24,24-Dimethylvitamin D3-26,23-lactones and their 2α-functionalized analogues as highly potent VDR antagonists

Novel vitamin D receptor (VDR) antagonists, 24,24-dimethyl-1α-hydroxyvitamin D3-26,23-lactones ( and ) and their C2α functionalized analogues ( and ) were efficiently synthesized and their biological activities were evaluated. The construction of vitamin D3 triene skeleton was achieved by palladium-catalyzed alkenylative cyclization of A-ring precursor enyne ( and ) with CD-ring bromoolefin having a 24,24-dimethyl-α-methylene-γ-lactone unit on the side chain ( and ). The CD-ring precursors and were prepared by using chromium-mediated allylation of the aldehyde derived from vitamin D2. On the other hand, the A-ring enyne having 2α-(3-hydroxypropyl) group () was newly synthesized from epoxide using regio- and stereoselective alkylation methodology. The potency of the antagonistic activity of the newly designed analogues ( and ) increased up to 12 times that of TEI-9647 (). Furthermore, introduction of the three motifs, that is, a methyl ( and ), an ω-hydroxypropyl ( and ) or an ω-hydroxypropoxyl group ( and ) into the C2α position of and , respectively, resulted in remarkable enhancement, up to 89 times, of the antagonistic activity on VDR.