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

The natural flavonoid macakurzin C () 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-activated receptor (PPAR) modulator affecting all three PPAR subtypes α, γ, and δ. In this study, increases in adiponectin biosynthesis-inducing activity by macakurzin C derivatives () were studied. The most potent adiponectin biosynthesis-inducing compound , macakurzin C 3,5-dimethylether, was elucidated as a dual PPARα/γ modulator. Compound may exhibit the most potent activity because of the antagonistic relationship between PPARδ and PPARγ. Docking studies revealed that the -methylation of macakurzin C to generate compound significantly disrupted PPARδ binding. Compound has therapeutic potential in hypoadiponectinemia-related metabolic diseases.