Novel Sila-Vitamin D Derivatives Targeting the Vitamin D Receptor for Application in Cancer Therapy

Cancer is a highly complex disease that affects millions of people worldwide, with nearly 20 million new cases reported in 2022. Despite significant advances, current treatments remain insufficient. In this context, the vitamin D receptor (VDR), a nuclear receptor involved in several biological processes, has emerged as a promising target for cancer therapy. Although calcitriol (1,25D₃) and other VDR agonists have shown therapeutic potential, their clinical application is limited by severe hypercalcaemic effects.

Here, the strategic incorporation of silicon into 1,25D₃ was explored for the first time. To this end, six novel analogues of 1,25D₃, in which a silicon atom was introduced as an isosteric replacement at the C25 position of the side chain, were rationally designed, synthesised, and biologically evaluated.

The designed sila-derivatives were successfully synthesised via a Wittig-Horner approach from the Inhoffen-Lythgoe diol. Structural studies of VDR complexes with the sila-derivatives revealed favourable interactions between the modified side chains and the VDR ligand-binding domain. Functional assays demonstrated that the analogues retained VDR-mediated activity while exhibiting markedly lower hypercalcaemic effects than 1,25D₃. Their biological effects were further investigated in cancer cell lines (HaCaT, SKOV-3, PC-3, MCF-7, and MDA-MB-231 cells), where, in combination with conventional chemotherapeutics, the analogues significantly reduced cancer cell proliferation, suggesting potential synergistic effects.

Overall, these results highlight the potential of silicon-modified secosteroidal VDR ligands and support further investigation of sila-vitamin D derivatives for applications in cancer-related contexts.