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

GARIBOTTO, FRANCISCO M.; SUVIRE, FERNANDO D.; TOSSO, RODRIGO; FUNES, MATIAS; ENRIZ, RICARDO D.

San Luis

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

Universidad Nacional de San Luis

Dual peroxisome proliferator-activated receptor-α/γ (PPARα/γ) agonists regulate both lipid and glucose homeostasis under different metabolic conditions and can exert antiinflammatory activity. We investigated the potential dual PPARα/γ agonism of prenylated benzopyrans polycerasoidol and polycerasoidin and their derivatives for novel drug development.Nine semisynthetic derivatives were prepared from the natural polycerasoidol andpolycerasoidin, which were evaluated for PPAR α, γ, δ and retinoid X receptor-α activity in transactivation assays. Polycerasoidol 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 exhibited a potent antiinflammatory effect by Inhibiting mononuclear leukocyte adhesion to the dysfunctional endothelium in a concentration-dependent manner via RXRα/PPARγ interactions. Therefore, polycerasoidol 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.