氟喹诺酮C-3均三唑硫醚酮缩氨基硫脲衍生物的合成及抗肿瘤活性

为发现氟喹诺酮由抗菌活性向抗肿瘤活性转化的结构修饰方法,基于生物电子等排药物设计原理,用唑杂环作为氧氟沙星(1)C-3羧基的等排体、硫醚酮缩氨基硫脲为其功能侧链修饰基,设计合成C-3均三唑硫醚酮缩氨基硫脲目标化合物(6a~6g),其结构经元素分析和光谱数据确证。 体外抗肿瘤活性结果表明,中间体C-3均三唑硫醚酮(5a~5g)和目标化合物(6a~6g)的活性均强于母体氧氟沙星的活性,其中缩氨基硫脲的活性强于相应硫醚酮的活性,尤其是苯环含硝基和氟原子目标化合物的活性与对照药阿霉素的活性相当。 因此,功能缩氨基硫脲链修饰的均三唑作为C-3羧基的等排体有利于提高氟喹诺酮的抗肿瘤活性。

Synthesis and Antitumor Activity of Fluoroquinolon-3-yl s-Triazole Sulfide-ketone Thiosemicarbazone Derivatives of Ofloxacin

To discover efficient structural modification strategy for the conversion of antibacterial activity of fluoroquinolones into antitumor activity, an azole heterocycle modified with sulfide-ketone thiosemicarbazone chain was designed as the bioisosteric replacement of the C-3 carboxylic acid group. Consequently, novel s-triazole-based thiosemicarbazone derivatives(6a~6g) were synthesized from ofloxacin 1, respectively. The structures of the title compounds(6a~6g) were characterized by elemental analysis and spectral data, and the in vitro antitumor activity was also evaluated by the MTT assay. Compounds(6a~6g) exhibit more significantly antiproliferative activity than both of parent ofloxacin 1 and the corresponding sulfide-ketone intermediates(5a~5g). These thiosemicarbazones, particularly those containing nitro group or fluorine atom, have comparable activity to doxorubicin. Therefore, it suggests that an azole ring modified with functional side-chain as the bioisosteric replacement of the C-3 carboxylic group is favorable for an improvement of antitumor activity of fluoroquinolones.