Macakurzin C Derivatives as a Novel Pharmacophore for Pan-Peroxisome Proliferator-Activated Receptor Modulator

Abstract

The natural flavonoid macakurzin C (1) exhibited adiponectin biosynthesis-inducing activity during adipogenesis in human bone marrow mesenchymal stem cells and its molecular mechanism was directly associated with a pan-peroxisome proliferator-activat-ed receptor (PPAR) modulator affecting all three PPAR subtypes a, ?, and 6. In this study, increases in adiponectin biosynthesis -inducing activity by macakurzin C derivatives (2-7) were studied. The most potent adiponectin biosynthesis-inducing compound 6, macakurzin C 3,5-dimethylether, was elucidated as a dual PPARa/? modulator. Compound 6 may exhibit the most potent activity because of the antagonistic relationship between PPAR6 and PPAR?. Docking studies revealed that the O-methylation of macakurzin C to generate compound 6 significantly disrupted PPAR6 binding. Compound 6 has therapeutic potential in hypoadi-ponectinemia-related metabolic diseases.