伊马替尼哌嗪环的结构优化及抗肿瘤活性研究  

Optimization and antitumor activity of imatinib N-methylpiperazine ring

作　　者：王秀军 夏丹丹 徐州 潘港 冯静 张振 刘钢 吉敬 WANG Xiujun;XIA Dandan;XU Zhou;PAN Gang;FENG Jing;ZHANG Zhen;LIU Gang;JI Jing(School of Pharmacy,Jiangsu Ocean University,Lianyungang 222005,China)

机构地区：[1]江苏海洋大学药学院,江苏连云港222005

出　　处：《沈阳药科大学学报》2022年第5期529-535,597,共8页Journal of Shenyang Pharmaceutical University

基　　金：江苏省特聘教授计划资助项目(No.KK19515);江苏海洋大学校级课题资助项目(No.KQ20014)。

摘　　要：目的设计、合成一系列2-苯氨基嘧啶类酪氨酸激酶抑制剂,进行体外抗肿瘤活性的研究。方法以伊马替尼为先导化合物,对其疏水区域的N-甲基哌嗪侧链进行结构改造。用2-溴-4-硝基甲苯和4-(3-吡啶基)-2-氨基嘧啶为起始原料,经偶联、还原、缩合、取代4步反应得到目标化合物,采用MTT法测定目标化合物对人乳腺癌细胞系(MDA-MB-231和MCF-7)、人宫颈癌细胞系(Hela)和人肾癌细胞系(A498)的增殖抑制活性。结果合成了11个新型伊马替尼衍生物,其结构经;H-NMR、;C-NMR和HR-MS谱确证;其中化合物7b、7d、7e、7f、7g、7h、7i和7j具有良好的抑制活性。结论初步测试结果显示目标化合物7h对MDA-MB-231、MCF-7、HeLa、A498细胞株均具有显著的抗肿瘤作用,值得进一步深入研究。Objective To synthesize a series of 2-phenylaminopyrimidine tyrosine kinase inhibitors and to evaluate their proliferation inhibition.Methods Taking imatinib as the lead compound,the target compounds were designed by modifying its hydrophobic group on N-methylpiperazine.With 2-bromo-4-nitrotoluene and 4-(pyridin-3-yl)pyrimidin-2-amine as starting materials,target compounds were prepared via four steps reaction involving coupling,reduction,condensation and substitution,and the antitumor activity of the target compounds were evaluated against human breast cancer cell line(MDA-MB-231 and MCF-7),cervical cancer cell line(Hela),renal cancer cell line(A498)by MTT assay in vitro.Results Eleven novel imatinib derivatives were synthesized and characterized by~1H-NMR,;C-NMR and HR-MS,and the results showed that compounds 7 b,7 d,7 e,7 f,7 g,7 h,7 i and 7 j showed good antitumor activities.Conclusion Preliminary results show that the compound 7 h have higher proliferation inhibitory activities in MDA-MB-231,MCF-7,HeLa and A498 tumor cells,and it is worth further study.

关 键 词：合成 酪氨酸激酶抑制剂 2-苯氨基嘧啶衍生物 抗肿瘤活性 

分 类 号：R914[医药卫生—药物化学]