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

• Published in: Chinese journal of natural medicines 2011, Vol.9 (4), p.274-279
• Main Authors: OU, Bing-Ning, LIAO, Zuo-Zhuang, LIANG, Gang, TANG, An-Zhou
• Format: Article
• Language: English
• Subjects: (−)-Epigallocatechin (EGC); (−)-Epigallocatechin gallate; Analogues; carcinoma; hepatoma; humans; inhibitory concentration 50; multiple drug resistance; nuclear magnetic resonance spectroscopy; Reversal of multidrug resistance; structure-activity relationships; Synthesis
• ISSN: 1875-5364; 1875-5364
• DOI: 10.1016/S1875-5364(11)60064-2

To investigate the reversal activity and structure-activity relationship of (−)-epigallocatechin gallate (EGCG) analogues on the multidrug-resistant tumor cells. (−)-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. 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. IC 50 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. 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.