摘要/Abstract

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K_I分别为1.07，20.61 μmol·L^-1，K_IS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
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. K_I values of C₈ and D₈ were 1.07 and 20.61 μmol·L^-1, respectively, and K_IS 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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