Synthesis of new glycyrrhetinic acid (GA) derivatives and their effects on tyrosinase activity.
To synthesize glycyrrhetinic acid (GA) derivatives (3, 4, 5, 10, 13, 14, 15, and 16), we first removed the ketonic group in the C-11 position, and the carboxylic function at the C-30 position was kept intact, reduced to an alcohol, or transformed to an aldehyde corresponding derivatives 10 and 13. Glycyrrhetinic acid (GA) derivatives (3, 4, 5, 15, and 16) were coupled with 4-amino piperpyridine derivatives (12 and 14) and 4-fluorobenzyl bromide at C-30 carboxylic acid position of glycyrrhetinic acid. In subsequent tyrosinase assays, we found that GA derivatives 4, 5, and 16 were not active at early time points, but strongly inhibited tyrosinase activity at late time points. Of the GA derivatives examined, derivative 5 was most active, with an IC(50) value of 50 microM after 2 h reaction. IC(50) values of derivatives 4 and 16 were 120 and 170 microM, respectively. Further kinetic data indicated that these derivatives are slow-binding inhibitors of tyrosinase. The time-dependent inhibition was reversed when vitamin C or kojic acid was used, that is, both compounds showed active inhibition at early time points. These results suggest that GA derivatives are much more stable than vitamin C or kojic acid, although their intrinsic inhibitory potentials are relatively low. Higher stability and activity suggest that GA derivative 5 might be a useful candidate for skin whitening.
Um
Soo-Jong
SJ
Department of Bioscience & Biotechnology/Institute of Bioscience, Sejong University, Seoul 143-747, South Korea.
Park
Myoung-Soon
MS
Park
Si-Ho
SH
Han
Hye-Sook
HS
Kwon
Youn-Ja
YJ
Sin
Hong-Sig
HS
D000363:Agaricales / Q000201:enzymology; D001205:Ascorbic Acid / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D007700:Kinetics; D015394:Molecular Structure; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors*; D011753:Pyrones / Q000494:pharmacology
D004791:Enzyme Inhibitors; D011753:Pyrones; C011890:kojic acid; D014442:Monophenol Monooxygenase; D006034:Glycyrrhetinic Acid; D001205:Ascorbic Acid