Comprehensive Synthesis of Side-Chain Fluorinated 2<i>α</i>-[2-(Tetrazol-2-yl)ethyl]-1<i>α</i>,25-dihydroxyvitamin D<sub>3</sub> Analogs and Preliminary Biological Activities
Twelve side-chain fluorinated 2α-[2-(tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D<sub>3</sub> (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)<sub>2</sub>D<sub>3</sub>.
Authors
- Akiko Takeuchi (ORCID: https://orcid.org/0000-0003-4003-6035)
- Yoshiki Miyata (ORCID: https://orcid.org/0000-0003-3322-5823)
- Kaori Yasuda (ORCID: https://orcid.org/0000-0003-3495-3216)
- Toshiyuki Sakaki (ORCID: https://orcid.org/0000-0001-7064-8185)
- Sayuri Mototani
- Tomofumi Yatsu (ORCID: https://orcid.org/0000-0002-7205-8573)
- Fumihiro Kawagoe (ORCID: https://orcid.org/0000-0002-7182-5240)
- Atsushi Kittaka (ORCID: https://orcid.org/0000-0003-3091-2476)
- Yusuke Akagi
- Hiroshi Saitoh (ORCID: https://orcid.org/0000-0001-6003-7911)
- Souma Murata
- Yuki Okamoto
- Toshie Fujishima
Institutions
- Teikyo Heisei University (JP)
- Waseda University (JP)
- Toyama Prefectural University (JP)
- Teikyo University (JP)
- Teijin (Japan) (JP)
Publication Details
- Journal
- Chemical and Pharmaceutical Bulletin
- Published
- 2026-01-29
- DOI
- https://doi.org/10.1248/cpb.c25-00710
- Primary Topic
- Click Chemistry and Applications
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Japan Society for the Promotion of Science