Methoxylated Chrysin and Quercetin as Potent Stimulators of Melanogenesis.

Polymethoxyflavonoids (PMFs) from plants are known to exhibit melanogenic activity. Very little is known about their structure-activity relationships, and this was the aim of this study. Several series of alkoxy flavonoids were synthesized via semisynthetic and total synthetic pathways. Their structures were identified by NMR analyses, followed by evaluating their potency on the stimulation of melanogenesis using mouse B16F10 and human MNT-1 cells. Among more than twenty methoxylated flavonoids, 5,7-dimethoxychrysin (dimethoxylated chrysin, ) and 3,3',4',5,7-pentamethoxyquercetin (pentamethoxylated quercetin, ) appeared to be the most active melanogenic-stimulating compounds in a dose-dependent manner. Both compounds showed no effect on cell viability as determined by MTT assay. The structure-activity relationship study of PMFs revealed that the -OCH substituent at 5 and 7 positions of A-ring are the most important as melanogenic-stimulating part (e.g., 5,7-dimethoxychrysin, ) followed by at 3' and 4' positions of B-ring, and at 3 positions of C-ring (e.g., 3,3',4',5,7-pentamethoxyquercetin, ), Therefore, both natural methoxylated flavonoid derivatives of chrysin and quercetin have a potential to be developed further as melanogenic stimulators.