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Date publication

novembre 2024

Journal

Journal of medicinal chemistry

Auteurs

Membres identifiés du Cancéropôle Est :
Dr ROCHEL-GUIBERTEAU Natacha


Tous les auteurs :
Loureiro J, Seoane S, Sampaio-Dias IE, Peluso-Iltis C, Guiberteau T, Brito B, Gregorio C, Pérez-Fernández R, Rochel N, Mouriño A, Rodríguez-Borges JE

Résumé

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 (1,25D), 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, but with significantly less hypercalcemic activity. The new analogues, when combined with chemotherapy, significantly decrease cell proliferation.

Référence

J Med Chem. 2024 11 29;: