Design And Synthesis Of EGCG Analogs As Proteasome Inhibitors

The majority of eukaryotic cell protein degradation by the ubiquitin-proteasome pathway (UPP) of the regulation and control. Have reported more than 80% of intracellular protein degradation in the proteasome. Proteasome is a widely distributed in the eukaryotic cell cytoplasm and the nucleus of multi-subunit macromolecular complex, is a function of a variety of protein hydrolysis of macromolecular complexes, which bear the cells in the pan-protein degradation Ub-proteasome pathway plays a catalytic role. Not only can catalytic proteasome degradation of abnormal proteins, and in many key regulatory proteins play an important role, these proteins involved in autoimmune diseases such as cancer and the pathogenesis of human diseases, cell metabolism is an important component of.Molecular Biology study found that epigallocatechin gallate (EGCG) on the proteasome (proteasome) has a strong inhibitory activity, in vitro IC50 = 86nM, in vivo activity of 18μM. However, EGCG as a lead compound instability in the human body, reducing bioavailability. In order to improve the stability of EGCG with fluorinated benzoic acid gallic acid replacement, design and semi-synthesized 16 new analogues of EGCG, a decrease of easily oxidized molecules in the number of phenolic hydroxyl group, and 6 EGCG methylated derivatives were synthesized.Among these analogs, the compounds 5,6,7,8 have shown better inhibit activities of proteasome than EGCG, and their per-acetates(5b, 6b, 7b, 8b) were more effective in killing human Leukaemia Raji cell (Jurkat T) than EGCG peracetate.The specific content of this paper include: The first, in the laboratory has been established on the TP extracts re-extraction derivatization method based on yield better and more convenient method of operation, by the pure intermediates that is, benzyl-protected EGC (Bn-EGC), methoxy-protected EGC (Me-EGC), which are synthetic analogs of EGCG the most important intermediates. Second, HPLC tracking the process of hydrolysis of acetylated EGCG. To determine the hydrolysis time, EGCG effectively avoid the occurrence of a variety of side effects. Third, this study was the first time synthesis the methylated flavanols elements. Established the synthetic methods, flavanol-rich type of active compounds and increased the stability of EGCG. Fourth, some of EGCG derivatives have done a preliminary proteasome, human leukemia cells and animal activity. Activity to be carried out need further tests.