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抗肿瘤氟喹诺酮C3等排衍生物(Ⅰ)——双噁二唑甲硫醚衍生物的合成和抗肿瘤活性

王国强1,段楠楠1,曹铁耀1,温晓漪1,银俊1,王伟1,谢松强1,黄文龙2,胡国强1*   

  1. (1.河南大学化学生物学研究所 开封 475001;2.中国药科大学新药研究中心 南京 210009)
  • 收稿日期:2011-08-17 修回日期:2011-11-09 出版日期:2012-07-10 发布日期:2012-07-10
  • 通讯作者: 胡国强,教授; Tel/Fax:0378-3880680; E-mail:hgqxy@sina.com.cn; 研究方向：新药分子的设计与合成
  • 基金资助:
    国家自然科学基金（20872028,21072045）和河南大学科研基金(06YB2R075)资助项目

Antitumor Fluoroquinolone C3-Isostere Derivatives(Ⅰ)——Synthesis and Activity of Bis-oxadiazole Methyl-sulfide Derivatives

WANG Guoqiang1, DUAN Nannan1, CAO Tieyao1, WEN Xiaoyi1, YIN Jun1, WANG Wei1, XIE Songqiang1, HUANG Wenlong2, HU Guoqiang1*   

  1. (1.Institute of Chemistry & Biology,Henan University,Kaifeng  475001,China;
    2.Center of Drug Discovery,China Pharmaceutical University,Nanjing  210009,China)
  • Received:2011-08-17 Revised:2011-11-09 Published:2012-07-10 Online:2012-07-10

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摘要： 基于抗菌氟喹诺酮的作用靶拓扑异构酶与哺乳动物的相似性，为寻找由抗菌活性到抗肿瘤活性转化的有效修饰方法，用噁二唑杂环作为诺氟沙星（1）的羧基电子等排体得中间体，1-乙基-6-氟-7-(哌嗪-1-基)-3-(5-巯基-1,3,4-噁二唑-2-基)-喹啉-4(1H)-酮（3），化合物3与氯甲基噁二唑（4a~4e）进行S-醚化得双噁二唑甲硫醚（5a~5e），再进一步甲基化和季铵化得相应的N-甲基双噁二唑甲硫醚（6a~6e）和N，N-二甲基双噁二唑甲硫醚碘化物（7a~7e）。 双噁二唑甲硫醚目标物的结构经元素分析、1H NMR、MS技术确证。 采用MTT法评价了目标化合物对体外培养人肝癌细胞株Hep-3B生长的抑制活性。 结果表明，15个目标化合物的抑制活性均显著高于对照化合物1的抑制活性，其季铵盐的IC50值低于25.0 μmol/L,显示出潜在的抗癌活性。

关键词: 氟喹诺酮, 电子等排体, 噁二唑, 季铵盐, 抗肿瘤评价

Abstract: To discover an efficient modification for shifting from an antibacterial fluoroquinolone to an antitumor one based on the topological similarities between targeting topoisomerases as the eukaryotic ones and mammals, using oxadiazole heterocycle as an intermediate for the isostere of C-3 carboxylic group of norfloxacin(1), 1-ethyl-6-fluoro-7-piperazin-1-yl-3-(5-mercapto-1,3,4-oxadiazol-2-yl)-quinolin-4(1H)-one(3) was subjected to thioetherfication with each of chloromethyl oxadiazole(4a~4e) to give bis-oxadiazole methylsulfides(5a~5e), respectively. The following N-methylations and quaternizations yielded the corresponding N-methyl bis-oxadiazole methylsulfides(6a~6e) and N,N-dimethyl bis-oxadiazole methylsulfide iodides(7a~7e). The structures of fifteen title compounds were characterized by elemental analysis, 1H NMR and MS, and their anticancer activities in vitro against Hep-3B cancer cell lines were also evaluated  with a MTT assay. The results reveal that fifteen title compounds show higher cytotoxicity than that of comparison 1, in which quaternary ammonium salts exhibit potential anticancer activity with IC50 values below 25.0 μmol/L.

Key words: fluoroquinolone, isostere, oxadiazole, quatemary ammonium salt, antitumor evaluation

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