化学学报 ›› 2012, Vol. 70 ›› Issue (18): 1974-1978.DOI: 10.6023/A12060317 上一篇    下一篇

研究论文

α-咔啉类GSK-3β抑制剂的合成、活性评价和分子对接研究

王媛a, 蒋勇军b, 张美青a, 沈银a   

  1. a 浙江大学化学系 杭州 310027;
    b 浙江大学宁波理工学院生化分院 宁波 315104
  • 收稿日期:2012-06-18 出版日期:2012-09-28 发布日期:2012-08-06
  • 通讯作者: 蒋勇军
  • 基金资助:

    项目受国家自然科学基金(No. 20803063)和宁波市自然科学基金(No. 2010A610024)资助.

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

Wang Yuana, Jiang Yongjunb, Zhang Meiqinga, Shen Yina   

  1. a Department of Chemistry, Zhejiang University, Hangzhou 310027;
    b Ningbo Institute of Technology, Zhejiang University, Ningbo 315104
  • Received:2012-06-18 Online:2012-09-28 Published:2012-08-06
  • Supported by:

    Project supported by the National Natural Science Foundation of China (No. 20803063) and the Natural Science Foundation of Ningbo (No. 2010A610024).

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5.1 μmol·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.

关键词: 糖原合成酶激酶3&beta, (GSK-3β), 分子对接, α-咔啉, 合成, GSK-3 抑制剂

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-dicyclohexylphosphino-2',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 IC50 value 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.

Key words: glycogen synthase kinase 3&beta, (GSK-3β), molecular docking, α-carboline, synthesis, GSK-3 inhibitor