Creation of Potent Vitamin D Receptor Agonists and Antagonists with 2?-(?-Hydroxyalkylation) Concept to the seco-Steroid Skeleton

Abstract

2?-modification on the vitamin D skeleton with a 2?-(?-hydroxyalkyl) or 2?-(?-hydroxyalkoxy) group improves vitamin D receptor (VDR) binding affinity, lengthens the half-life in target cells because of increased resistance to CYP24A1 metabolism, and enhances biological activity. The introduced terminal hydroxy group forms an additional hydrogen bond to Arg274, which is the most important amino acid residue for recognizing the ligand hormone 1?,25-dihydroxyvitamin D3 of human VDR. According to our 2?-functionalization concept, we synthesized several hundred vitamin D analogs, and some had selective potent biological activity, such as bone formation (by AH-1) or anticancer activity (by MART-10), without the side-effects of vitamin D such as hypercalcemia. A potent hVDR antagonist NS-74c and stable 14-epi-tachysterol derivatives are also described in this short review.