基于Survivin靶点的齐墩果酸类似物合成及生物活性研究

Synthesis and Biological Evaluation of Oleanolic Acid Analogs Based on Survivin Target

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。

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 ceils were used to screen the antitumor activity in vitro through the standard MTY method. RESULTS Ten new oleanolic acid derivatives were designed and synthesized, and their structures were confirmed by MS and NMR. The compounds Ⅰ 5 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.