Molecular Inflammation Research Centre for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Kumjeong-Gu, Busan 609-735, Republic of Korea.
Bioorg Med Chem Lett. 2013 Jul 15;23(14):4172-6. doi: 10.1016/j.bmcl.2013.05.029. Epub 2013 May 18.
In this study, we have synthesized and studied de novo tyrosinase inhibitor, MHY1556, which showed significantly better efficacy than other pre-existing tyrosinase inhibitors in vitro experiments. The IC50 value of MHY1556 was 0.50μM which was significantly lower than that of kojic acid (IC50=53.95μM), which is a well-known tyrosinase inhibitor and was used as a positive control in this study. We predicted the tertiary structure of tyrosinase, simulated the docking with compound MHY1556 and confirmed that the compound strongly interacts with mushroom tyrosinase residues. Substitutions with a hydroxy group at both R1 and R3 of the phenyl ring indicated that these groups play a major role in the high binding affinity to tyrosinase, especially through the hydrogen bonding interaction of the hydroxyl group at R1 with GLY281. In addition, MHY1556 showed concentration-dependent inhibitory effects in melanin content assay where B16F10 melanoma cells were treated with α-melanocyte stimulating hormone (α-MSH), and also there is no significant cytotoxicity of this compound in cell viability assay conducted in B16F10 melanoma cells. The tyrosinase activity assay results with MHY1556 also support its potent inhibitory effects. Therefore, our data strongly suggest MHY1556 suppresses the melanogenesis via a tyrosinase inhibitory effect.
在这项研究中，我们合成并研究了新型酪氨酸酶抑制剂 MHY1556，它在体外实验中表现出比其他现有的酪氨酸酶抑制剂更好的效果。MHY1556 的 IC50 值为 0.50μM，明显低于作为阳性对照的曲酸（IC50=53.95μM）。我们预测了酪氨酸酶的三级结构，模拟了与化合物 MHY1556 的对接，并证实该化合物与蘑菇酪氨酸酶残基强烈相互作用。苯环的 R1 和 R3 上都带有羟基取代基表明这些基团在与酪氨酸酶的高结合亲和力中起主要作用，特别是通过 R1 上的羟基与 GLY281 的氢键相互作用。此外，MHY1556 在 B16F10 黑素瘤细胞用 α-促黑素细胞激素（α-MSH）处理的黑色素含量测定中表现出浓度依赖性抑制作用，并且在 B16F10 黑素瘤细胞中进行的细胞活力测定中该化合物也没有明显的细胞毒性。MHY1556 的酪氨酸酶活性测定结果也支持其强效的抑制作用。因此，我们的数据强烈表明 MHY1556 通过抑制酪氨酸酶来抑制黑色素生成。
