Katona Bryson W, Cummins Carolyn L, Ferguson Andrew D, Li Tingting, Schmidt Daniel R, Mangelsdorf David J, Covey Douglas F
Department of Molecular Biology and Pharmacology, Washington University in St. Louis School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
J Med Chem. 2007 Nov 29;50(24):6048-58. doi: 10.1021/jm0707931. Epub 2007 Oct 27.
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.
胆汁酸是具有受体介导生理作用的内源性甾体去污剂，其生理作用包括激活G蛋白偶联受体TGR5以及由核受体介导的基因调控。在本研究中，我们报道了通过表睾酮（3）首次合成对映体石胆酸（ent-LCA，ent-1）和鹅去氧胆酸（ent-CDCA，ent-2）。ent-1经21步总反应合成，产率为4.2%，而ent-2经23步总反应得到，产率为0.8%。发现对映体胆汁酸的临界胶束浓度与其天然对应物相同。此外，还测试了对映体胆汁酸调节胆汁酸激活蛋白的能力：法尼醇X受体、维生素D受体、孕烷X受体和TGR5。有趣的是，与相应的天然胆汁酸相比，ent-1和ent-2与这些蛋白表现出不同的相互作用。这些数据突出了利用对映选择性来区分天然胆汁酸的受体介导和非受体介导功能的潜力。
