目的 设计并合成一系列基于Survivin靶点,具有抗肿瘤活性的齐墩果酸类似物。方法 采用计算机药物辅助设计,在Survivin与已知活性小分子进行模拟对接的基础上,解析靶蛋白发挥活性作用的关键氨基酸残基片段,确定能够和关键位点结合的活性基团,并以天然产物齐墩果酸为母体,在其A环上创新性的引入活性基团,同时对其C-28位羧基进行酰胺化结构修饰。采用四甲基偶氮唑蓝(MTT)法,选用SGC-7901和A549细胞进行了初步的体外抗肿瘤活性筛选。结果 合成了10个新的齐墩果酸类似物,结构经MS、NMR表征;活性测试表明化合物Ⅰ5、Ⅱ5与阳性对照药物相比表现出更强的抑制作用。结论 新合成的齐墩果酸类似物抗肿瘤活性明显优于母体,值得进一步研究。
Abstract
OBJECTIVE To design and synthesize a series of oleanolic acid analogs posessing anti-tumor activity based on survivin target. METHODS Using the techniques of computer-aided drug design, the docking of Survivin and known active small molecules was simulated and then the key amino acid residue fragment of the target protein was analyzed. It led to the discovery of active groups capable of binding to the critical sites. Through using the natural product, oleanolic acid, as a lead compound, the active groups were introduced onto its A-ring, and the carboxyl group at the C-28 position was modified using amidation. SGC-7901 and A549 cells were used to screen the antitumor activity in vitro through the standard MTT method. RESULTS Ten new oleanolic acid derivatives were designed and synthesized,and their structures were confirmed by MS and NMR. The compounds Ⅰ5 and Ⅱ5 exhibited more potent cytotoxicity than the positive control drugs. CONCLUSION The novel oleanolic acid analogues have better antitumor activity than the parent compound, which are worthy of further study.
关键词
齐墩果酸类似物 /
Survivin靶点合成 /
抗肿瘤活性 /
计算机辅助设计
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Key words
oleanolic acid derivatives /
Survivin target synthesis /
anti-tumor activity /
computer-aided drug design
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中图分类号：
R914
R965
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参考文献
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基金
国家自然科学基金项目项目资助(21372156); 辽宁省自然科学基金资助(201605288); 沈阳市科学技术计划项目资助(F-16-230-6-00)
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