Polycerasoidol, a Natural Prenylated Benzopyran with a Dual PPARα/PPARγ Agonist Activity and Anti-inflammatory Effect.

Autor:	Bermejo A; Department of Pharmacology , University of Valencia , 46113 Valencia Spain.; Center of Citriculture and Vegetal Production , IVIA , Moncada, 46100 Valencia , Spain., Collado A; Department of Pharmacology , University of Valencia , 46113 Valencia Spain., Barrachina I; Department of Pharmacology , University of Valencia , 46113 Valencia Spain., Marqués P; Department of Pharmacology , University of Valencia , 46113 Valencia Spain.; Institute of Health Research-INCLIVA , University Clinic Hospital of Valencia , 46010 Valencia , Spain., El Aouad N; Department of Pharmacology , University of Valencia , 46113 Valencia Spain., Franck X; UMR CNRS 6014/FR 3038, COBRA, Université de Rouen , Mont-Saint-Aignan 76821 , France., Garibotto F; Facultad de Química, Bioquímica y Farmacia , Universidad Nacional de San Luis-IMIBIO-SL-CONICET , Chacabuco 915 , San Luis , Argentina., Dacquet C; Départament des Sciences Expérimentales , Institut de Recherches Servier , Suresnes 92150 , France., Caignard DH; Départament des Sciences Expérimentales , Institut de Recherches Servier , Suresnes 92150 , France., Suvire FD; Facultad de Química, Bioquímica y Farmacia , Universidad Nacional de San Luis-IMIBIO-SL-CONICET , Chacabuco 915 , San Luis , Argentina., Enriz RD; Facultad de Química, Bioquímica y Farmacia , Universidad Nacional de San Luis-IMIBIO-SL-CONICET , Chacabuco 915 , San Luis , Argentina., Piqueras L; Department of Pharmacology , University of Valencia , 46113 Valencia Spain.; Institute of Health Research-INCLIVA , University Clinic Hospital of Valencia , 46010 Valencia , Spain., Figadère B; UMR CNRS 8076, LERMIT , Université Paris-Sud, UFR de Pharmacie , Châtenay-Malabry 92290 , France., Sanz MJ; Department of Pharmacology , University of Valencia , 46113 Valencia Spain.; Institute of Health Research-INCLIVA , University Clinic Hospital of Valencia , 46010 Valencia , Spain., Cabedo N; Department of Pharmacology , University of Valencia , 46113 Valencia Spain.; Institute of Health Research-INCLIVA , University Clinic Hospital of Valencia , 46010 Valencia , Spain., Cortes D; Department of Pharmacology , University of Valencia , 46113 Valencia Spain.
Jazyk:	angličtina
Zdroj:	Journal of natural products [J Nat Prod] 2019 Jul 26; Vol. 82 (7), pp. 1802-1812. Date of Electronic Publication: 2019 Jul 03.
DOI:	10.1021/acs.jnatprod.9b00003
Abstrakt:	Dual peroxisome proliferator-activated receptor-α/γ (PPARα/γ) agonists regulate both lipid and glucose homeostasis under different metabolic conditions and can exert anti-inflammatory activity. We investigated the potential dual PPARα/γ agonism of prenylated benzopyrans polycerasoidol ( 1 ) and polycerasoidin ( 2 ) and their derivatives for novel drug development. Nine semisynthetic derivatives were prepared from the natural polycerasoidol ( 1 ) and polycerasoidin ( 2 ), which were evaluated for PPARα, -γ, -δ and retinoid X receptor-α activity in transactivation assays. Polycerasoidol ( 1 ) exhibited potent dual PPARα/γ agonism and low cytotoxicity. Structure-activity relationship studies revealed that a free phenol group at C-6 and a carboxylic acid at C-9' were key features for dual PPARα/γ agonism activity. Molecular modeling indicated the relevance of these groups for optimal ligand binding to the PPARα and PPARγ domains. In addition, polycerasoidol ( 1 ) exhibited a potent anti-inflammatory effect by inhibiting mononuclear leukocyte adhesion to the dysfunctional endothelium in a concentration-dependent manner via RXRα/PPARγ interactions. Therefore, polycerasoidol ( 1 ) can be considered a hit-to-lead molecule for the further development of novel dual PPARα/γ agonists capable of preventing cardiovascular events associated with metabolic disorders.
Databáze:	MEDLINE
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