Molecular Inflammation Research Center for Aging Intervention, College of Pharmacy, Pusan National University, Kumjeong-Gu, Busan 609-735, Republic of Korea.
Biochimie. 2012 Feb;94(2):533-40. doi: 10.1016/j.biochi.2011.09.002. Epub 2011 Sep 17.
Herein we describe the design, synthesis and biological activities of 2-(substituted phenyl)thiazolidine-4-carboxylic acid derivatives as novel tyrosinase inhibitors. The target compounds 2a-2j were designed and synthesized from the structural characteristics of N-phenylthiourea, tyrosinase inhibitor and tyrosine, and l-DOPA, the natural substrates of tyrosinase. Among them, (2R/S,4R)-2-(2,4-dimethoxyphenyl)thiazolidine-4-carboxylic acid (2g) caused the greatest inhibition 66.47% at 20 μM of l-DOPA oxidase activity of mushroom tyrosinase. Kinetic analysis of tyrosinase inhibition revealed that 2g is a competitive inhibitor. We predicted the tertiary structure of tyrosinase, and simulated the docking of mushroom tyrosinase with 2g. These results suggest that the binding affinity of 2g with tyrosinase is high. Also, 2g effectively inhibited tyrosinase activity and reduced melanin levels in B16 cells treated with α-MSH. These data strongly suggest that 2g can suppress the production of melanin via the inhibition of tyrosinase activity.
在此，我们描述了 2-(取代苯基)噻唑烷-4-羧酸衍生物作为新型酪氨酸酶抑制剂的设计、合成和生物活性。目标化合物 2a-2j 是根据 N-苯硫脲、酪氨酸酶抑制剂和酪氨酸以及酪氨酸酶的天然底物 l-DOPA 的结构特征设计和合成的。其中，（2R/S，4R）-2-（2,4-二甲氧基苯基）噻唑烷-4-羧酸（2g）在 20 μM l-DOPA 氧化酶活性下对蘑菇酪氨酸酶的抑制作用最大，为 66.47%。酪氨酸酶抑制的动力学分析表明，2g 是一种竞争性抑制剂。我们预测了酪氨酸酶的三级结构，并模拟了蘑菇酪氨酸酶与 2g 的对接。这些结果表明，2g 与酪氨酸酶的结合亲和力很高。此外，2g 还能有效抑制α-MSH 处理的 B16 细胞中的酪氨酸酶活性，降低黑色素含量。这些数据强烈表明，2g 可以通过抑制酪氨酸酶活性来抑制黑色素的生成。
