新型PI3K抑制剂邻苯二甲酰亚胺及其衍生物的设计合成与抗肿瘤活性

目的设计合成新的磷脂酰肌醇3-激酶抑制剂,并测定其体外活性。方法通过结构替换、分子对接技术设计一系列邻苯二甲酰亚胺类化合物。以4-溴邻苯二甲酸酐为原料经胺解反应得到N-芳基-4-溴邻苯二甲酰亚胺Ⅰ1～Ⅰ8;Ⅰ1～Ⅰ8再与3-(4-氟苯磺酰胺基)苯硼酸经Suzuki偶联得到N-芳基-4-(3-对氟苯磺酰胺苯基)邻苯二甲酰亚胺Ⅲ1～Ⅲ8;以阿霉素为阳性对照,采用MTT法进行体外活性测定。结果与结论合成了16个未见文献报道的邻苯二甲酰亚胺类化合物,目标化合物的结构经1H-NMR、MS谱确证;体外活性实验结果显示,N-芳基-4-(3-对氟苯磺酰胺苯基)邻苯二甲酰亚胺衍生物具有潜在的抑制肿瘤生长作用,其中,化合物Ⅲ1对A549、MCF-7肿瘤细胞表现出显著的抑制活性,具有进一步研究的价值。

Design, synthesis and evaluation of antiproliferative activity of isoindoline-1,3-dione derivatives as novel PI3K inhibitors

Different methods, such as structure replacement and docking have been contributed to design six- teen isoindoline-1,3-dione derivatives,which have potential anticancer activities as PI3K inhibitors. The tar- get compounds were prepared through a 1-step or 2-step reaction. In addition all structures of the target com- pounds were verified by 1H-NMR and MS, and the results of anticancer activity based on MTT assay dis- played that the compounds had obvious anticancer effect on different cell lines. The IC50 values of compound Ⅲ1 on A549,MCF-7,PC-3 were 12.90 μg·mL^-1 ,2.90 μg·mL^-1 ,15.60 μg·mL^-1,respectively and those of compound Ⅰ2 on A549 ,HEPG2 ,U87 were 15.75μg·mL^-1, 18.74μg·mL^-1,16.94μg·mL^-1 ,respec- tively. All results showed that isoindoline-1,3-dione structure may be a potential scaffold for further study.