A potential prodrug for a green tea polyphenol proteasome inhibitor: evaluation of the peracetate ester of (-)-epigallocatechin gallate [(-)-EGCG]
A potential prodrug for a green tea polyphenol proteasome inhibitor: evaluation of the peracetate ester of (-)-epigallocatechin gallate [(-)-EGCG]
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DOI：
10.1016/j.bmc.2004.08.002
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发表时间：
2004-11-01
影响因子：
3.5
通讯作者：
Chan, TH
中科院分区：
文献类型：
--
作者：
Lam, WH;Kazi, A;Chan, TH
绿茶已被证明具有许多生物学效应，包括对新陈代谢、血管生成、氧化和细胞增殖的影响。遗憾的是，绿茶中含量最丰富的多酚(-)-表没食子儿茶素没食子酸酯或(-)-EGCG在中性或碱性介质中非常不稳定。这种不稳定性导致了低生物利用度。为了提高(-)-EGCG的稳定性，我们在(-)-EGCG的反应性羟基上引入过氧乙酸酯保护基团(在正文中记为1)。高效液相色谱分析表明，在弱碱性条件下，保护的(-)-EGCG类似物比天然的(-)-EGCG稳定6倍。一系列的生物测定表明，1在体外对纯化的20S蛋白酶体没有抑制活性，但在天然的(-)-EGCG作用下，在完整的白血病细胞中显示出更强的蛋白酶体抑制活性，表明存在细胞间转换。1抑制细胞蛋白酶体活性与诱导细胞死亡有关。因此，我们的结果表明，受保护的类似物1可能是绿茶多酚蛋白酶体抑制剂(-)-EGCG的前药。(C)2004爱思唯尔有限公司。保留所有权利。
Green tea has been shown to have many biological effects, including effects on metabolism, angiogenesis, oxidation, and cell proliferation. Unfortunately, the most abundant green tea polyphenol (-)-epigallocatechin gallate or (-)-EGCG is very unstable in neutral or alkaline medium. This instability leads to a low bioavailability. In an attempt to enhance the stability of (-)-EGCG, we introduced peracetate protection groups on the reactive hydroxyls of (-)-EGCG (noted in text as 1). HPLC analysis shows that the protected (-)-EGCG analog is six times more stable than natural (-)-EGCG under slightly alkaline conditions. A series of bioassays show that 1 has no inhibitory activity against a purified 20S proteasome in vitro, but exhibits increased proteasome-inhibitory activity in intact leukemic cells over natural (-)-EGCG, indicating an intercellular conversion. Inhibition of cellular proteasome activity by 1 is associated with induction of cell death. Therefore, our results indicate that the protected analog 1 may function as a prodrug of the green tea polyphenol proteasome inhibitor (-)-EGCG. (C) 2004 Elsevier Ltd. All rights reserved.