Carborane-based design of a potent vitamin D receptor agonist.
Fiche publication
Date publication
février 2016
Journal
Chemical science
Auteurs
Membres identifiés du Cancéropôle Est :
Dr ROCHEL-GUIBERTEAU Natacha
Tous les auteurs :
Otero R, Seoane S, Sigüeiro R, Belorusova AY, Maestro MA, Pérez-Fernández R, Rochel N, Mouriño A
Lien Pubmed
Résumé
The vitamin D nuclear receptor (VDR) is a potential target for cancer therapy. It is expressed in many tumors and its ligand shows anticancer actions. To combine these properties with the application of boron neutron capture therapy (BNCT), we design and synthesize a potent VDR agonist based on the skeleton of the hormone 1α,25-dihydroxyvitamin D (1,25D) and an -carborane (dicarba--1,2-dodecaborane) at the end of its side chain. The present ligand is the first secosteroidal analog with the carborane unit that efficiently binds to VDR and functions as an agonist with 1,25D-like potency in transcriptional assay on vitamin D target genes. Moreover it exhibits similar antiproliferative and pro-differentiating activities but is significantly less hypercalcemic than 1,25D. The crystal structure of its complex with VDR ligand binding domain reveals its binding mechanism involving boron-mediated dihydrogen bonds that mimic vitamin D hydroxyl interactions. In addition to the therapeutic interest, this study establishes the basis for the design of new unconventional vitamin D analogs containing carborane moieties for specific molecular recognition, and drug research and development.
Référence
Chem Sci. 2016 Feb 1;7(2):1033-1037