Studies On The Synthesis And Bioactivity Of α-carbolines As GSK-3β Inhibitors

Diabetes has become the third killer after cardiovascular disease and cancer which cause significant health concern. The most clinically effective anti-diabetes agents are associated with problems of weight gain, lactic acidosis, hepatoxicity, liver damage and gastrointestinal side-effects. Therefore, it becomes a hotspot to develop novel antidiabetic agents with high efficacy and low toxicity.Glycogen synthase kinase3β(GSK-3(3) is an important drug target of diabetes type Ⅱ, Alzheimer’s and cancer.α-carbolines have broad biological activities, but they are rarely reported as kinase inhibitors. As a-carboline has hydrophobic aromatic rings with enough room for optimization, it is considered to increase the inhibitory activity by introducing amino-group to4-site of the compound.Thus, a-carboline was synthesized from benzotriazol and2-chloropyridine by modified Graebe-Ullmann reaction. After oxidation and chlorination, an important intermediate4-chloro-α-carboline was given. Buchwald-Hartwig coupling reaction was choosed to be the appropriate route for4-N substituted a-carboline.9compounds were screened by Caliper Mobility Shift Assay on kinase GSK-3β in vitro. The result showed that we had4moderate active inhibitors. The lowest IC50value of all is compound35c which was5.1μmol·L-1. Moreover, the molecular docking was studied on2typical compouds via Autodock. By discussing the interaction mode of small molucular and GSK-3(3, we found that hydrogen bond may play an improtant role in inhibitory activity, we believe that hydrogen bond strenthen the integration of inhibitor and GSK-3β, stablizied the inhibitor. Our result will be helpful in the futrue designing of GSK-3β inhibitors.In order to investigate the inhibitory effects of different substitution sites, we designed2-uramido-a-carboline derivatives and utilize the molecular docking method to confirm the rationality of the plan.2-amino-a-carboline was synthesized by modified Cu-catalyzed Ullmann reaction. By reacting with all kinds of isocyanates, we synthezed9derivatives which were all confirmed to be new compounds by searching the database. This synthesis method provides a convenient and effective way to synthesize such derivatives.