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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。
In order to find out the effective structural modification of fluoroquinolones from antimicrobial activity to anti-tumor activity, the isothiazolylthio (keto) heterocycle is an isostere of C-3 carboxyl group, (6a ~ 6g) were further optimized to give C-3 S-thioether ketone thiosemicarbazone (7a ~ 7g) and C-3 thiazolotriazole fused heterocycles (8a ~ 8g). The structure of the compounds was confirmed by elemental analysis and spectral data. The MTT assay was used to evaluate the anti-proliferative activity of 3 compounds against Hep-3B, Capan-1 and HL60 in vitro. The results showed that all the above three compounds were more potent anti-tumor activity than ciprofloxacin, the order of activity of these compounds was 7> 8> 6, and their selectivity for tumor cells was Capan-1> Hep-3B> HL60. At the same time, the target compounds (6f, 7f, 8f and 6g, 7g, 8g) substituted with electron-withdrawing group (F, NO2) are stronger than the activity of other substituents, especially thiosemicarbazone ) The IC50 value for Capan-1 is comparable to the control drug doxorubicin. For this reason, thioether ketone thiosemicarbazone modified triazole heterocyclic heterocyclic ring as C-3 carboxyl is worth attention and further development.