3,4-二芳基吡咯酮衍生物的合成和生物活性  

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

作　　者：韦丽[1] 杨晓丽[1,2] 袁吉文[1] 胡宏纹[1] 陆国元[1] 

机构地区：[1]南京大学化学化工学院,南京210093 [2]江苏省姜堰中学,姜堰225500

出　　处：《有机化学》2012年第12期2339-2343,共5页Chinese Journal of Organic Chemistry

基　　金：国家自然科学基金(No.20872061)资助项目~~

摘　　要：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0.03～0.05μmol·L-1.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 acetophe- none, via a four steps reaction, a-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 （lb） shows significant antitumor activity （0.03- 0.05 μmol.L-1）, which is closely to the natural CA-4,

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 

分 类 号：TQ460.1[化学工程—制药化工] O626.13[理学—有机化学]