The Discovery Of Carbolines Of GSK-3β Inhibitors

Glycogen synthase kinase-3p (GSK-3β) plays a key role in the course of insulin signal transduction, which affects the concentration of blood sugar by phosphorylating the glycogen kinase. Potential GSK-3β inhibitors provide an alternative strategy for treating type II diabetes. In this dissertation, in order to discover novel high-efficiency GSK-3β small molecule inhibitors by the computer molecular design and synthesis, GSK-3β was taken as the target. It can be divided into two parts as follows:In the first part, based on the previous work of our laboratory, four representative compounds were selected from the target compounds which were synthesized, then we evaluated the interaction model between these compounds and GSK-3(3by molecular docking with AutoDock software. The result indicates that:the hydrogen bonding plays a role between all the target compounds and GSK-3p, and there are some inhibitory activities in all of them.In the second part, β-carboline is a kind of compound of the pyridine and indole ring, the classic method of cyclization reaction is P-S reaction, some3-substituted β-carbolines and two1-keto-substituted β-carbolines were synthesized by using the L-tryptamine or L-tryptophan as raw materials, then the structure of the target compounds were verified with ESI-MS、1HNMR. After GSK-3β inhibitory activity testing in vitro, several new GSK-3β kinase inhibitors were found, and the IC50values of which are in the level of micro mole per liter. Among them, the inhibitory activity of3-carboxylic acid-p-carboline is the best, and its IC50value is1.428μmol/L.