1,4二羰基类化合物的合成及其抗肿瘤活性研究

目的：：寻找新型靶向抗肿瘤小分子。方法：通过高通量筛选得到先导物,合成其衍生物,采用MTT法对衍生物的体外抗肿瘤活性进行测试,并通过细胞周期实验、体外抗 HCT116细胞(p53-/-)活性实验以及免疫共沉淀实验探索其可能的抗肿瘤作用机制。结果：化合物9对 HCT116细胞抑制活性达到9.382μM、化合物1对MCF7细胞抑制活性达到3.636μM、化合物7与化合物10对 HepG2细胞的抑制活性分别为6.677μM和8.746μM,均优于阳性药 Nutlin-3a 与5-Fuorouracil。并推测出衍生物抗肿瘤作用机制为 p 53-MDM2相互作用。结论：1,4二羰基化合物具有良好的体外抗肿瘤活性,其作用机制为p 53-MDM2相互作用。

Synthesis and Biological Evaluation of 1,4-dicarbonyl Compounds as Antitumour Agents

Obj ective:To find new type of small molecules targeting antineoplastic.Methods:Leads were obtained by a high-throughput screening.The synthesized compounds were examined for their antiproliferative activities using the MTT assay.We further analyzed the antitumour mechanisms of compounds using a series of biological experiments.Results:The IC50 value of compound 9 against HCT116 cells was 9.382μM,the IC50 value of compound 1 against MCF7 cells was 3.636μM,and the IC50 values of compounds 7 and 10 against HepG2 cells were 6.677μM and 8.746μM.These results indicate that the mechanism of action for these compounds likely occurs via an inhibition of p53-MDM2 binding.Conclusion:1,4-dicarbonyl compounds showed significantly growth-inhibitory activity against antitumor activity in vitro and a preliminary mechanistic study suggested that these compounds inhibit p53-MDM2 binding.