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2020 , Vol. 40 >Issue 9: 2980 - 2987

DOI: https://doi.org/10.6023/cjoc202005006

研究简报

肉桂酸-香豆素酯类似物的合成及抑制酪氨酸酶活性研究

  • 林芷晴 ,
  • 夏婉铃 ,
  • 刘仁义 ,
  • 姜少华 ,
  • 马志强
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  • a 五邑大学生物科技与大健康学院 广东江门 529000;
    b 华南理工大学化学与化工学院 广州 510641

收稿日期: 2020-05-04

  修回日期: 2020-05-29

  网络出版日期: 2020-06-19

基金资助

广东省教育厅基金（Nos.2017KSYS010，2017KZDXM084，2019KZDZX2003，2019KZDXM035）资助项目.

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Synthesis of Cinnamic Acid-Coumarin Ester Analogs and Inhibition of Tyrosinase Activity

  • Lin Zhiqing ,
  • Xia Wanling ,
  • Liu Renyi ,
  • Jiang Shaohua ,
  • Ma Zhiqiang
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  • a School of Biotechnology and Grand Health, Wuyi University, Jiangmen, Guangdong 529000;
    b School of Chemistry & Chemical Engineering, South China University of Technology, Guangzhou 510641

Received date: 2020-05-04

  Revised date: 2020-05-29

  Online published: 2020-06-19

Supported by

Project supported by the Department of Education of Guangdong Province (Nos. 2017KSYS010, 2017KZDXM084, 2019KZDZX2003, 19KZDXM035).

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摘要

在药物化学中，天然产物结构修饰和骨架杂合策略是拓展骨架生物学活性和寻找高活性先导化合物的重要途径.以取代肉桂酸和羟基香豆素为原料，合成了两个系列的肉桂酸-香豆素酯类似物，并评估了合成化合物对酪氨酸酶的抑制活性.结果表明，肉桂酸-香豆素类似物均有较好的抑制酪氨酸酶活性，其中2-氧代-2H-苯并吡喃-4-基（E）-3-（4-羟基苯基）丙烯酯（C8）和2-氧代-2H-苯并吡喃-7-基（E）-3-（4-羟基苯基）丙烯酯（D8）抑制酪氨酸酶的活性最强，IC50分别为（10.7±0.7）和（2.2±0.2）μmol·L-1，分别是曲酸[IC50：（28.5±1.1）μmol·L-1]的3倍和13倍.构效关系分析结果显示，3个取代基（F，Cl，OH）的引入可显著提高化合物的酪氨酸酶抑制活性，取代肉桂酸与7-羟基香豆素缩合产物的活性高于其与4-羟基香豆素缩合产物.动力学研究表明，化合物C8和D8对酪氨酸酶的抑制是一种可逆、混合型的抑制作用.C8和D8的KI分别为1.07，20.61 μmol·L-1，KIS分别为3.72，27.09 μmol·L-1.最后，采用分子对接模拟了化合物C8和D8与酪氨酸酶的结合情况.

关键词： 酪氨酸酶; 香豆素; 肉桂酸; 分子对接

本文引用格式

林芷晴 , 夏婉铃 , 刘仁义 , 姜少华 , 马志强 . 肉桂酸-香豆素酯类似物的合成及抑制酪氨酸酶活性研究[J]. 有机化学, 2020 , 40(9) : 2980 -2987 . DOI: 10.6023/cjoc202005006

Abstract

In medicinal chemistry, the structural modification of natural product and skeleton hybridization strategies is important way to improve the biological activity of template compound and find highly active lead compounds. In this work, two series of cinnamic acid-coumarin ester analogs were synthesized by using cinnamic acid and hydroxycoumarin as raw materials. And the tyrosinase inhibitory activity of the synthesized compounds was evaluated. The results indicated that the cinnamic acid-coumarin analogs had favourable tyrosinase inhibitory activity, especially 2-oxo-2H-benzopyran-4-yl(E)-3-(4-hydroxyphenyl)propenyl ester (C8), 2-oxo-2H-benzopyran-7-yl(E)-3-(4-hydroxyphenyl)propenyl ester and (D8) with IC50 of (10.7±0.7) and (2.2±0.2) μmol·L-1, respectively, which are 3 and 13 times that of kojic acid (IC50 (28.5±1.1) μmol·L-1). The structure-activity relationship analysis results showed that the introduction of substituents like F, Cl, and OH could efficiently enhance the tyrosinase inhibitory activity, and the inhibitory activity of condensation product of substituted cinnamic acid with 7-hydroxycoumarin was higher than that of substituted cinnamic acid with 4-hydroxycoumarin. Kinetic studies showed that the inhibitions of tyrosinase by compounds C8 and D8 are reversible mixed-type inhibitory effects. KI values of C8 and D8 were 1.07 and 20.61 μmol·L-1, respectively, and KIS values were 3.72 and 27.09 μmol·L-1, respectively. Finally, molecular docking was carried out to simulate the docking between compounds C8 and D8 with tyrosinase.

Key words： tyrosinase; coumarin; cinnamic acid; molecular docking

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