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

描述（由申请人提供）： 本研究的目的是开发酰化方法，以提高绿色茶中主要多酚物质表没食子儿茶素没食子酸酯（EGCG）的稳定性、生物利用度和癌症预防活性。以往的研究表明，EGCG抑制不同动物模型的致癌作用和肿瘤生长。然而，EGCG不是很稳定，生物利用度有限。该项目的基本原理是基于我们最近的研究结果，即与EGCG相比，全乙酰化的EGCG在细胞培养系统中具有更大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。在本计画中，我们将合成短链及长链的酰化表没食子儿茶素衍生物，并比较这些衍生物与表没食子儿茶素的稳定性、细胞摄取、细胞生长抑制及诱导细胞凋亡。将大量合成两种最具生物利用度和生物活性的衍生物，以研究其对氧化偶氮甲烷（AOM）处理的小鼠模型中异常隐窝灶（ACF）形成的抑制作用。抑制作用将与结肠组织和血液中的EGCG水平相关。我们计划在以下具体目标中实现我们的目标：1.合成表没食子儿茶素没食子酸酯酰化衍生物，并比较其稳定性、细胞摄取、细胞生长抑制和诱导人结肠癌细胞株（HCT-116和HT-29）凋亡。2.在AOM处理的小鼠模型中确定酰化EGCG在预防ACF形成中的生物利用度和功效。

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.