氟喹诺酮C-3均三唑硫醚酮及其衍生物的合成和抗肿瘤活性  

Synthesis and antitumor activity of fluoroquinolon-3-yl-s-triazole sulfide ketones and their derivatives from ciprofloxacin

作　　者：倪礼礼 闫强[1] 吴书敏[1] 谢玉锁 高留州[1] 刘英杰[2] 黄文龙[3] 胡国强[1] 

机构地区：[1]河南大学化学生物学研究所,河南开封475001 [2]河南大学医学院微生物学教研室,河南开封475001 [3]中国药科大学新药研究中心,江苏南京210009

出　　处：《药学学报》2015年第10期1258-1262,共5页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(20872028;21072045);河南省高等学校重点科研项目(15A350004)

摘　　要：为发现氟喹诺酮由抗菌活性到抗肿瘤活性转化的有效结构修饰策略,以均三唑硫醇(酮)杂环为C-3羧基的等排体,经硫醚化修饰得C-3均三唑硫醚酮(6a^6g),进一步优化得C-3均三唑硫醚酮缩氨基硫脲(7a^7g)和C-3噻唑并三唑稠杂环类(8a^8g)。用元素分析和光谱数据确证化合物的结构,用MTT方法评价3类化合物对Hep-3B、Capan-1和HL60的体外抗增值活性。结果表明,上述3类化合物的体外抗肿瘤活性均强于环丙沙星,其中相应化合物的活性次序为7>8>6,对肿瘤细胞的选择性为Capan-1>Hep-3B>HL60。同时,含吸电子基(F、NO2)取代的目标化合物(6f、7f、8f和6g、7g、8g)均强于其他取代基目标物的活性,尤其是缩氨基硫脲类(7f、7g)对Capan-1的IC50值与对照药多柔比星相当。为此,硫醚酮缩氨基硫脲修饰的均三唑杂环作为C-3羧基等排体值得关注和进一步发展。To discover an efficient strategy for the conversion of the antibacterial activity of fluoroquinolones into the antitumor activity, the three series of C-3 s-triazole-based derivatives including sulfide ketones （6a-6g）, thiosemiearbazones （Ta-Tg） and fused heterocyclic thiazolotriazoles （8a-8g） were synthesized from ciprofloxacin （1）, respectively. The structures were characterized by elemental analysis and spectral data. The antitumor activity was tested against three tumor cell lines （Hep-3B, Capan-1 and HL60） using the MTT assay. The three types of compounds all exhibited stronger anti-proliferative activities than ciprofloxacin in the test. The order of their activities was in compounds 7〉8〉6, and the order of selectivity against cancer cell lines was Capan-1, Hep-3B and HLf60. Meanwhile, the SAR revealed that some compounds with electron-drawing group substituted such as fluoro- and nitro-phenyl compounds （6f, 7f, 8f） and （6g, 7g, 8g） displayed more significant activity than the control compounds, especially the IC50 values of thiosemicarbazone compounds 7f and 7g against Capan-1 was comparable to doxorubicin. Thus, a five-membered triazole as the C-3 bioisostere modified with thefunctionalized side-chain of sulfide-ketone thiosemicarbazone warrants special attention and further investigation.

关 键 词：氟喹诺酮 环丙沙星 均三唑 硫醚酮 缩氨基硫脲 噻唑并三唑 抗肿瘤活性 

分 类 号：R916[医药卫生—药学]