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有机化学 ›› 2012, Vol. 32 ›› Issue (12): 2339-2343.DOI: 10.6023/cjoc201207043 上一篇    下一篇

研究简报

3,4-二芳基吡咯酮衍生物的合成和生物活性

韦丽a, 杨晓丽a,b, 袁吉文a, 胡宏纹a, 陆国元a   

  1. a 南京大学化学化工学院 南京 210093;
    b 江苏省姜堰中学 姜堰 225500
  • 收稿日期:2012-07-27 修回日期:2012-08-30 发布日期:2012-09-03
  • 通讯作者: 陆国元 E-mail:lugyuan@nju.edu.cn
  • 基金资助:
    国家自然科学基金(No. 20872061)资助项目.

Synthesis and in vitro Antitumor Activities of 3,4-Diaryl Substituted Pyrrolones Derivatives

Wei Lia, Yang Xiaolia,b, Yuan Jiwena, Hu Hongwena, Lu Guoyuana   

  1. a Department of Chemistry, State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing 210093;
    b Jiangyan High School, Jiangyan 225500
  • Received:2012-07-27 Revised:2012-08-30 Published:2012-09-03
  • Supported by:
    Project supported by the National Natural Science Foundation of China (No. 20872061).

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考布他汀-A4 (Combretastatins-A4, CA-4)是从天然产物中分离得到的抗癌活性化合物, 其分子中Z-构型烯键易异构化转变为无抗癌活性的E-构型. 以吡咯-2,5-二酮或吡咯-2-酮代替烯键, 设计合成了4个新的CA-4类似物. 它们的合成是以3,4-二甲氧基苯乙酮或3-氟-4-甲氧基苯乙酮为起始原料, 经α-溴化、改良的Gabriel合成法、与3,4,5-三甲氧基苯乙酸缩合、环化-氧化或环化四步反应完成. 其结构用1H NMR, 13C NMR, ESI-MS及元素分析进行了表征. 用MTT法测试了CA-4类似物对人白血病细胞HL-60、肝癌细胞SMMC-7721和肺腺癌细胞A549的体外抗肿瘤活性. 初步结果表明, 含氟化合物3,4-二芳基-2,5-吡咯酮(1b)的抗肿瘤活性接近CA-4, IC50值达到0.03～0.05 μmol·L-1.

关键词: 考布他汀类似物, 合成, 抗肿瘤活性, 3,4-二芳基吡咯二酮, 3,4-二芳基吡咯酮

Combretastatins-A4 (CA-4) is a natural product with extraordinary anticancer activity, which was isolated from the South African Tree-Combretum caffrum. However, the cis-isomer exhibits strong antitubulin activity only, but the cis-isomer tends to isomerize the inactive trans-isomer. In this paper, an additional pyrrolidone ring system was used to replace the cis double bond to arrest the cis-conformation. Thus, four new compounds of 3,4-diaryl pyrrolediones and 3,4-diaryl pyrrolones as CA-4 analogues were synthesized from the starting materials 3,4-dimethoxyacetophenone or 3-fluoro-4-methoxy acetophenone, via a four steps reaction, α-bromination, improved Gabriel reaction, condensation with 3,4,5-trimethoxyphenylacetic acid and intramolecular cyclization under air or nitrogen. The structures of these new compounds were confirmed by 1H NMR, 13C NMR, ESI-MS and elemental analysis. The in vitro antitumor activities of CA-4 analogues against HL-60, SMMC-7721 and A549 human gastric cancer cell lines were tested using colorimetric MTT assay. The preliminary result indicates that 3-(3-fluoro-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)pyrrole-2,5-dione (1b) shows significant antitumor activity (0.03～0.05 μmol·L-1), which is closely to the natural CA-4.

Key words: combretastatin A-4 analogues, synthesis, antitumor activity, 3,4-diaryl pyrroledione, 3,4-diaryl pyrrolone