培氟沙星C-3羧基等排体的合成及抗肿瘤活性(Ⅷ).均三唑硫醚酮缩氨基硫脲衍生物
Synthesis and antitumor activities of fluoroquinolone C-3 isosteres(VIII):s-triazole sulfide-one thiosemicarbazone derivatives from pefloxacin
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摘要: 以均三唑杂环作为培氟沙星C-3羧基的等排体，功能侧链-硫醚酮缩氨基硫脲为其修饰基，设计合成了12个C-3均三唑硫醚酮缩氨基硫脲目标化合物( 6a ~ 6l )，其结构经元素分析和光谱数据确证，评价了它们体外对SMMC-7721、L1210和HL60 3种肿瘤细胞株的抗增殖活性。初步药理学实验结果表明:目标化合物的抗肿瘤活性显著高于母体化合物 1 和相应中间体硫醚酮( 5a ~ 5l )，尤其是苯环含羟基和氟原子的目标化合物IC50已达到微摩尔水平，与阳性对照药阿霉素的效力相当。这提示被功能基侧链修饰的唑杂环替代C-3羧基有利于提高其抗肿瘤活性。Abstract: To improve the antitumor activity of fluoroquinolones for a promising development of druggability, twelve novel fluoroquinolone C-3 s-triazole sulfide-one thiosemicarbazone derivatives( 6a - 6l )were designed and synthesized with a functionalized sulfide-one thiosemicarbazone as a modified side-chain for the C-3 bioisteric s-triazole ring of pefloxacin( 1 ). The structures were characterized by elemental analysis and spectral data。The in vitro antitumor activity of novel compounds against SMMC-7721, L1210 and HL60 cell lines was evaluated. The preliminary pharmacological results demonstrated that the title compounds exhibited more significantly antiproliferative activity than either the parent 1 or the corresponding sulfide-one intermediates( 5a - 5l ). In particular, compounds bearing a hydroxyl group or a fluorine atom attached to benzene ring were comparable to the control doxorubicin with an IC50 value of micro-molar concentration, respectively. It suggests that an azole ring modified with functional side-chain instead of the C-3 carboxylic group is favorable to the improve ment of antitumor activity.
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Keywords:
- pefloxacin /
- s-triazole /
- sulfide-one /
- thiosemicarbazone /
- antitumor activity
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