Design, Synthesis, Biological Activity, and Structural Analysis of Novel Des-C-Ring and Aromatic-D-Ring Analogues of 1α,25-Dihydroxyvitamin D.
Fiche publication
Date publication
septembre 2022
Journal
Journal of medicinal chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr ROCHEL-GUIBERTEAU Natacha
Tous les auteurs :
Seoane S, Gogoi P, Zárate-Ruíz A, Peluso-Iltis C, Peters S, Guiberteau T, Maestro MA, Pérez-Fernández R, Rochel N, Mouriño A
Lien Pubmed
Résumé
The toxic calcemic effects of the natural hormone 1α,25-dihydroxyvitamin D (1,25D, 1,25-dihydroxycholecalciferol) in the treatment of hyperproliferative diseases demand the development of highly active and noncalcemic vitamin D analogues. We report the development of two highly active and noncalcemic analogues of 1,25D that lack the C-ring and possess an -phenylene ring that replaces the natural D-ring. The new analogues (, ) are characterized by an additional six-carbon hydroxylated side chain attached either to the aromatic nucleus or to the triene system. Both compounds were synthesized by the Pd-catalyzed tandem cyclization/cross coupling approach starting from alkyne and diphenol . Key steps include a stereoselective Cu-assisted addition of a Grignard reagent to an aromatic alkyne and a Takai olefination of an aromatic aldehyde. The new compounds are noncalcemic and show transcriptional and antiproliferative activities similar to 1,25D. Structural analysis revealed that they induce a large conformational rearrangement of the vitamin D receptor around helix 6.
Référence
J Med Chem. 2022 09 27;: