引用本文:
王国强, 段楠楠, 曹铁耀, 温晓漪, 银俊, 王伟, 谢松强, 黄文龙, 胡国强. 抗肿瘤氟喹诺酮C3等排衍生物(Ⅰ)——双二唑甲硫醚衍生物的合成和抗肿瘤活性[J]. 应用化学,
2012, 29(7): 769-774.
doi:
10.3724/SP.J.1095.2012.00360
Citation: WANG Guoqiang, DUAN Nannan, CAO Tieyao, WEN Xiaoyi, YIN Jun, WANG Wei, XIE Songqiang, HUANG Wenlong, HU Guoqiang. Antitumor Fluoroquinolone C3-Isostere Derivatives(Ⅰ)——Synthesis and Activity of Bis-oxadiazole Methyl-sulfide Derivatives[J]. Chinese Journal of Applied Chemistry, 2012, 29(7): 769-774. doi: 10.3724/SP.J.1095.2012.00360
Citation: WANG Guoqiang, DUAN Nannan, CAO Tieyao, WEN Xiaoyi, YIN Jun, WANG Wei, XIE Songqiang, HUANG Wenlong, HU Guoqiang. Antitumor Fluoroquinolone C3-Isostere Derivatives(Ⅰ)——Synthesis and Activity of Bis-oxadiazole Methyl-sulfide Derivatives[J]. Chinese Journal of Applied Chemistry, 2012, 29(7): 769-774. doi: 10.3724/SP.J.1095.2012.00360
抗肿瘤氟喹诺酮C3等排衍生物(Ⅰ)——双二唑甲硫醚衍生物的合成和抗肿瘤活性
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-1,3,4-二唑-2-基)-喹啉-4(1H)-酮(3),化合物3与氯甲基二唑(4a~4e)进行S-醚化得双二唑甲硫醚(5a~5e),再进一步甲基化和季铵化得相应的N-甲基双二唑甲硫醚(6a~6e)和N,N-二甲基双二唑甲硫醚碘化物(7a~7e)。双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。
English
Antitumor Fluoroquinolone C3-Isostere Derivatives(Ⅰ)——Synthesis and Activity of Bis-oxadiazole Methyl-sulfide Derivatives
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.
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Key words:
- fluoroquinolone
- / isostere
- / oxadiazole
- / quaternary ammonium salt
- / antitumor evaluation
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