations of ent-LCA and ent-CDCA were found to be identical to their natural counterparts. We also examined enantiomeric bile acid modulation of the FXR, PXR, and VDR nuclear receptors. Interestingly, ent-LCA and ent-CDCA showed differential interactions with these nuclear receptors compared to the natural steroids. This data highlights the potential utility of ent-bile acids in uncovering the non-receptor mediated functions of natural bile acids.
 

General Oral Session
1:30 PM-4:50 PM, Thursday, August 23, 2007 BCEC -- 210A, Oral

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007