First Sila-Vitamin D Analogues: Design, Synthesis, Structural Analysis and Biological Activity

The
incorporation of silicon bioisosteres into pharmacological
structures has been used as a strategy to improve the therapeutic
potential of drugs. However, no secosteroidal silicon-containing VDR
ligands have been developed. Here we report the design, synthesis,
and biological activity of six analogues of the natural hormone 1,25-dihydroxyvitamin
D3 (1,25D3), which incorporate a silicon atom as a side
chain-C25 isostere. The analogues were synthesized by the Wittig–Horner
approach starting from Inhoffen-Lythgoe diol. The crystal structures
of the complexes formed by the sila-analogues with the ligand binding
domain of VDR revealed additional interactions of the sila-containing
side chains that stabilize the VDR active conformation. These sila-analogues
show similar VDR binding and transcriptional activity in comparison
with the natural hormone 1,25D3, but with significantly
less hypercalcemic activity. The new analogues, when combined with
chemotherapy, significantly decrease cell proliferation.