氟喹诺酮C-3均三唑并[3,4-b][1,3,4]噻二唑稠杂环衍生物的合成及抗肿瘤活性

Synthesis and antitumor evaluation of heterocyclic C-3 s-triazolo[3,4-b][1,3,4]thiadiazole derivatives from ciprofloxacin

[目的]寻找氟喹诺酮C-3羧基的有效生物等排体。[方法]用均三唑并噻二唑稠杂环作为环丙沙星C-3羧基的生物电子等排体,合成了10个新氟喹诺酮C-3均三唑并噻二唑稠杂环目标化合物(5a^5j),其结构经元素分析和光谱数据确证,评价了体外对SMMC-7721、L1210和HL60 3种癌细胞的生长抑制活性。[结果]目标物对3种试验癌细胞的生长抑制活性显著强于母体化合物,其中苯环含有氟原子和羟基的化合物的活性强于其他化合物,其IC50与对照阿霉素相当。[结论]C-3羧基并非是抗肿瘤所必需的药效团,用稠杂环替代可提高其抗肿瘤活性。

〔Objective〕To search the bioistere of the C-3 carboxylic acid for an efficient transformation of antibacterial fluoroquinoles into antitumor fluoroquinolones.〔Methods〕A heterocyclic ring of s-triazolothiadiazole as the C-3 bioistere resulted in ten novel title fluoroquinolone C-3 heterocyclic derivatives starting from ciprofloxacin.The structures were characterized by elemental analysis and spectral data,and the in vitro antitumor activity against three tested cancer cell lines was evaluated by the MTT assay.〔Results〕The title compounds had more potent inhibitory activity than the parent.Meanwhile,some title compounds containing fluorophenyl group(6h)and hydroxylphenyl atom(5b,6f)exhibited more significant activity than the other compounds with a comparable cytotoxicity to the control doxorubicin.〔Conclusion〕The result suggests that it is not necessary for the C-3 carboxylic acid group as an antitutmor pharmacophore,but a heterocyclic ring as the C-3 bioisosteric replacement is able to significantly increase the activity.