表没食子儿茶素没食子酸酯类似物的合成及体外逆转肝癌多药耐药性的研究(英文)  

Synthesis and Reversal Activity of Multidrug Resistance of Hepatocellular Carcinoma of(—)-Epigallocatechin Gallate Analogues

作　　者：欧冰凝[1] 廖作庄[1] 梁钢[1] 唐安洲[2] 

机构地区：[1]广西医科大学药学院,南宁530021 [2]广西医科大学第一附属医院耳鼻喉科,南宁530021

出　　处：《中国天然药物》2011年第4期274-279,共6页

基　　金：supported by the National Natural Science Foundation of China(No.30760310);Guangxi Natural Science Foundation(No.0728113);Guangxi Institute of Chinese Medicines Pharmaceutical Science Key Laboratory Founda-tion(No.0801);Innovation Project of Guangxi Graduate Educa-tion(No.2010105981007D36)~~

摘　　要：目的:评价表没食子儿茶素没食子酸酯(EGCG)类似物逆转肝癌多药耐药性及分析其构效关系。方法:合成EGCG类似物并通过1H,13CNMR和二维核磁共振确定结构;首次用MTT法研究表没食子儿茶素(EGC)及EGCG类似物对正常肝细胞LO2,肝癌细胞BEL-7402,和耐药肝癌细胞BEL-7402/5-FU的细胞毒性,及对BEL-7402/5-FU的逆转作用。结果:共合成并纯化得到4个化合物:5,7,3′,4′,5′,3″,4″,5″-八乙酰基-EGCG(AcEGCG),5,7,3′,4′,3″,4″,5″-七乙酰基-ECG(AcECG),7,3′,4′,5′,3″,4″,5″-七乙酰基-EGCG(Ac-A)和3′,4′,5′,3″,4″,5″-六乙酰基-EGCG(Ac-B),其中Ac-A和Ac-B的结构首次被报道。在细胞毒方面,化合物AcECG,Ac-A,Ac-B和EGC对BEL-7402和BEL-7402/5-FU细胞的细胞毒都比EGCG增强,而AcEGCG对BEL-7402/5-FU的细胞毒比EGCG的减弱。在逆转多药耐药性作用方面,AcEGCG和AcECG,特别是AcEGCG对耐药肝癌细胞BEL-7402/5-FU的逆转作用比同浓度的EGCG显著增强(P<0.05);而Ac-A和Ac-B对BEL-7402/5-FU基本无逆转作用,可认为EGCG分子中的羟基一旦乙酰化,全部乙酰化产物比部分乙酰化产物有更强的逆转BEL-7402/5-FU多药耐药作用;EGC基本无逆转BEL-7402/5-FU多药耐药作用。结论:EGCG分子中的没食子酰基是逆转BEL-7402/5-FU多药耐药作用的活性基团;AcEGCG从结构上看比EGCG更稳定,逆转肝癌多药耐药作用也较EGCG增强,因此AcEGCG在逆转肝癌多药耐药作用方面比EGCG更具潜力。AIM：To investigate the reversal activity and structure-activity relationship of（-）-epigallocatechin gallate（EGCG） analogues on the multidrug-resistant tumor cells.METHODS：（—）-Epigallocatechin gallate analogues were synthesized and confirmed by ^1H,^13C NMR and 2DNMR data.MTT method was used to evaluate their cytotoxicities against human normal hepatocellular cells LO2,hepatic carcinoma cells BEL-7402,and the hepatic carcinoma 5-FU-resiatant cells BEL-7402/5-FU.RESULTS：5,7,3＇,4＇,5＇,3″,4″,5″-octa-acetyl-EGCG（AcEGCG）,5,7,3＇,4＇,3″,4″,5″-hepta-acetyl-ECG（AcECG）,7,3＇,4＇,5＇,3″,4″,5″-hepta-acetyl-EGCG（Ac-A）,and 3＇,4＇,5＇,3″,4″,5″-hexa-acetyl-EGCG（Ac-B） were synthesized.Compounds Ac-A and Ac-B were reported for the first time.IC50 of AcECG,Ac-A,and Ac-B against the BEL-7402 and BEL-7402/5-FU cells appeared to be lower than EGCG,whereas that of AcEGCG appeared to be lower than EGCG against the BEL-7402 cells,but much higher against the BEL-7402/5-FU cells.Although the peracetates of EGCG and AcEGCG significantly reversed the 5-FU resistant BEL-7402/5-FU cells,partly acetated EGCG,Ac-A and Ac-B showed weaker reversal effect,indicating that after the acetyl（Ac） was introduced to EGCG,the introduction of more Ac units will enhance the reversal activity.AcEGCG and AcECG,especially AcEGCG,showed significant reversal activity in BEL-7402/5-FU cells,while EGC showed only weak reversal effect.CONCLUSION：The galloyl in EGCG could be necessary to its reversal activity.AcEGCG significantly increased the sensitivity of the BEL-7402 /5-FU cells towards 5-FU and could be used as a potential reversal agent for drug-resistant tumor cells.

关 键 词：表没食子儿茶素没食子酸酯 表没食子儿茶素 类似物 合成 逆转多药耐药性 

分 类 号：R914[医药卫生—药物化学] R965[医药卫生—药学]