Structure-activity relationship study of vitamin D analogs with oxolane group in their side chain.
Fiche publication
Date publication
juillet 2017
Journal
European journal of medicinal chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr ROCHEL-GUIBERTEAU Natacha
Tous les auteurs :
Belorusova AY, Martínez A, Gándara Z, Gómez G, Fall Y, Rochel N
Lien Pubmed
Résumé
Synthetic analogs of 1α,25-dihydroxyvitamin D (1,25(OH)D) have been developed with the goal of improving the biological profile of the natural hormone for therapeutic applications. Derivatives of 1,25(OH)D with the oxolane moiety branched in the side chain at carbon C20, act as Vitamin D nuclear Receptor (VDR) superagonists being several orders of magnitude more active than the natural ligand. Here, we describe the synthesis and biological evaluation of three diastereoisomers of (1S, 3R)-Dihydroxy-(20S)-[(2″-hydroxy-2″-propyl)-tetrahydrofuryl]-22,23,24,25,26,27-hexanor-1α-hydroxyvitamin D3, with different stereochemistry at positions C2 and C5 of the oxolane ring branched at carbon C22 (1, C2RC5S; 2, C2SC5R; 3, C2SC5S). These compounds act as weak VDR agonist in transcriptional assays with compound 3 being the most active. X-ray crystallographic analysis of the VDR ligand-binding domain accommodating the three compounds indicates that the oxolane group branched at carbon C22 is not constrained as in case of compound with oxolane group branched at C20 leading to the loss of interactions of the triene group and increased flexibility of the C/D-rings and of the side chain.
Mots clés
Animals, COS Cells, Calcitriol, analogs & derivatives, Cercopithecus aethiops, Crystallography, X-Ray, HEK293 Cells, Humans, Models, Molecular, Receptors, Calcitriol, agonists, Stereoisomerism, Structure-Activity Relationship, Zebrafish
Référence
Eur J Med Chem. 2017 Jul 7;134:86-96