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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 good antitumor activity, seven novel 6-substituted-1 - ((1-substituted phenyl-1 , 2,3-triazol-4-yl) methyl) -4-carbonylquinoline-3-carboxylic acid ethyl ester compounds in vitro antitumor activity evaluation and preliminary structure-activity relationship study. Methods: The substituted aniline was used as the starting material to condense with diethyl ethoxymethylenemalonate. Gould-Jacobs cyclization produced ethyl 6-substituted-4-oxoquinoline-3-carboxylate; substituted phenyl azide Brominated propyne with click chemistry to give 4-bromomethyl-1-substituted phenyl-1,2,3-triazole; and 6-substituted-4-carbonylquinoline-3- 4-bromomethyl-1-substituted phenyl-1,2,3-triazole by N alkylation reaction of the target compound. The structure of the compound was confirmed by IR, 1H-NMR and elemental analysis. The antitumor activity of the target compound was determined by MTT assay. Results: The compounds showed different degrees of antitumor activity. The IC50 values of Hep G2 and HT29 for compounds 4c and 4e were close to or higher than that of control drug DDP, especially for human leukemia cell line HL60. The IC50 values of compound 4c and 4e were 15.03 and 13.32μmol·L-1, respectively. CONCLUSION: The preliminary structure-activity relationship study shows that the para-position of the phenyltriazole at the 6- and 1-position of the title compound is replaced by 6-substituted-1 - ((1-substituted phenyl- Triazol-4-yl) methyl) -4-oxoquinoline-3-carboxylate has antitumor activity against Hep G2, HT29 and HL60.