Lithocholic Acid Derivatives as Potent Vitamin D Receptor Agonists
Harue Sasaki, Hiroyuki Masuno, Haru Kawasaki, Ayana Yoshihara, Nobutaka Numoto, Nobutoshi Ito, Hiroaki Ishida, Keiko Yamamoto, Naoya Hirata, Yasunari Kanda, Emiko Kawachi, Hiroyuki Kagechika, Aya Tanatani
Abstract
Lithocholic acid (2) was identified as a second endogenous ligand of vitamin D receptor (VDR), though its activity is very weak. In this study, we designed novel lithocholic acid derivatives based on the crystal structure of VDR–ligand-binding domain (LBD) bound to 2. Among the synthesized compounds, 6 bearing a 2-hydroxy-2-methylprop-1-yl group instead of the 3-hydroxy group at the 3α-position of 2 showed dramatically increased activity in HL-60 cell differentiation assay, being at least 10 000 times more potent than lithocholic acid (2) and 3 times more potent than 1α,25-dihydroxyvitamin D3 (1). Although the binding affinities of 6 and its epimer 7 were less than that of 1, their transactivation activities were greater than that of 1. X-ray structure analyses of VDR LBD bound to 6 or 7 showed that the binding positions of these compounds in the ligand-binding pocket are similar to that of 1.