Further Studies on the Highly Active Des-C-Ring and Aromatic-D-Ring Analogues of 1α,25-Dihydroxyvitamin D (Calcitriol): Refinement of the Side Chain.
Fiche publication
Date publication
novembre 2023
Journal
Journal of medicinal chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr ROCHEL-GUIBERTEAU Natacha
Tous les auteurs :
Zárate-Ruíz A, Seoane S, Peluso-Iltis C, Peters S, Gregorio C, Guiberteau T, Maestro M, Pérez-Fernández R, Rochel N, Mouriño A
Lien Pubmed
Résumé
Current efforts in the vitamin D field are directed toward the development of highly antiproliferative yet noncalcemic analogues of the natural hormone 1α,25-dihydroxyvitamin D (1,25D). We have recently reported the design, synthesis, biological evaluation, and crystal structures of a series of novel analogues that both lack the steroidal C-ring and have an -phenylene ring replacing the steroidal cyclopentane D-ring. We have now investigated the potentiating effects of incorporating selected modifications (hexafluorination and/or an internal triple bond) within the steroidal side chain in our series. An alternative synthetic strategy (Wittig-Horner approach instead of our previously used Pd-catalyzed tandem cyclization/cross-coupling) for the construction of the vitamin D triene system was found convenient for the target compounds , , , and of this report. These modifications enhance vitamin D nuclear receptor (VDR) interactions and consequently VDR-associated biological properties compared to parental PG-136 compound while maintaining normal calcium levels.
Référence
J Med Chem. 2023 11 1;: