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Comprehensive Synthesis of Side-Chain Fluorinated 2α-[2-(Tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D3 Analogs and
Fumihiro Kawagoe1, Sayuri Mototani1, Yuki Okamoto2
1Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
None:
Twelve side-chain fluorinated 2α-[2-(tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D3 (AH-1) analogs were designed, synthesized, and evaluated regarding their biological activities. Synthesis was carried out employing the palladium-catalyzed Trost coupling reaction between side-chain fluorinated CD-ring bromo-olefins 41-52 and A-ring enyne 53. Some analogs, including C26,27-hexafluoro-AH-1 (31) and 24,24-difluoro-AH-1 (34), exhibited much higher human vitamin D receptor binding affinity, VDR-ligand binding domain transcriptional activity, osteocalcin promoter transactivation activity, and metabolic resistance to CYP24A1-mediated inactivation than 1α,25(OH)2D3.
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