Design, Synthesis, Evaluation and Structure of Allenic 1a,25- Dihydroxyvitamin D3 Analogs with Locked Mobility at C-17.
Fiche publication
Date publication
juillet 2021
Journal
Chemistry (Weinheim an der Bergstrasse, Germany)
Auteurs
Membres identifiés du Cancéropôle Est :
Dr ROCHEL-GUIBERTEAU Natacha, Dr LAVERNY Gilles
Tous les auteurs :
Mourino A, Fraga R, Len K, Lutzing G, Laverny G, Loureiro J, Maestro M, Rochel N, Rodriguez-Borges JE
Lien Pubmed
Résumé
Vitamin D receptor ligands have potential for the treatment of hyperproliferative diseases and disorders related to the immune system. However hypercalcemic effects limit their therapeutical uses and call for the development of tissue-selective new analogs. We have designed and synthesized the first examples of 1α,25- dihydroxyvitamin D 3 analogs bearing an allenic unit attached to the D ring to restrict the side-chain conformational mobility. The triene system was constructed by a Pd 0 -mediated cyclization/Suzuki- Miyaura cross-coupling process in the presence of an allenic side chain. The allenic moiety was built through an orthoester-Claisen rearrangement of a propargylic alcohol. The biological activity and structure of (22 S )-1 a ,25-dihydroxy-17,20-dien-24-homo-21-nor- vitamin D 3 bound to binding domain of the vitamin D receptor, provide information concerning side-chain conformational requirements for biological activity.
Mots clés
Vitamin D analogs * allenes * synthesis * orthoester- Claisen rearrangement * Pd-catalyzed reactions *
Référence
Chemistry. 2021 Jul 5;: