3-(5-苄叉基噻唑并均三唑酮)氟喹诺酮类化合物的合成及其抗肿瘤活性
Synthesis and antitumor activity of 3-(5-benzylidenethuzolo-triazlone)fluoroquinolones
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摘要: 为发现氟喹诺酮抗菌活性向抗肿瘤活性转化的有效方法，用稠杂环噻唑并均三唑酮作为培氟沙星( 1 )C-3羧基的生物等排体，芳甲叉基为其修饰基团，设计合成了12个新的C-3噻唑并均三唑不饱和酮目标化合物( 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、Capan-1和HL60 3种肿瘤细胞株的抗增殖活性。初步药理筛选结果表明，目标化合物的活性显著高于母体化合物 1 的抗肿瘤活性，含氟苯基和邻甲氧苯基化合物的活性与对照抗肿瘤药阿霉素相当。因此，噻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。Abstract: To discover an efficient approach for the conversion of antibacterial fluoroquinolones into an antitumor activity, a fused heterocycle ring core, thiazolo［3, 2-b］［1, 2, 4］triazol-5-one was used as an isostere and further modified with an arylidene group. Then, 12 novel C-3 fused heterocyclic unsaturated ketones, 1- ethyl-6-fluoro-7-(4-methyl-piperazin-1-yl)-3-［6-arylidene-thiazolo［3, 2-b］［1, 2, 4］triazol-5(6H)-one-3-yl］- quinolon-4(1H)-ones( 6a - 6l ), were designed and synthesized from pefloxacin( 1 ). The structures were characterized by elemental analysis and spectral data, and the in vitro antitumor activity of the title compounds against SMMC-7721, Capan-1 and HL60 cell lines was evaluated. The preliminary pharmacological results demonstrated that the title compounds exhibited more significantly antiproliferative activity than the parent 1 . The compounds with fluorophenyl or o-methoxyphenyl showed comparable activity to the comparasion doxorubicin. Thus, it appears to be an alternative route for a fused heterocyclic unsaturated ketone as an isostere of the C-3 carboxylic group to improve the antitumor activity.
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Keywords:
- fluoroquinolone /
- s-triazole /
- thiazole /
- thiazolotriazole /
- unsaturated ketone /
- synthesis /
- antitumor activity
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