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

Fumihiro Kawagoe; Sayuri Mototani; Yuki Okamoto; Souma Murata; Akiko Takeuchi; Tomofumi Yatsu; Kaori Yasuda; Yusuke Akagi; Toshie Fujishima; Yoshiki Miyata; Hiroshi Saitoh; Toshiyuki Sakaki; Atsushi Kittaka

doi:10.1248/cpb.c25-00710

Regular Article

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

Fumihiro Kawagoe, Sayuri Mototani, Yuki Okamoto, Souma Murata, Akiko Takeuchi, Tomofumi Yatsu, Kaori Yasuda, Yusuke Akagi, Toshie Fujishima, Yoshiki Miyata, Hiroshi Saitoh, Toshiyuki Sakaki, Atsushi Kittaka

Author information

Fumihiro Kawagoe
Faculty of Pharmaceutical Sciences, Teikyo University, 2–11–1 Kaga, Itabashi-ku, Tokyo 173–8605, Japan
Sayuri Mototani
Faculty of Pharmaceutical Sciences, Teikyo University, 2–11–1 Kaga, Itabashi-ku, Tokyo 173–8605, Japan
Yuki Okamoto
Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama 939–0398, Japan
Souma Murata
Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama 939–0398, Japan
Akiko Takeuchi
Teijin Institute for Bio-medical Research, Teijin Pharma Limited, Hino, Tokyo 191–8512, Japan
Tomofumi Yatsu
Faculty of Pharmaceutical Sciences, Teikyo University, 2–11–1 Kaga, Itabashi-ku, Tokyo 173–8605, Japan
Kaori Yasuda
Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama 939–0398, Japan
Yusuke Akagi
Faculty of Pharmaceutical Sciences, Teikyo Heisei University, 4–21–2 Nakano, Nakano-ku, Tokyo 164–8530, Japan
Toshie Fujishima
Faculty of Pharmaceutical Sciences, Teikyo University, 2–11–1 Kaga, Itabashi-ku, Tokyo 173–8605, Japan
Yoshiki Miyata
Faculty of Pharmaceutical Sciences, Teikyo University, 2–11–1 Kaga, Itabashi-ku, Tokyo 173–8605, Japan
Hiroshi Saitoh
Teijin Institute for Bio-medical Research, Teijin Pharma Limited, Hino, Tokyo 191–8512, Japan
Toshiyuki Sakaki
Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama 939–0398, Japan
Atsushi Kittaka Corresponding author
Faculty of Pharmaceutical Sciences, Teikyo University, 2–11–1 Kaga, Itabashi-ku, Tokyo 173–8605, Japan
Faculty of Science and Engineering, Waseda University, 3–4–1 Ohkubo, Shinjuku-ku, Tokyo 169–8555, Japan

Keywords: synthesis, fluorovitamin D₃ analog, AH-1, vitamin D receptor, transactivation, CYP24A1

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Supplementary material

2026 Volume 74 Issue 1 Pages 103-118

DOI https://doi.org/10.1248/cpb.c25-00710

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Abstract

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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