March 3, 2026Open Access

Comprehensive Synthesis of Side-Chain Fluorinated 2α-2-(Tetrazol-2-yl)ethyl-1α,25-dihydroxyvitamin D3 Analogs and Preliminary Biological Activities

Puntos clave

Higher vitamin D receptor binding affinity was observed in select fluorinated analogs, enhancing biological effectiveness.
Notable compounds included C26,27-hexafluoro-AH-1 and 24,24-difluoro-AH-1, which showed significantly improved activities.
Synthesis applied the palladium-catalyzed Trost coupling reaction to create side-chain fluorinated CD-ring compounds with notable properties.
These findings may suggest further exploration of fluorinated analogs for potential therapeutic uses in vitamin D-related conditions.

Resumen

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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