Prenylated Chrysin Derivatives as Partial PPAR Agonists with Adiponectin Secretion-Inducing Activity

Decreased circulating adiponectin levels are associated with an increased risk of human metabolic diseases. The chemical-mediated upregulation of adiponectin biosynthesis has been proposed as a novel therapeutic approach to managing hypoadiponectinemia-associated diseases. In preliminary screening, the natural flavonoid chrysin (1) exhibited adiponectin secretion inducing activity during adipogenesis in human bone marrow mesenchymal stem cells (hBM-MSCs). Here, we provide the 7prenylated chrysin derivatives, chrysin 5-benzyl-7-prenylether compound 10 and chrysin 5,7-diprenylether compound 11, with the improved pharmacological profile compared with chrysin (1). Nuclear receptor binding and ligand-induced coactivator recruitment assays revealed that compounds 10 and 11 functioned as peroxisome proliferator-activated receptor (PPAR)gamma partial agonists. These findings were supported by molecular docking simulation, followed by experimental validation. Notably, compound 11 showed PPAR gamma binding affinity as potent as that of the PPAR gamma agonists pioglitazone and telmisartan. This study presents a novel PPAR gamma partial agonist pharmacophore and suggests that prenylated chrysin derivatives have therapeutic potential in various human diseases associated with hypoadiponectinemia.