First Sila-Vitamin\nD Analogues: Design, Synthesis,\nStructural Analysis and Biological Activity

The\nincorporation of silicon bioisosteres into pharmacological\nstructures has been used as a strategy to improve the therapeutic\npotential of drugs. However, no secosteroidal silicon-containing VDR\nligands have been developed. Here we report the design, synthesis,\nand biological activity of six analogues of the natural hormone 1,25-dihydroxyvitamin\nD3 (1,25D<sub>3</sub>), which incorporate a silicon atom as a side\nchain-C25 isostere. The analogues were synthesized by the Wittig–Horner\napproach starting from Inhoffen-Lythgoe diol. The crystal structures\nof the complexes formed by the sila-analogues with the ligand binding\ndomain of VDR revealed additional interactions of the sila-containing\nside chains that stabilize the VDR active conformation. These sila-analogues\nshow similar VDR binding and transcriptional activity in comparison\nwith the natural hormone 1,25D<sub>3</sub>, but with significantly\nless hypercalcemic activity. The new analogues, when combined with\nchemotherapy, significantly decrease cell proliferation.