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目的寻找由抗菌氟喹诺酮向抗肿瘤氟喹诺酮转化的有效结构修饰途径。方法以抗菌氟喹诺酮药物氧氟沙星1为原料,其相应的酰肼2与二硫化碳缩环合得C-3噁二唑硫醇3中间体,然后分别与5-取代苯基-2-氯甲基-1,3,4-噁二唑4a～4g缩合得含氟喹诺酮骨架的双噁二双唑甲硫醚5a～5g,接着用碘甲烷进行季铵化反应得相应的季铵盐6a～6g。用MTT方法评价了目标化合物5a～5g和6a～6g体外对肿瘤细胞的生长抑制活性。结果合成了14个新的目标化合物,体外均显示潜在的抗癌活性(IC50<25μmol.L-1),其中季铵盐6a～6g的活性高于相应游离碱5a～5g的活性。结论基于抗菌氟喹诺酮C-3杂环的抗肿瘤氟喹诺酮的设计值得进一步研究。
OBJECTIVE: To find an effective structural modification pathway for the conversion of antifungal fluoroquinolones to antitumor fluoroquinolones. Methods The antibacterial fluoroquinolone ofloxacin 1 as the raw material, the corresponding hydrazide 2 and carbon disulfide carbon ring-closure C-3 oxadiazole thiol 3 intermediate, and then respectively 5-substituted phenyl-2-chloro Methyl-1,3,4-oxadiazole 4a ~ 4g condensation fluorine-containing quinolone skeleton of bis-oxadiazolium methyl sulfide 5a ~ 5g, followed by quaternization with methyl iodide to give the corresponding quaternary ammonium salt 6a ~ 6g. The growth inhibitory activity of target compounds 5a ~ 5g and 6a ~ 6g on tumor cells was evaluated by MTT assay. Results Fourteen novel target compounds were synthesized and showed potential anticancer activity (IC50 <25μmol.L-1) in vitro. The activity of 6a ~ 6g quaternary ammonium salt was higher than 5a ~ 5g of the corresponding free base. Conclusion The design of antitumor fluoroquinolone based on the antibacterial fluoroquinolone C-3 heterocycle deserves further study.