Side-Chain Fluorine Engineering of Vitamin D<sub>3</sub> Derivatives for VDR-Silent SREBP Inhibitors
The present study reports on the structure-activity relationships of side-chain shortened and fluorinated vitamin D<sub>3</sub> analogs (5-13), with the goal of developing vitamin D analogs that are silent toward the vitamin D receptor (VDR) while retaining inhibitory activity against sterol regulatory element-binding protein (SREBP). The biological activities of the synthesized fluorinated vitamin D<sub>3</sub> analogs were assessed through their effects on the VDR ligand-binding domain (VDR<sub>LBD</sub>), full-length VDR transcriptional activity, and SREBP transcriptional activity. Among the synthesized analogs, 8, 11, and 13 exhibited notable SREBP inhibitory activity, although their potency was lower than that of the natural vitamin D<sub>3</sub> metabolite, 25(OH)D<sub>3</sub> (1). Compound 11 emerged as the most effective analog, displaying selective SREBP inhibition with minimal VDR activation.
Authors
- Yoshiki Miyata (ORCID: https://orcid.org/0000-0003-3322-5823)
- Sayuri Mototani
- Tomofumi Yatsu (ORCID: https://orcid.org/0000-0002-7205-8573)
- Fumihiro Kawagoe (ORCID: https://orcid.org/0000-0002-7182-5240)
- Motonari Uesugi (ORCID: https://orcid.org/0000-0002-8515-445X)
- Yusuke Akagi (ORCID: https://orcid.org/0000-0002-4303-8733)
- Yasushi Takemoto (ORCID: https://orcid.org/0000-0002-9988-4613)
- Toshie Fujishima
- Atsushi Kittaka (ORCID: https://orcid.org/0000-0003-3091-2476)
Institutions
- Fukushima Medical University (JP)
- Teikyo Heisei University (JP)
- Waseda University (JP)
- Fudan University (CN)
- Instituto de Investigaciones Químicas (ES)
- Teikyo University (JP)
Publication Details
- Journal
- Chemical and Pharmaceutical Bulletin
- Published
- 2025-09-19
- DOI
- https://doi.org/10.1248/cpb.c25-00363
- Citations
- 1
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.81