Acylation as an Approach to Enhance the Cancer Preventive Effect of EGCG

描述(由申请人提供)： 本项目的目标是开发酰化反应作为一种方法来提高(-)-表没食子儿茶素没食子酸酯(EGCG)的稳定性、生物利用度和防癌活性。表没食子儿茶素没食子酸酯是绿茶中的主要多酚。以前的研究已经证明，EGCG在不同的动物模型中抑制肿瘤的发生和生长。然而，EGCG不是很稳定，生物利用度有限。这个项目的基本原理是基于我们最近的结果，与EGCG相比，过乙酰化的EGCG在细胞培养系统中具有更高的细胞摄取和生长抑制活性，并且在小鼠中具有更高的生物利用度。在本项目中，我们将合成短链和长链酰化的EGCG衍生物，并比较这些衍生物与EGCG的稳定性、细胞摄取、细胞生长抑制和诱导细胞凋亡的作用。将大量合成两种生物利用率最高、生物活性最高的衍生物，以研究其对偶氮甲烷(AOM)处理的小鼠模型中异常隐窝病灶(ACF)形成的抑制作用。这种抑制作用将与结肠组织和血液中的EGCG水平相关。我们计划在以下特定目标上实现我们的目标：1.合成EGCG的酰化衍生物，并比较它们与EGCG在人结肠癌细胞系(HCT-116和HT-29)中的稳定性、细胞摄取、细胞生长抑制和诱导凋亡。2.研究乙酰化EGCG预防AOM模型小鼠ACF形成的生物利用度和有效性。

DESCRIPTION (provided by applicant): The objective of this project is to develop acylation as an approach to increase the stability, bioavailability, and cancer preventive activity of (-)-Epigallocatechin-3-gallate (EGCG), the major polyphenol from green tea. Previous studies have demonstrated that EGCG inhibited carcinogenesis and tumor growth in different animal models. However, EGCG is not very stable and has limited bioavailability. The rationale of this project is based on our recent results that peracetylated EGCG has greater cellular uptake and growth inhibitory activity in cell culture systems and higher bioavailability in mice as compared to EGCG. In this project, we will synthesize short-chain and long-chain acylated EGCG derivatives and compare the stability, cellular uptake, cell growth inhibition, and induction of apoptosis of these derivatives with those of EGCG. The two most bioavailable and bioactive derivatives will be synthesized in large quantities to study its inhibitory effect against aberrant crypt foci (ACF) formation in the azoxymethane (AOM)-treated mouse model. The inhibitory action will be correlated with the levels of EGCG in colon tissues and blood. We plan to accomplish our objective in the following specific aims: 1. To synthesize acylated derivatives of EGCG and to compare their stability, cellular uptake, cell growth inhibition, and induction of apoptosis in human colon cancer cell lines (HCT-116 and HT-29) with those of EGCG. 2. To determine the bioavailability and efficacy of acylated EGCG in the prevention of ACF formation in the AOM-treated mouse model.