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

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