Design and synthesis of potent vitamin D receptor antagonists with A-ring modifications: remarkable effects of 2α-methyl introduction on antagonistic activity

Abstract

Novel A-ring analogues of the vitamin D receptor (VDR) antagonist ( 3a), ZK-159222, and its 24-epimer ( 3b) were convergently synthesized. Preparation of the CD-ring portions with the side chains of 3a, b, followed by palladium-catalyzed cross-coupling with the A-ring enyne precursors ( 15a, b), (3 S,4 S,5 R)- and (3 S,4 S,5 S)-bis[( tert-butyldimethylsilyl)oxy]-4-methyloct-1-en-7-yne, afforded the 2α-methyl-introduced analogues ( 4a, b) and their 3-epimers ( 5a, b). The biological profiles of the hybrid analogues were assessed in terms of affinity for VDR, and antagonistic activity to inhibit HL-60 cell differentiation induced by the natural hormone, 1α,25-dihydroxyvitamin D 3. The analogue 4a showed an approximately fivefold higher antagonistic activity compared with 3a. The 2α-methyl introduction into 3a increased the receptor affinity, thereby enhancing VDR antagonism. This approach to design potent antagonists based on hybridization of structural motifs in the A-ring and in the side chain may prove to be valuable.