糖原合成酶激酶3β（GSK-3β）是神经退化性疾病如早老性痴呆、II型糖尿病、癌症等多种重复杂性疾病的药物靶标,α-咔啉类化合物具有多种生物活性.以GSK-3β为作用靶点,利用Graebe-Ullmann反应合成了α-咔啉,并采用Buchwald-Hartwig偶联反应合成了9个4位取代的α-咔啉胺类衍生物.体外的GSK-3β激酶酶抑制活性测试表明其中4个化合物具有一定的抑制活性,其中化合物3c的IC50值达到了5.1μmol L-1.同时采用了分子对接方法分别研究了化合物2,3c与大分子蛋白的作用模式,初步探讨了影响抑制活性的原因,为进一步的研究提供了依据.%Glycogen synthase kinase 3β（GSK-3β） is an important drug target of neurodegenerative diseases including Alzheimer’s,diabetes type II,cancer.α-Carboline derivatives have many biological activities such as anti-anxiolytic effect,anti-inflammatory,and central nervous system stimulating activities.In this work,a series of 4-N substituted α-carbolines derivatives were discussed as GSK-3β inhibitors.The modified Graebe-Ullmann reaction was optimized to synthesize α-carboline,and polyphosphoric acid was used as cyclizing agent and solvent.After oxidation and chlorination,an important intermediate 4-chloro-α-carboline was obtained.Buchwald-Hartwig coupling reaction was choosed to be the appropriate route for 4-N substituted α-carboline,tris（dibenzylideneacetone） dipalladium（0） and 2-dicyclohexylphosphino2’,4’,6’-triisopropylbiphenyl were used as catalyst and ligand respectively.All the compounds were confirmed by 1H NMR,13C NMR and ESI-MS techniques.9 compounds were screened by Caliper Mobility Shift Assay on kinase GSK-3β in vitro and staurosporine was used as the reference compound.Four new inhibitors with moderate inhibitory activities were found and the smallest IC50value of compound 3c was 5.1 μmol L-1.Moreover,the molecular docking method was used to study the interaction modes of the inhibitors and GSK-3β.Our results will be helpful in the future designing of GSK-3β inhibitors.
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