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

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

JOURNAL OF NATURAL PRODUCTS

AMER CHEMICAL SOC

Año: 2019 vol. 82 p. 1802 - 1812

0163-3864

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/γagonism 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, -δand retinoid X receptor-α activity in transactivation assays. Polycerasoidol (1) exhibited potent dual PPARα/γagonism 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/γagonism activity. Molecular modeling indicated the relevance of these groups for optimal ligand binding to the PPARα and PPARγdomains. 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/PPARγinteractions. Therefore, polycerasoidol (1) can be considered a hit-to-lead molecule for the further development of novel dual PPARα/γagonists capable of preventing cardiovascular events associated with metabolic disorders.