含异羟肟酸喹唑啉类非可逆EGFR/HDAC双靶点抑制剂的合成及抗肿瘤活性研究  

Synthesis and antiproliferative activity evaluation of quinazoline derivatives containing hydroxamic acid as dual irriversible EGFR/HDAC inhibitors

作　　者：黄卫 陈文腾 邵加安 俞永平 HUANG Wei;CHEN Wen-teng;SHAO Jia-an;YU Yong-ping(Zhejiang Province Key Laboratory of Anti-Cancer Drug Research,College of Pharmaceutical Science,Zhejiang University,Hangzhou 310058,China)

机构地区：[1]浙江大学药学院浙江省抗肿瘤重点实验室,浙江杭州310058

出　　处：《中国药物化学杂志》2021年第1期1-7,共7页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金项目(81273356,2013-2016)。

摘　　要：目的设计、合成含异羟肟酸片段的4-芳氨基喹唑啉类衍生物,评价其体外抗肿瘤活性。方法以4-芳氨基-6-硝基-7-羟基喹唑啉为起始原料,经取代、还原、酰化、还原、缩合及脱保护6步反应得到目标化合物,采用MTT法测定目标化合物对人表皮癌细胞系A431、人肺腺癌细胞系H1975、人宫颈癌细胞系HeLa和人肝癌细胞系HepG2的增殖抑制活性。结果合成了12个未见报道的新化合物,其结构均经1H-NMR和HRMS谱确证;初步生物活性测试结果表明,该系列化合物具有良好的抗肿瘤细胞增殖活性,其中化合物5的活性优于吉非替尼,接近阿法替尼和SAHA。结论本研究设计的EGFR/HDAC双靶点抑制剂对进一步优化设计喹唑啉类EGFR多靶点抑制剂具有参考价值。Drug resistance occurred in some patients after they received the treatment of the first generation of EGFR inhibitors.To some extent,the second generation of EGFR inhibitors alleviated the problem.M eanw hile,HDAC inhibitors could be incorporated into other antitumor molecules to play a synergistic role and overcome the drug resistance of other antitumor drugs.Through combination principles,key motif of HDAC inhibitors w ere fused to the irreversible EGFR inhibitors to build EGFR/HDAC dual inhibitors.Tw elve compounds w ere synthesized and characterized by1H-NM R,HRM S and melting point.The antiproliferative activity of the 12 compounds w ere tested in vitro through M TT method.The results show ed that some compounds show ed good antiproliferative activities on tumor cell lines A431,H1975,He La and Hep G2.Among them,the activity of compound 5 w as relatively better.

关 键 词：EGFR酪氨酸激酶抑制剂 HDAC抑制剂 4-芳氨基喹唑啉 异羟肟酸 多靶标 抗肿瘤 

分 类 号：R914[医药卫生—药物化学]