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Acta Chimica Sinica >

2012 , Vol. 70 >Issue 18: 1974 - 1978

DOI: https://doi.org/10.6023/A12060317

Article

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

  • Wang Yuan ,
  • Jiang Yongjun ,
  • Zhang Meiqing ,
  • Shen Yin
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  • a Department of Chemistry, Zhejiang University, Hangzhou 310027;
    b Ningbo Institute of Technology, Zhejiang University, Ningbo 315104

Received date: 2012-06-18

  Online 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).

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Abstract

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 3β (GSK-3β); molecular docking; α-carboline; synthesis; GSK-3 inhibitor

Cite this article

Wang Yuan , Jiang Yongjun , Zhang Meiqing , Shen Yin . Synthesis, Biological Activity and Molecular Docking Research of α-Carbolines as GSK-3β Inhibitors[J]. Acta Chimica Sinica, 2012 , 70(18) : 1974 -1978 . DOI: 10.6023/A12060317

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