Design, Synthesis, and Biological Evaluation of Sila-Derivatives of Vitamin D with Application in Breast Cancer Therapy

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.