Study On The Design, Synthesis And Structure - Activity Relationship Of Benzylthiazinones GSK 3β Non - ATP Competitive Inhibitors

Glycogen Synthase Kinase 30 (GSK 30) is a multifunctional serine/threonine protein kinase; it has important relations with a variety of diseases, such as type 2 diabetes, Alzheimer’s disease and cancers. Therefore, study of GSK 30 inhibitors has a promising application prospect.The recent progress in development of GSK 3β inhibitors was reviewed in chapter 1. Recently, mainly three kinds of small molecular GSK 3β inhibitors had been reported. The first class was metal ions; the second kind was ATP competitive inhibitor with preferable activity but poor selectivity; the last type of inhibitor was non-ATP competitive which had a higher selectivity and more promising application.In chapter 2, the leading compound HZjb (IC50=100μM) and VP0.7 (IC50=3 μM) were modified and optimized by reasonable design.58 derivatives were synthesized, in which 6 active compounds (IC50<30μM) were found. These compounds were all unreported and had a new core structure of benzothiazinone. By kinetic analysis, the compounds WBc-8 (IC50=11.9μM) was confirmed to be non-ATP competitive and non-substrate competitive. Active compounds WBc-8 and WBc-11 were selected for cell experiment of GSK 3β inhibitory, and the result demonstrated that their inhibitory activities were as good as positive control compound TDZD-8. Based on these results, the preliminary SARs of this series derivatives were also summarized, which could guide the subsequent work of structural modification in the future.In chapter 3, main works were focused on the modification and optimization of BTZs by hopping and other CADD methods. The preliminary activity information had been got.