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

GARIBOTTO F; FUNES M; SUVIRE F; ENRIZ R; TOSSO R

San Luis

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

UNSL

Dual peroxisome proliferator-activated receptor-α/γ (PPARα/γ) agonists regulate both lipidand glucose homeostasis under different metabolic conditions and can exert antiinflammatoryactivity. We investigated the potential dual PPARα/γ agonism of prenylatedbenzopyrans polycerasoidol and polycerasoidin and their derivatives for novel drugdevelopment.Nine semisynthetic derivatives were prepared from the natural polycerasoidol andpolycerasoidin, which were evaluated for PPAR α, γ, δ and retinoid X receptor-α activity intransactivation assays. Polycerasoidol exhibited potent dual PPARα/γ agonism and lowcytotoxicity. 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/γ agonism activity.Molecular modeling indicated the relevance of these groups for optimal ligand binding tothe PPARα and PPARγ domains. In addition, polycerasoidol exhibited a potent antiinflammatoryeffect by inhibiting mononuclear leukocyte adhesion to the dysfunctionalendothelium in a concentration-dependent manner via RXRα/PPARγ interactions.Therefore, polycerasoidol can be considered a hit-to-lead molecule for the furtherdevelopment of novel dual PPARα/γ agonists capable of preventing cardiovascular eventsassociated with metabolic disorders.