The Semi-synthesis Of Epigallocatechin Analogs As Proteasome Inhibitors

It has been already 4000-5000 years since Chinese used tea as health-drinks. It is extensively absorbed that tea helped to health. The bioactivities of green tea are often attributed to the polyphenols, in particular, Epigallocatechin gallate (EGCG). Further researches disclosed that EGCG displayed the potential anticarcinogenic activity which associated with the inhibitory activity to proteasome. The 20s proteasome is a multicatalytic protease responsible for the degradation of most cellular proteins. One of the mechanism researches found that the ester bond of EGCG is necessary for the inhibitory activity to proteasome. However, the natural EGCG has some disadvantages, such as instability and low bioavailability. In order to optimize the structure of EGCG and improve its bio-activity, 12 EGCG analogs with fluoro-group were designed and synthesized according to the SAR of EGCG and the Docking results. Among these analogs, the compounds 9a, 9b, 9c, 9d have shown better inhibitory activities of proteasome than EGCG, and their per-acetates(10a, 10b, 10c, 10d) were more effective in killing human Leukaemia Raji cell(Jurkat T) than EGCG peracetate.In this thesis, a series of novel fluoro-catechins were first reported, and the semi-synthesis method was explored. These significantly improved the study of EGCG analogs as proteasome inhibitors and candidates of anti-tumor agents.