新型4,8-二取代-8,9-二氢吡嗪[2,3-g]喹唑啉-7(6H)-酮化合物合成及抗肿瘤细胞增殖构效关系研究  

4,8-Disubstituted-8,9-dihydro-pyrazine[2,3-g]quinazoline-7(6H)-ketones:A novel class of antitumor agents

作　　者：叶子奇[1] 丁文波[2] 陈哲[1] 章砚东[2] 俞永平[2] 楼宜嘉[1] 

机构地区：[1]浙江大学药学院药理毒理与生化药学研究所,浙江杭州310058 [2]浙江大学药学院药物研究所,浙江杭州310058

出　　处：《浙江大学学报（医学版）》2010年第1期49-56,共8页Journal of Zhejiang University(Medical Sciences)

基　　金：国家自然科学基金(№30772652;№30672564)

摘　　要：目的:评价新型4,8-二取代-8,9-二氢吡嗪[2,3-g]喹唑啉-7(6H)-酮系列化合物体外抗肿瘤活性,获得高效抗肿瘤小分子化合物用于后续药物研发。方法:固相合成17个设计作用于表皮细胞生长因子受体(epidermal growth factor receptor,EGFR),结构为4,8-二取代-8,9-二氢吡嗪[2,3-g]喹唑啉-7(6H)-酮的新型系列化合物。采用MTT法对人肺癌细胞株A549、人慢性髓细胞性白血病细胞株K562及人胃癌细胞株SGC7901加药96 h后进行抗肿瘤活性筛选。结果:对于人肺癌细胞株A549,化合物7-13和7-14抑制效果最佳,其IC50值分别为8.10和8.12μmol/L。共有8个化合物对人慢性髓细胞性白血病细胞株K562有抑制作用,其中化合物7-2、7-13和7-17抑制效果最佳,其IC50值分别为2.22、0.57和7.20μmol/L。而对于人胃癌细胞株SGC7901,化合物7-3和7-13具有抑制效果,其IC50值分别为4.20和9.71μmol/L。结论:17个化合物对3种肿瘤细胞株呈现不同抑制效果,为结构修饰以提高化合物抗肿瘤活性提供了很好的依据。其中化合物7-13对所测瘤株均具增殖抑制活性,可作为潜在药物用于后续抗肿瘤药物研发。Objective： To evaluate the antitumor activity of a novel class of 4,8-Disubstituted-8,9-dihydropyrazine[2,3-g]quinazoline-7（6H）-ketones in vitro,and to screen potential anticancer compounds for further study.Methods： Seventeen compounds of 4,8-Disubstituted-8,9-dihydropyrazine[2,3-g]quinazoline-7（6H）-ketones were synthesized with solid-phase method for biological evaluation of EGFR tyrosine kinase.MTT method was used to evaluate the cytotoxic activity in vitro against three human cancer cell lines（human lung carcinoma cell line A549,human leukemia cell lines K562 and human gastric carcinoma cell line SGC7901）.Results： Compound 7-13 and 7-14 showed potent antitumor activities against A549 cells,with IC50 values of 8.10 and 8.12 mol/L,respectively.Eight compounds showed proliferative inhibition effect on K562 cells,especially 7-2,7-13 and 7-17,with IC50 values of 2.22,0.57 and 7.20 mol/L,respectively.And compound 7-13 and 7-3 showed potent antitumor activity against SGC7901 cells,with IC50 values of 4.20 and 9.71 mol/L,respectively.Conclusion： The synthesized compounds 4,8-Disubstituted-8,9-dihydropyrazine[2,3-g] quinazoline-7（6H）-ketones show inhibition effects on human cancer cell lines in vitro.Compound 7-13 has anticancer activity in all three cancer cell lines,which might be used as a potential antitumor drug for further study.

关 键 词：受体 表皮生长因子 拮抗剂 抑制剂 抗肿瘤药 治疗应用 喹唑啉类 细胞系 肿瘤 药物作用 

分 类 号：R73-3[医药卫生—肿瘤]