氟喹诺酮C-3羧基等排体的合成及抗肿瘤活性Ⅵ.均三唑-酰腙甲硫醚衍生物

Synthesis and antitumor activities of fluoroquinolone C-3 isosteres(Ⅵ) : s-triazole-acylhydrazone methylsulfide derivatives

为寻找氟喹诺酮羧基等排体的优化方法,基于药效团拼合原理,用功能酰腙链作为培氟沙星C-3羧基等排体均三唑的修饰基团,设计合成了C-3均三唑酰腙硫醚衍生物17个(6a^6q),其结构经元素分析和光谱数据确证,并评价其对SMMC-7721、L1210和HL60 3种肿瘤细胞株的体外增殖抑制活性。初步研究表明,目标化合物的抗肿瘤活性显著高于母体化合物;同时,酰腙修饰基芳香环上带吸电子取代基的化合物其抗肿瘤活性显著高于供电子基的活性,尤其是苯环带羧酸基的化合物其活性与对照阿霉素相当,这提示等排体修饰基羧基的存在有利于提高抗肿瘤活性。

To discover an efficient optimization method for modification of the fluoroquinolone C-3 carboxylicgroup, the title fluoroquinolon-3-yl s-triazole-acylhydrazone methylsulfide derivatives （6a-6q） were designed andsynthesized from pefloxacin on the basis of pharmacophore combination principle with a functionalized acylhydra-zone group as a modified side-chain for the C-3 bioisosteric s-triazole of pefloxacin. The structures were characte-rized by element analysis and spectral data, and the in vitro antitumor activity against SMMC-？721, L1210 andHL60 cell lines was evaluated by MTT assay. The results showed that the title compounds exhibited moresignificant inhibitory activity than that of the parent pefloxacin, in which compounds with electron-withdrawing groupattached on aryl ring had more potency than that of compounds with electron-donating group, especiallycompounds with carboxylic substituent were comparable to control doxorubicin. It suggests that carboxylic residuearound the C-3 bioisostere is favorable to improve the antitumor activity.