Repositioning of Thiourea-Containing Drugs as Tyrosinase Inhibitors.
Repositioning of Thiourea-Containing Drugs as Tyrosinase Inhibitors.
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DOI：
10.3390/ijms161226114
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发表时间：
2015-12-02
影响因子：
5.6
通讯作者：
Jee JG
中科院分区：
文献类型：
--
作者：
Choi J;Jee JG
酪氨酸酶催化黑色素生物合成中两个不同的连续反应：酪氨酸羟基化为二羟基苯丙氨酸（DOPA）和DOPA氧化为多巴醌。开发酪氨酸酶的功能性调节剂对于治疗和美容目的是重要的。鉴于已知酪氨酸酶抑制剂中硫脲部分的丰富性，我们研究了其他含硫脲的药物作为潜在的酪氨酸酶抑制剂。检索了临床使用的含硫脲类药物，并对其抑制酪氨酸酶的能力进行了测试。我们观察到，甲巯咪唑，硫氧嘧啶，甲基硫氧嘧啶，丙基硫氧嘧啶，安巴松，和thioacetazone抑制蘑菇酪氨酸酶。除甲巯咪唑外，关于其他药物对酪氨酸酶的活性的信息有限。硫代乙酰腙和ambazone均显著抑制酪氨酸酶，IC 50分别为14和15 μM。在B16 F10细胞中，20 μM的Ambazone可降低黑色素含量，但不引起细胞毒性。无论是酶活性还是黑色素含量测定，安巴松的活性均强于曲酸。酶抑制动力学表明，硫脲类药物为非竞争性抑制剂。通过对接模拟的复杂模型表明，分子间的氢键通过硫脲的氮和接触，通过双硫键的酪氨酸酶是同样重要的相互作用。这些数据与硫脲类似物的酶测定结果一致。
Tyrosinase catalyzes two distinct sequential reactions in melanin biosynthesis: The hydroxylation of tyrosine to dihydroxyphenylalanine (DOPA) and the oxidation of DOPA to dopaquinone. Developing functional modulators of tyrosinase is important for therapeutic and cosmetic purposes. Given the abundance of thiourea moiety in known tyrosinase inhibitors, we studied other thiourea-containing drugs as potential tyrosinase inhibitors. The thiourea-containing drugs in clinical use were retrieved and tested for their ability to inhibit tyrosinase. We observed that methimazole, thiouracil, methylthiouracil, propylthiouracil, ambazone, and thioacetazone inhibited mushroom tyrosinase. Except for methimazole, there was limited information regarding the activity of other drugs against tyrosinase. Both thioacetazone and ambazone significantly inhibited tyrosinase, with IC50 of 14 and 15 μM, respectively. Ambazone decreased melanin content without causing cellular toxicity at 20 μM in B16F10 cells. The activity of ambazone was stronger than that of kojic acid both in enzyme and melanin content assays. Kinetics of enzyme inhibition assigned the thiourea-containg drugs as non-competitive inhibitors. The complex models by docking simulation suggested that the intermolecular hydrogen bond via the nitrogen of thiourea and the contacts via thione were equally important for interacting with tyrosinase. These data were consistent with the results of enzyme assays with the analogues of thiourea.