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

BERMEJO, ALMUDENA; COLLADO, AIDA; BARRACHINA, ISABEL; MARQUÉS, PATRICE; EL AOUAD, NOUREDDINE; FRANCK, XAVIER; GARIBOTTO, FRANCISCO; DACQUET, CATHERINE; CAIGNARD, DANIEL H.; SUVIRE, FERNANDO D.; ENRIZ, RICARDO D.; PIQUERAS, LAURA; FIGADÈRE, BRUNO; SANZ, MARÍA-JESÚS; CABEDO, NURIA; CORTES, DIEGO

JOURNAL OF NATURAL PRODUCTS

AMER CHEMICAL SOC

Lugar: Washington; Año: 2019 vol. 82 p. 1802 - 1812

0163-3864

Dual peroxisome proliferator-activated receptor-α/γ(PPARα/γ) agonists regulate both lipid and glucose homeostasisunder different metabolic conditions and can exert anti-inflammatoryactivity. We investigated the potential dual PPARα/γ agonism ofprenylated benzopyrans polycerasoidol (1) and polycerasoidin (2)and their derivatives for novel drug development. Nine semisyntheticderivatives were prepared from the natural polycerasoidol (1) andpolycerasoidin (2), which were evaluated for PPARα, -γ, -δ andretinoid 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 phenolgroup at C-6 and a carboxylic acid at C-9′ were key features for dualPPARα/γ agonism activity. Molecular modeling indicated the relevance of these groups for optimal ligand binding to thePPARα and PPARγ domains. In addition, polycerasoidol (1) exhibited a potent anti-inflammatory effect by inhibitingmononuclear leukocyte adhesion to the dysfunctional endothelium in a concentration-dependent manner via RXRα/PPARγinteractions. Therefore, polycerasoidol (1) can be considered a hit-to-lead molecule for the further development of novel dualPPARα/γ agonists capable of preventing cardiovascular events associated with metabolic disorders.