Side-Chain Fluorine Engineering of Vitamin D₃ Derivatives for VDR-Silent SREBP Inhibitors

The present study reports on the structure-activity relationships of side-chain shortened and fluorinated vitamin D₃ 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 D₃ analogs were assessed through their effects on the VDR ligand-binding domain (VDR_LBD), 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 D₃ metabolite, 25(OH)D₃ (1). Compound 11 emerged as the most effective analog, displaying selective SREBP inhibition with minimal VDR activation.