Komori Yu, Imai Masahiko, Yamauchi Takayasu, Higashiyama Kimio, Takahashi Noriko
Laboratory of Physiological Chemistry, Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan.
Synthetic Organic Chemistry Research Laboratory, Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan.
Bioorg Med Chem. 2014 Aug 1;22(15):3994-4000. doi: 10.1016/j.bmc.2014.05.073. Epub 2014 Jun 11.
Tyrosinase is involved in the synthesis of melanin in the skin and hair as well as neuromelanin in the brain. This rate limiting enzyme catalyzes two critical steps (reactions) in melanogenesis; the hydroxylation of tyrosine to form DOPA and the subsequent oxidation of DOPA into dopaquinone. Several new aminophenol derivatives have been synthesized based on structure-activity relationship studies of N-(4-hydroxyphenyl)retinamide (1), a derivative of retinoic acid. In order to find new tyrosinase inhibitors, we investigated the effects of these p-aminophenols, including p-decylaminophenol (3), on the activity of mushroom tyrosinase. Compound 3 was the most potent agent, showing significant inhibition as compared with control. The inhibitory effects of 3 on tyrosinase activities were greater than seen with kojic acid, a well-known potent inhibitor of tyrosinase activity, which also causes adverse effects, including rash and dermatitis. A Lineweaver-Burk kinetic analysis of inhibition showed that 3 suppresses tyrosinase activity in a non-competitive fashion for both substrates, tyrosine and DOPA. These results suggest that 3 might be a useful alternative to kojic acid as a tyrosinase inhibitor.
酪氨酸酶参与皮肤和毛发中黑色素以及大脑中神经黑色素的合成。这种限速酶催化黑色素生成过程中的两个关键步骤（反应）：酪氨酸羟基化形成多巴以及随后多巴氧化为多巴醌。基于视黄酸衍生物N-(4-羟基苯基)视黄酰胺（1）的构效关系研究，已经合成了几种新的氨基酚衍生物。为了寻找新的酪氨酸酶抑制剂，我们研究了这些对氨基酚，包括对癸基氨基酚（3）对蘑菇酪氨酸酶活性的影响。化合物3是最有效的试剂，与对照相比显示出显著的抑制作用。3对酪氨酸酶活性的抑制作用大于曲酸（一种著名的酪氨酸酶活性强效抑制剂，也会引起包括皮疹和皮炎在内的不良反应）。抑制作用的Lineweaver-Burk动力学分析表明，3以非竞争性方式抑制酪氨酸酶对酪氨酸和多巴这两种底物的活性。这些结果表明，3可能是一种有用的替代曲酸的酪氨酸酶抑制剂。
