Design, synthesis, evaluation, and structure of vitamin D analogues with furan side chains.
Fiche publication
Date publication
janvier 2012
Auteurs
Membres identifiés du Cancéropôle Est :
Dr MORAS Dino, Dr ROCHEL-GUIBERTEAU Natacha
Tous les auteurs :
Fraga R, Zacconi F, Sussman F, Ordonez-Moran P, Munoz A, Huet T, Molnar F, Moras D, Rochel N, Maestro M, Mourino A
Lien Pubmed
Résumé
Based on the crystal structures of human vitamin D receptor (hVDR) bound to 1alpha,25-dihydroxy-vitamin D(3) (1,25 D) and superagonist ligands, we previously designed new superagonist ligands with a tetrahydrofuran ring at the side chain that optimize the aliphatic side-chain conformation through an entropy benefit. Following a similar strategy, four novel vitamin D analogues with aromatic furan side chains (3a, 3b, 4a, 4b) have now been developed. The triene system has been constructed by an efficient stereoselective intramolecular cyclization of an enol triflate (A-ring precursor) followed by a Suzuki-Miyaura coupling of the resulting intermediate with an alkenyl boronic ester (CD-side chain, upper fragment). The furan side chains have been constructed by gold chemistry. These analogues exhibit significant pro-differentiation effects and transactivation potency. The crystal structure of 3a in a complex with the ligand-binding domain of hVDR revealed that the side-chain furanic ring adopts two conformations.
Référence
Chemistry. 2012 Jan 9;18(2):603-12