Synthesis of 2α- and 2β-(3-hydroxypropyl)- 7,8-cis-14-epi-1α,25-dihydroxy-19-norvitamin D₃ and their biological activity

According to the binding mode of 14-epi-1α,25-dihydroxy-19-nortachysterol in the ligand binding domain of human vitamin D receptor (hVDR), i.e., 5,6- and 7,8-s-trans configuration that was shown by X-ray co-crystallographic analysis, 7,8-cis-locked 1α,25(OH)₂D₃ analogs were synthesized. In this paper, the synthesis and biological activity of 2α- and 2β-(3-hydroxypropyl)-7,8-cis-14-epi-1α,25-dihydroxy-19-norvitamin D₃ are reported. The A-ring and CD-ring precursors for the Julia-Kociensky coupling reaction to create a diene system of the target molecules were prepared using our original methods. hVDR binding affinity and osteocalcin promoter transactivation activity of the new 7,8-cis-14-epi-vitamin D₃ analogs were evaluated. Interestingly, the 2β-substituted 7,8-cis-analog was a better binder for hVDR than the 2α-isomeric counterpart.