Galangin 3-benzyl-5-methylether derivatives function as an adiponectin synthesis-promoting peroxisome proliferator-activated receptor γ partial agonist

Abstract

The upregulation of adiponectin production has been suggested as a novel strategy for the treatment of metabolic diseases. Galangin, a natural flavonoid, exhibited adiponectin synthesis-promoting activity during adipogenesis in human bone marrow mesenchymal stem cells. In target identification, galangin bound both peroxisome proliferator-activated receptor (PPAR) gamma and estrogen receptor (ER) beta. Novel galangin derivatives were synthesized to improve adiponectin synthesis-promoting compounds by increasing the PPAR gamma activity of galangin and reducing its ER beta activity, because PPAR gamma functions can be inhibited by ER beta. Three galangin 3-benzyl-5-methylether derivatives significantly promoted adiponectin production by 2.88-, 4.47-, and 2.76-fold, respectively, compared to the effect of galangin. The most potent compound, galangin 3-benzyl-5,7-dimethylether, selectively bound to PPAR gamma (Ki, 1.7 mu M), whereas it did not bind to ER beta. Galangin 3-benzyl-5,7-dimethylether was identified as a PPAR gamma partial agonist in docking and pharmacological competition studies, suggesting that it may have diverse therapeutic potential in a variety of metabolic diseases.