1. Discovery of 3,3′-pyrrolidinyl-spirooxindoles as cardioprotectant prohibitin ligands
- Author
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Sabria Elderwish, Anaïs Audebrand, Laurent Désaubry, Canan G. Nebigil, Nanomédecine Régénérative (NanoRegMed), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Cardio-Oncologie et Chimie Médicinale, Centre National de la Recherche Scientifique (CNRS), Laboratoire des biomolécules (LBM UMR 7203), Institut National de la Santé et de la Recherche Médicale (INSERM)-Chimie Moléculaire de Paris Centre (FR 2769), Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Tianjin University of Science and Technology (TUST)
- Subjects
Scaffold protein ,Cardiotonic Agents ,Cell Survival ,Apoptosis ,[CHIM.THER]Chemical Sciences/Medicinal Chemistry ,Pharmacology ,Ligands ,01 natural sciences ,Cell Line ,Structure-Activity Relationship ,03 medical and health sciences ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Prohibitins ,Drug Discovery ,medicine ,Humans ,Initiation factor ,Myocytes, Cardiac ,Spiro Compounds ,Doxorubicin ,Prohibitin ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Cardioprotection ,0303 health sciences ,Cardiotoxicity ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Translation (biology) ,General Medicine ,Oxindoles ,3. Good health ,0104 chemical sciences ,Repressor Proteins ,eIF4A ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,medicine.drug - Abstract
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.
- Published
- 2020