Synthesis of new glycyrrhetinic acid (GA) derivatives and their effects on tyrosinase activity
Synthesis of new glycyrrhetinic acid (GA) derivatives and their effects on tyrosinase activity
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DOI：
10.1016/j.bmc.2003.09.046
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发表时间：
2003-12-01
影响因子：
3.5
通讯作者：
Sin, HS
中科院分区：
文献类型：
--
作者：
Um, SJ;Park, MS;Sin, HS
为了合成甘草酸（GA）衍生物（3、4、5、10、13、14、15和16），我们首先去除了C-11位的酮基，而C-30位的羧基保持不变，还原为醇，或转化为醛对应的衍生物10和13。甘次酸（GA）衍生物（3、4、5、15和16）在甘次酸的C-30羧酸位置与4-氨基胡椒吡啶衍生物（12和14）和4-氟苯溴偶联。在随后的酪氨酸酶测定中，我们发现GA衍生物4、5和16在早期时间点没有活性，但在后期时间点强烈抑制酪氨酸酶活性。在所检测的GA衍生物中，衍生物5活性最强，反应2 h后IC50值为50 muM。衍生物4和16的IC50值分别为120和170 muM。进一步的动力学数据表明，这些衍生物是酪氨酸酶的慢结合抑制剂。当使用维生素C或曲酸时，时间依赖性的抑制作用被逆转，即两种化合物在早期时间点都表现出活性抑制。这些结果表明，GA衍生物比维生素C或曲酸稳定得多，尽管它们的内在抑制电位相对较低。较高的稳定性和活性表明GA衍生物5可能是皮肤美白的有用候选者。(C) 2003, Elsevier Ltd.出版
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 IC50 value of 50 muM after 2 h reaction. IC50 values of derivatives 4 and 16 were 120 and 170 muM 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. (C) 2003 Published by Elsevier Ltd.