C-3芳节叉基噻二唑并均三唑酮氧氟沙星衍生物的合成及抗肿瘤活性

目的发现氟喹诺酮由抗菌活性向抗肿瘤活性转化的有效结构修饰策略。方法基于药效团和骨架迁越药物设计原理,用均三唑杂环和α,β-不饱和酮分别作为C-3羧基的等排体和稠合修饰基,设计合成了C-3噻二唑并均三唑不饱和酮目标化合物(6a^61)。用元素分析和光谱数据确证化合物的结构,四甲基偶氮唑盐微量酶反应比色法(MTT)方法评价了目标化合物体外对SMMC-7721、Capan-1和HL603种癌细胞株的抗增值活性。结果合成了12个新结构的C-稠杂环不饱和酮化合物,体外抗肿瘤活性显著强于母体化合物1,其中含氟苯基和邻甲氧苯基化合物的活性与对照抗肿瘤药多柔比星相当。结论噻二唑并均三唑不饱和酮骨架替代氟喹诺酮C-3羧基有利于提高其抗肿瘤活性。

Synthesis and Antitumor Activity of C-3 Arylidene Thiazolotriazolone of Ofloxacin Derivatives

OBJECTIVE To discover an efficient strategy for a conversion of the antibacterial activity into an antitumor activity.METHODS Pharmacophore and scaffold hopping-based rational drug design principles,the title fluoroquinolone C-3 thiazolotriazole unsaturated ketones(6a-61)were designed and synthesized with a 5-triazole ring andα,β-unsaturated ketone,respectively,as an isostere and fused modified group from ofloxacin(1),and their structures were characterized by elemental analysis and spectral data,and the in vitro antitumor activity against the tested tumor cell lines was evaluated by a MTT assay.RESULTS Twelve new title compounds were synthesized,and exhibited more significant potency than parent 1.The title compounds wth fluorophenyl or O-methoxy-phenyl displayed comparable activity to comparasion doxorubicin.CONCLUSION A fused heterocyclic unsaturated ketone skeleton as an isostere of the G-3 carboxylic acid group are shown to be an alternative route for further design of lead antitumor fluoroquinolone.