表没食子儿茶素没食子酸酯（EGCG）氧化物的选择性合成、分离及抗肿瘤活性研究

Cancer is one of the major diseases threatening human health, and dietary factors on cancer prevention and treatment. Epigallocatechin-3-O-gallate (EGCG) is the most abundant catechin of green tea catechin compounds, which has higher antitumor activity. However, the use of EGCG is often hindered by problems such as poor stability, easily oxidized to form complex polymers, is offen limited its application in cancer chemotherapy. Some studies indicated that the activity of EGCG oxides may be stronger than EGCG, but the chemical structures and antitumor activities of the oxide were limitedly reported at home and abroad. In our previously study, part of the EGCG oxides have been chemoselectively synthesized and isolated by EGCG, and found that the quinoid oxide exhibited more potent activity by combined with EGFR in the intestinal Caco2 cell line. In this research: (1) The EGCG oxides will be chemoselectively synthesized through chemical oxidant, and are isolated by Sephadex LH-20 combined with HPLC separation, and guided by LC-MS. 30-40 oxides will be isolated from the above process. (2) Through the pharmacological experimental methods of computer simulation, molecular interactions, flow cytometry and Western Blot, the anti-cancer mechanism of the EGCG oxides is explored. This study has important significance that the antitumor material basis and mechanism research of the EGCG oxides are clarified.

癌症是威胁人类健康的主要疾病之一，膳食因素对癌症具有预防和治疗作用。表没食子儿茶素没食子酸酯（EGCG）是绿茶中含量最丰富的儿茶素类化合物，具有较高的抗肿瘤活性。但EGCG稳定性较差、易氧化形成复杂的聚合物，限制了其作为抗癌药物的研究。有研究表明EGCG氧化物可能比EGCG更强的活性，但国内外对氧化物的化学结构及抗肿瘤活性的报道甚少。前期工作已从EGCG选择性的合成、分离了部分氧化物，并发现水合醌式氧化物可以通过与EGFR结合在肠道细胞Caco2中发挥较好的抗肿瘤作用。本课题的研究：（1）通过化学氧化剂继续选择性的合成氧化物，并以LC-MS导向Sephadex LH-20结合HPLC制备分离，鉴定30-40个氧化物。（2）通过计算机模拟、分子相互作用、流式细胞术、Western Blot等实验方法探索其抗癌机制。本课题对阐明EGCG氧化物抗肿瘤作用物质基础及作用机制的研究有重要意义。

表没食子儿茶素没食子酸酯（EGCG）是绿茶中含量最丰富的儿茶素类化合物，具有较高的抗肿瘤活性，但是EGCG稳定性较差，容易氧化，限制其作为抗癌药物的研究。该项目中研究EGCG的氧化物及其抗肿瘤活性，项目进展顺利，完成了预期的研究目标，主要成果包括如下：通过不同的化学氧化剂氧化分离、纯化得到氧化物45个，由结构鉴定得40个氧化物，其中新化合物有20个；通过计算机辅助药物筛选、分子互作技术以及MTT方法等筛选得到8个具有较强抗肿瘤活性的化合物；在前期合成富集单体化合物以及初筛活性的基础上，进一步通过模拟\实验、细胞\蛋白、体外\体内实验等相结合，对其中的4个化合物完成了抗肿瘤活性机制的研究。通过项目的开展明确了EGCG氧化的化学结构基础；阐明了氧化物通过靶向Notch 1抑制T-ALL细胞的增殖，也为Notch 1为靶点的T-ALL治疗提供研究思路；氧化物与Nimozutumab单抗联合使用为EGFR靶向治疗提供了新的方案和方向。综上所述本项目为EGCG氧化物的抗肿瘤作用物质基础及作用机制奠定了坚实的工作基础。项目资助发表SCI论文6篇，待发表4篇，申请发明专利1项；培养研究生4名。项目投入经费20万元，各项支出与预算相符。