Fiche publication
Date publication
novembre 2019
Journal
European journal of medicinal chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DESAUBRY Laurent
Tous les auteurs :
Elderwish S, Audebrand A, Nebigil CG, Désaubry L
Lien Pubmed
Résumé
The scaffold proteins prohibitins-1 and 2 (PHB1/2) play many important roles in coordinating many cell signaling pathways and represent emerging targets in cardiology and oncology. We previously reported that a family of natural products derivatives, flavaglines, binds to PHB1/2 to exert cardioprotectant and anti-cancer effects. However, flavaglines also target the initiation factor of translation eIF4A, which doesn't contribute to cardioprotection and may even induce some adverse effects. Herein, we report the development of a convenient and robust synthesis of the new PHB2 ligand 2'-phenylpyrrolidinyl-spirooxindole, and its analogues. We discovered that these compounds displays cardioprotective effect against doxorubicin mediated cardiotoxicity and uncovered the structural requirement for this activity. We identified in particular some analogues that are more cardioprotectant than flavaglines. Pull-down experiments demonstrated that these compounds bind not only to PHB2 but also PHB1. These novel PHB ligands may provide the basis for the development of new drugs candidates to protect the heart against the adverse effects of anticancer treatments.
Mots clés
Cardiotoxicity, Doxorubicin, Oxindoles, Prohibitins, STAT3
Référence
Eur J Med Chem. 2019 Nov 9;:111859
