Polycerasoidol, a Natural Prenylated Benzopyran with a Dual PPAR alpha/PPAR gamma Agonist Activity and Anti-inflammatory Effect

摘要

Dual peroxisome proliferator-activated receptor-alpha/gamma (PPAR alpha/gamma) agonists regulate both lipid and glucose homeostasis under different metabolic conditions and can exert anti-inflammatory activity. We investigated the potential dual PPAR alpha/gamma agonism 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 PPAR alpha/gamma, -delta and retinoid X receptor-alpha activity in transactivation assays. Polycerasoidol (1) exhibited potent dual PPAR alpha/gamma 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 PPAR alpha/gamma agonism activity. Molecular modeling indicated the relevance of these groups for optimal ligand binding to the PPAR alpha and PPAR gamma domains. 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 RXR alpha/PPAR gamma interactions. Therefore, polycerasoidol (1) can be considered a hit-to-lead molecule for the further development of novel dual PPAR alpha/gamma agonists capable of preventing cardiovascular events associated with metabolic disorders.