6-取代-1-((1-取代苯基-1,2,3-三唑-4-基)甲基)-4-羰基喹啉-3-甲酸乙酯的合成表征及抗肿瘤活性  

Synthesis,characterization and antitumor activities of ethyl 6-substituted-1-((1-(4-substituted phenyl)-1,2,3-triazol-4-yl) methyl)-4-oxoquinoline-3-carboxylate

作　　者：邹敏[1] 马方[1] 陈慧平[1] 张长征[1] 赵志鸿[1] 王桂芳[1] 张小俊[1] 张壮丽[1] 张艳[1] 王东阳[1] 

机构地区：[1]河南省(郑州大学)医药科学研究院,郑州450052

出　　处：《中国新药杂志》2014年第24期2919-2924,共6页Chinese Journal of New Drugs

基　　金：河南省教育厅科学技术研究重点项目(14A350007);河南省2014基础与前沿技术研究计划项目(142300410398)

摘　　要：目的:为了寻找新型抗肿瘤活性优良的先导化合物,依据喹诺酮及1,2,3-三唑类化合物抗肿瘤特性,设计7个新的6-取代-1-((1-取代苯基-1,2,3-三唑-4-基)甲基)-4-羰基喹啉-3-甲酸乙酯类化合物进行合成、体外抗肿瘤活性评价及初步构效关系研究。方法:以取代苯胺为原料,与乙氧亚甲基丙二酸二乙酯缩合,Gould-Jacobs环合制得6-取代-4-羰基喹啉-3-甲酸乙酯;取代苯基叠氮与溴丙炔经点击化学(click chemistry)制得4-溴甲基-1-取代苯基-1,2,3-三唑;6-取代-4-羰基喹啉-3-甲酸乙酯与4-溴甲基-1-取代苯基-1,2,3-三唑经N烷基化反应制得目标化合物。化合物结构经IR,1H-NMR,元素分析证实,MTT法测目标化合物体外抗肿瘤活性。结果:化合物表现出不同程度抗肿瘤活性。化合物4c,4e对Hep G2,HT29的IC50接近或高于对照药物DDP,尤其对人白血病细胞株HL60具有很强抑制增殖作用,活性高于DDP,IC50分别为15.03,13.32μmol·L-1。结论:初步构效关系研究表明,标题化合物6位及1位上苯基三唑的苯环对位都被Cl,F等卤素原子取代的6-取代-1-((1-取代苯基-1,2,3-三唑-4-基)甲基)-4-羰基喹啉-3-甲酸乙酯对Hep G2,HT29和HL60具有抗肿瘤活性。Objective： To find novel lead compounds with promising antitumor activity through designing and synthesizing a series of novel ethyl 6-substituted-1-（（1-（4-substituted phenyl）-1,2,3-triazol-4-yl） methyl）-4-oxoquinoline-3-carboxylate derivatives based on the antitumor characteristics of quinolones and 1,2,3-triazol derivatives. Methods： Title compounds were synthesized through Gould-Jacobs reaction,click chemistry,and alkylation.The structures of the title compounds were confirmed by1H-NMR,IR,and elemental analysis. The compounds were evaluated for antitumor activity against five selected human tumor cell lines of Hep G2,A549,Hela,HT29,and HL60 by MTT assay. Results： The title compounds exhibited moderate to potent antitumor activity. Among them,several compounds displayed excellent antitumor activities against Hep G2,HT29,and HL60. Particularly,compounds 4 c and 4 e were more potent than DDP against HL60 with IC50 values of 15. 03 and 13. 32 μmol·L^-1.Conclusions： The analysis of structure-activity relationship showed that the title compounds which were substitutedby Cl or F at positions 1 and benzene of 6 were a kind of promising antitumor compounds against Hep G2,HT29,and HL60.

关 键 词：4-羰基喹啉 合成 表征 抗肿瘤 

分 类 号：R914.5[医药卫生—药物化学]