9gyk
Vitamin D receptor in complex with Sila-fVitamin D receptor in complex with Sila-f
Structural highlights
FunctionVDRA_DANRE Nuclear hormone receptor. Transcription factor that mediates the action of vitamin D3 by controlling the expression of hormone sensitive genes. Regulates transcription of hormone sensitive genes via its association with the WINAC complex, a chromatin-remodeling complex. Plays a central role in calcium homeostasis.[1] Publication Abstract from PubMedThe 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 (1,25D(3)), 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 1,25D(3), but with significantly less hypercalcemic activity. The new analogues, when combined with chemotherapy, significantly decrease cell proliferation. First Sila-Vitamin D Analogues: Design, Synthesis, Structural Analysis and Biological Activity.,Loureiro J, Seoane S, Sampaio-Dias IE, Peluso-Iltis C, Guiberteau T, Brito B, Gregorio C, Perez-Fernandez R, Rochel N, Mourino A, Rodriguez-Borges JE J Med Chem. 2024 Nov 29. doi: 10.1021/acs.jmedchem.4c02404. PMID:39610329[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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