氟喹诺酮C-3羧基等排体的合成及抗肿瘤活性:均三唑-二唑甲硫醚曼尼希碱衍生物  

Synthesis and antitumor activities of fluoroquinolone C-3 isosteres(IV):s-triazole-oxadiazole methylsulfide Mannich-base derivatives

作　　者：孙玉生[1] 许秋菊[2] 侯莉莉[2] 岳喜波[2] 仵钊锋 黄文龙[3] 谢松强[2] 胡国强[2] 

机构地区：[1]河南大学公共卫生研究所,开封475001 [2]河南大学化学生物学研究所,开封475001 [3]中国药科大学新药研究中心,南京210009

出　　处：《中国药科大学学报》2014年第1期39-42,共4页Journal of China Pharmaceutical University

基　　金：国家自然科学基金资助项目(No.20872028,21072045)~~

摘　　要：为寻找抗肿瘤氟喹诺酮C-3羧酸等排体的有效优化策略,基于C-3均三唑-二唑甲硫醚(6a^6j)结构特征,在培氟沙星(1)羧基等排体均三唑环上发生氨甲基化反应得新的曼尼希碱目标化合物(7a^7j),其结构经元素分析和光谱数据确证。用MTT方法评价了硫醚及其曼尼希碱化合物体外对SMMC-7721、L1210和HL60 3种肿瘤细胞的生长抑制活性。结果表明,硫醚及其曼尼希碱对3种肿瘤细胞的生长抑制活性不但显著强于母体化合物1,而且曼尼希碱的活性也高于其相应硫醚的活性,尤其对肝癌SMMC-7721细胞的活性明显高于对白血病细胞L1210和HL60的活性,显示出了一定的抗肿瘤选择性。To search for an efficient modification strategy for a bioisostere of the C-3 carboxylic acid group of antitumor fluoroquinolones, an aminomethylation reaction based on the structural characteristics of the C-3 s-triazole-oxadiazole sulfides（6a-6j）was carried out on a five-member azole ring of s-triazole to give 1-ethyl-6-fluoro-7-（4-methyl-piperazin-1-yl）-3-［1-dimethy-l amino-methyl-5-（5-substituted-phenyl-［1, 3, 4］oxadia-zol-2-yl methylsulfanyl）-1H-［1, 2, 4］-triazol-3-yl］-quinolin-4（1H）-ones（7a-7j）as novel C-3 s-triazole-oxadiazole sulfide Mannich-base derivatives starting from pefloxacin（1）. The structures of the title compounds were characterized by elemental analysis and spectral data and their in vitro antitumor activity against SMMC-7721, L1210 and HL60 cell lines was evaluated by a MTT assay. The results showed that the of sulfides（6a-6j）and their corresponding Mannich-base compounds（7a-7j）had more potent inhibitory activity than the compound 1, and the Mannich-base compound 7 also exhibited more potent cytotoxicity than the corresponding compound 6, especially both had better activity against SMMC-7721 cell line than the other cancer cell lines.

关 键 词：氟喹诺酮 均三唑 口恶二唑 生物电子等排体 合成 硫醚 曼尼希碱 抗肿瘤活性 

分 类 号：R914.5[医药卫生—药物化学] R965[医药卫生—药学]