氟喹诺酮C3稠杂环体系的合成及抗肿瘤活性(Ⅲ):恩诺沙星均三唑并噻二嗪酮衍生物  

Synthesis and Antitumor Activity of Fluoroquinolon-3-yl Fused Heterocyclic Systems (Ⅲ):s-Triazolothiadiazinone Derivatives Derived Enrofloxacin

作　　者：胡国强[1] 张忠泉[1] 王海燕[1] 毋小魁[1] 王新[1] 杜钢军[1] 谢松强[1] 黄文龙[2] 张惠斌[2] 

机构地区：[1]河南大学药物研究所,开封475001 [2]中国药科大学新药中心,南京210009

出　　处：《化学学报》2009年第22期2592-2596,共5页Acta Chimica Sinica

基　　金：国家自然科学基金(No.20872028);河南大学科研基金(No.XK02041)资助项目

摘　　要：基于抗菌氟喹诺酮作用靶拓扑异构酶设计发展新型抗肿瘤氟喹诺酮药物已成为新的研究方向.为扩展氟喹诺酮C-3稠杂环体系的研究领域,以恩诺沙星1为起始原料经C-3羧基反应到C-31-氨基-5-巯基-均-三唑(5),与氯乙酸缩环合到C-3均三唑[3,4-b][1,3,4]噻二嗪-6-酮(7),接着与取代苯甲醛缩合得C-37-取代苯甲叉基-均三唑[2,1-b][1,3,4]噻二嗪-6-酮(8)目标化合物.新化合物的结构经元素分析和光谱数据表征,用MTT方法评价了它们体外对CHO,HL60和L12103种癌细胞株的体外生长抑制活性.结果表明,所合成的11个新化合物中均具有潜在的体外抑制癌细胞生长活性,其中氨基均三唑硫乙酸中间体6及目标化合物8活性最强,其IC50值已达到或接近微摩尔浓度,预示氟喹诺酮类抗菌剂的C-3位稠杂环抗肿瘤构-效关系值得进一步研究.The topoisomerase-based design and development for the shift from an antibacterial to an antitumor agent have been a new strategy in the fluoroquinolone field. To further expand the research of the C-3 fused heterocyclic rings attached to the quinolinone skeleton, the key intermediate of 1-amino-5-mercapto- 1,3,4-triazole （5） derived from the C-3 carboxyl group of enrofloxacin 1 was synthesized, then, the corresponding fused heterocyclic ring, s-triazolo[2,1-b][1,3,4]thiadiazin-3-one （7）, was produced by a cyclocondensation of 5 with chloroacetic acid. The further modification for the above fused core 7 by a Perkin reaction with substituted benzaldehydes yielded the title compounds, 1-cyclopropyl-7-（4-ethylpiperazin-l-yl）-6- fluoro-3-{2-（substituted-benzylidene）-3,4-dihydro-[ 1,3,4]triazolo[2, 1-b] [ 1,3,4]thiadiazin-3-（2H）-one-5- yl）}quinolin-4-（1H）ones （8）, respectively. The structures of new compounds synthesized were characterized by elemental analysis and spectral data, and their in vitro anticancer activity against the three cancer cell lines of CHO, HL60 and L1210 was evaluated. The bioactive assay showed that all new compounds, especially the intermediate 6 exhibited a significant antitumor activity with a range of the micromole concentrations for IC50 value. Thus, the C-3 mono or fused heterocycle-based substituted antitumor fluoroquinolones are valuable for further study.

关 键 词：氟喹诺酮 均三唑 均三唑并噻嗪唑 抗肿瘤活性评价 

分 类 号：R914[医药卫生—药物化学]