Polycerasoidol, a natural prenylated benzopyran with a dual PPARα/PPAR agonist activity and anti-inflammatory effect

FRANCISCO GARIBOTTO; F.D.SUVIRE; MATIAS FUNES; ENRIZ, RICARDO D.

San Luis

Congreso; XLVIII Reunión Anual de la Sociedad Argentina de Biofísica,; 2019

Sociedad Argentina de Biofísica-UNSL

Dual peroxisome proliferator-activated receptor-α/g (PPARα/γ) agonists regulate bothlipid and glucose homeostasis under different metabolic conditions and canexert anti-inflammatory activity. We investigated the potential dual PPARα/g agonism of prenylated benzopyranspolycerasoidol (1) and polycerasoidin (2) and their derivatives for novel drugdevelopment. Nine semisynthetic derivatives were preparedfrom the natural polycerasoidol and polycerasoidin, which were evaluated for PPARα, g, δ and retinoid X receptor-αactivity in transactivation assays. Polycerasoidol exhibited potent dual PPARα/g agonism and low cytotoxicity.Structure-activity relationship studies revealed that a free phenol group atC-6 and a carboxylic acid at C-9? were key features for dual PPARα/g agonism activity. Molecularmodeling indicated the relevance of these groups for optimal ligand binding tothe PPARα and PPARg domains. Inaddition, polycerasoidol exhibited a potent anti-inflammatory effect by inhibitingmononuclear leukocyte adhesion to the dysfunctional endothelium in aconcentration-dependent manner via RXRα/PPARγ interactions. Therefore,polycerasoidol can be considered a hit-to-lead molecule for the further developmentof novel dual PPARα/g agonists capable of preventing cardiovascular events associated withmetabolic disorders.