左氧氟沙星的噻唑并均三唑衍生物的合成及抗肿瘤活性

Synthesis and Antitumor Activities of C-3 Thiazolotriazole Unsaturated Ketone Derivatives of Levofloxacoin

为进一步发展抗菌药氟喹诺酮向抗肿瘤活性转化的有效结构修饰策略,基于药效团骨架的迁越药物设计原理,用噻唑并均三唑稠环取代左氧氟沙星(1) C-3羧基的等排体,α,β-不饱和酮为其修饰基,设计合成了C-3噻唑并均三唑稠杂环目标化合物(6a-6l)。体外抗肿瘤活性结构表明,所合成的12个化合物的活性均强于母体左氧氟沙星,化合物6e、6i、6j的活性与对照抗肿瘤药阿霉素相当。因此,α,β-不饱和酮修饰的均三唑骨架替代C-3羧基有利于提高氟喹诺酮的抗肿瘤活性。

To further develop an efficient structural modification strategy for the conversion of the antibacterial activity of fluoroquinolone into an antitumor activity,fused heterocyclic with unsaturated ketone was designed as the bioisosteric replacement of the C-3 carboxylic acid group. Accordingly,twelve novel C-3 thiazolotriazole unsaturated ketones( 6a-6l) were synthesized from levofloxacin 1. The in vitro antitumor activity of the title compounds exhibited more significant potency than that of levofloxacin. The compounds with fluorophenyl or o-methoxyphenyl displayed comparable activity to doxorubicin. Thus,a fused heterocyclic unsaturated ketone skeleton as an isostere of the C-3 carboxylic acid group appears to be an alternative route for further design of lead antitumor fluoroquinolone.