The strategic incorporation of silicon into bioactive molecules has emerged as an effective approach to enhance drug properties, including metabolic stability and target specificity. However, no secosteroidal vitamin D receptor (VDR) ligands containing silicon have been reported to date. Here, we describe the rational design, synthesis, and biological evaluation of six novel analogues of 1,25-dihydroxyvitamin D₃ (1,25D₃), in which a silicon atom is introduced as an isosteric replacement at the C25 side chain position.

The sila-derivatives were synthesised via a Wittig-Horner approach starting from the Inhoffen-Lythgoe diol, enabling precise silicon incorporation at the C25 position of the side chain, while preserving the stereochemistry of the secosteroidal structure. X-ray crystallographic analysis of VDR ligand-binding domain complexes (PDB codes 9GY8, 9GYJ, 9GYC, 9GYA, and 9GYK, available at Protein Data Bank) revealed additional stabilising interactions mediated by the silicon-containing side chains, supporting the receptor’s active conformation.

Functional assays showed that these analogues maintain VDR binding and transcriptional activity comparable to 1,25D₃, while exhibiting markedly lower hypercalcaemic effects in cellular models. Notably, in combination with conventional chemotherapeutics, the analogues significantly reduced cancer cell proliferation, indicating potential synergistic effects.

Overall, these results provide a framework for the development of silicon-modified secosteroidal VDR ligands with improved safety and therapeutic potential, highlighting new avenues for applications in both metabolic and cancer-related contexts.