Inhibitors of mammalian melanocyte tyrosinase:: In vitro comparisons of alkyl esters of gentisic acid with other putative inhibitors
Inhibitors of mammalian melanocyte tyrosinase:: In vitro comparisons of alkyl esters of gentisic acid with other putative inhibitors
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DOI：
10.1016/s0006-2952(98)00340-2
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发表时间：
1999-03-15
影响因子：
5.8
通讯作者：
Dooley, TP
中科院分区：
文献类型：
--
作者：
Curto, EV;Kwong, C;Dooley, TP
为了发现安全有效的局部皮肤美白剂，我们已经评估了天然产物龙胆酸（GA）的烷基酯，这与我们的先导化合物龙胆酸甲酯（MG）和四种推定的酪氨酸酶抑制剂有关，利用哺乳动物黑素细胞细胞培养物和无细胞提取物。期望的特征包括抑制细胞中黑素生成的能力（IC 50 < 100 μ g/mL），而没有细胞毒性，优选由于酪氨酸酶抑制。在合成的六种酯中，较小的酯（例如甲基和乙基）是更有效的酶抑制剂（IC 50分别类似于11和20 μ g/mL）。相比之下，氢醌（HQ），一种商业皮肤“漂白”剂，是一种不太有效的酶抑制剂（IC 50类似于72 μ g/mL），在体外浓度大大低于酶抑制的IC 50时，对黑素细胞具有高度细胞毒性。曲酸是哺乳动物酶的有效抑制剂（IC 50类似于6 μ g/mL），但不减少细胞中的色素沉着。熊果苷和抗坏血酸磷酸镁在无细胞和鳗鱼检测中均无效。100 μ g/mL的MG对DHICA氧化酶（TRP-1）表现出最小的抑制作用，对多巴色素互变异构酶（TRP 2）没有影响，表明MG主要通过酪氨酸酶抑制来抑制黑素生成。MG和GA在V79中国仓鼠细胞中的hprt基因座处无致突变性，而Ha具有高度致突变性和细胞毒性。MG的体外性质，包括（1）黑素细胞中的色素沉着抑制，（2）酪氨酸酶抑制和选择性，（3）相对于HQ降低的细胞毒性，和（4）在哺乳动物细胞中的致突变潜力，确立MG作为上级候选美白剂。(C)1999 Elsevier Science Inc.
To discover safe and effective topical skin-lightening agents, we have evaluated alkyl esters of the natural product gentisic acid (GA), which is related to our lead compound methyl gentisate (MG), and four putative tyrosinase inhibitors, utilizing mammalian melanocyte cell cultures and cell-free extracts. Desirable characteristics include the ability to inhibit melanogenesis in cells (IC50 < 100 mu g/mL) without cytotoxicity, preferably due to tyrosinase inhibition. Of the six esters synthesized, the smaller esters (e.g. methyl and ethyl) were more effective enzyme inhibitors (IC50 similar to 11 and 20 mu g/mL, respectively). For comparison, hydroquinone (HQ), a commercial skin "bleaching" agent, was a less effective enzyme inhibitor (IC50 similar to 72 mu g/mL), and was highly cytotoxic to melanocytes in vitro at concentrations substantially lower than the IC50 for enzymatic inhibition. Kojic acid was a potent inhibitor of the mammalian enzyme (IC50 similar to 6 mu g/mL), but did not reduce pigmentation in cells. Both arbutin and magnesium ascorbyl phosphate were ineffective in the cell-free and eel-based assays. MG at 100 mu g/mL exhibited a minimal inhibitory effect on DHICA oxidase (TRP-1) and no effect on DOPAchrome tautomerase (TRP 2), suggesting that MG inhibits melanogenesis primarily via tyrosinase inhibition. MG and GA were non-mutagenic at the hprt locus in V79 Chinese hamster cells, whereas Ha was highly mutagenic and cytotoxic. The properties of MG in vitro, including (1) pigmentation inhibition in melanocytes, (2) tyrosinase inhibition and selectivity, (3) reduced cytotoxicity relative to HQ, and (4) rack of mutagenic potential in mammalian cells, establish MG as a superior candidate skin-lightening agent. (C) 1999 Elsevier Science Inc.