Synthesis of 14-epi-2α-hydroxypropoxy-1α,25-dihydroxy-19- nortachysterol and its hVDR binding

Recently, we evaluated a novel skeleton in the vitamin D family, 14-epi-1α,25(OH)₂-19-nortachysterol, and discovered its unique binding configuration in the human vitamin D receptor (VDR) with the C5,6-and C7,8-s-trans triene configuration. Because of its unprecedented form, this skeleton has a promising characteristic profile for clinical use, and also the synthesis of its derivatives should be versatile. Therefore, we synthesized the novel analog, 2α-hydroxypropoxy substituted 14-epi-1α,25(OH) ₂-19-nortachysterol, and evaluated its human VDR binding affinity. Although this substitution is one of the promising modification of vitamin D₃ such as eldecalcitol (ED-71), it had negative effects on the binding affinity, and the compound showed lower affinity than 1α,25(OH)₂D₃ and its parent compound, 14-epi-1α,25(OH)₂-19-nortachysterol. It was thought that the unprecedented binding configuration of this skeleton should not allow the terminal hydroxyl group of the 2α-substituent to construct effective hydrogen bond networks around the amino acid residues in the binding pocket.