24,24-Dimethylvitamin D 3-26,23-lactones and their 2α-functionalized analogues as highly potent VDR antagonists

Abstract

Novel vitamin D receptor (VDR) antagonists, 24,24-dimethyl-1α-hydroxyvitamin D 3-26,23-lactones ( 8 and 9 ) and their C2α functionalized analogues ( 8a– c and 9a– c ) were efficiently synthesized and their biological activities were evaluated. The construction of vitamin D 3 triene skeleton was achieved by palladium-catalyzed alkenylative cyclization of A-ring precursor enyne ( 22 and 22a– c ) with CD-ring bromoolefin having a 24,24-dimethyl-α-methylene-γ-lactone unit on the side chain ( 13 and 14 ). The CD-ring precursors 13 and 14 were prepared by using chromium-mediated allylation of the aldehyde 10 derived from vitamin D 2. On the other hand, the A-ring enyne having 2α-(3-hydroxypropyl) group ( 22b ) was newly synthesized from epoxide 15 using regio- and stereoselective alkylation methodology. The potency of the antagonistic activity of the newly designed analogues ( 8 and 9 ) increased up to 12 times that of TEI-9647 ( 2 ). Furthermore, introduction of the three motifs, that is, a methyl ( 8a and 9a ), an ω-hydroxypropyl ( 8b and 9b ) or an ω-hydroxypropoxyl group ( 8c and 9c ) into the C2α position of 8 and 9 , respectively, resulted in remarkable enhancement, up to 89 times, of the antagonistic activity on VDR.