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

GARIBOTTO, FRANCISCO; SUVIRE, FERNANDO DANIEL; TOSSO, RODRIGO D.; FUNES, MATÍAS; ENRIZ, RICARDO D.

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

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 and polycerasoidin, 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.