摘要
目的设计合成积雪草酸衍生物并检测其体外抗肿瘤活性。方法采用计算机辅助药物设计的方法设计并筛选目标化合物的结构;以天然产物积雪草酸为起始原料,对其C-2、C-3、C-23位羟基以及C-28位羧基进行结构改造;采用MTT法测试目标化合物对人肝癌细胞(HepG2)和人肺癌细胞(A549)的体外抗肿瘤活性。结果目标化合物对这两种细胞株的抑制活性均优于母体积雪草酸,其中化合物Ⅰ_8和Ⅱ_2表现出较强的抗肿瘤活性,且分子对接模拟也显示化合物Ⅰ_8和Ⅱ_2与Survivin蛋白的结合力较强。结论经结构改造后的积雪草酸衍生物具有一定的抗肿瘤活性,值得进一步研究。
Survivin protein is a member of the apoptotic protein family and is considered to be an important target for antitumor therapy today because it can be specifically expressed in tumor cells.How ever,only few Survivin protein inhibitors have been developed,and the pentacyclic triterpenoids w ith ursolic skeleton,asiatic acid,can promote cell apoptosis by activating Caspase-3,Caspase-9 to inhibit the expression of Survivin protein.In this paper,ten novel compounds w ith better binding ability w ere screened by simulating the interaction of compounds w ith Survivin protein by the techniques of computer-aided drug design.The C-2,C-3,C-23,and C-28 positions of asiatic acid w ere modified by chemical synthesis to obtain ten target compounds,and the structures w ere confirmed by M S and~1H-NM R.Then the antitumor activity of the target compounds w ere tested in vitro.The results show ed that all of the target compounds w ere superior to asiatic acid.CompoundsⅠ_8andⅡ_2had strong antitumor activity similar to the docking simulation.In general,the virtual molecular docking and reasonable modification of asiatic acid have guiding significance for the next step of structural design and optimization,and lay a good foundation for the future research and development of antitumor drugs.■
引文
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