α-咔啉类GSK-3β抑制剂的合成、活性评价和分子对接研究  

Synthesis, Biological Activity and Molecular Docking Research of α-Carbolines as GSK-3β Inhibitors

作　　者：王媛[1] 蒋勇军[2] 张美青[1] 沈银[1] 

机构地区：[1]浙江大学化学系,杭州3100271 [2]浙江大学宁波理工学院生化分院,宁波315104

出　　处：《化学学报》2012年第18期1974-1978,共5页Acta Chimica Sinica

基　　金：国家自然科学基金(No.20803063);宁波市自然科学基金(No.2010A610024)资助~~

摘　　要：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.

关 键 词：糖原合成酶激酶3β(GSK-3β) 分子对接 α-咔啉 合成 GSK-3抑制剂 

分 类 号：O626.23[理学—有机化学]