2. Academic Validation
  3. Design, synthesis, biological evaluation of 6-(2-amino-1H-benzo[d]imidazole-6-yl)quinazolin-4(3H)-one derivatives as novel anticancer agents with Aurora kinase inhibition

Design, synthesis, biological evaluation of 6-(2-amino-1H-benzo[d]imidazole-6-yl)quinazolin-4(3H)-one derivatives as novel anticancer agents with Aurora kinase inhibition

  • Eur J Med Chem. 2020 Mar 15;190:112108. doi: 10.1016/j.ejmech.2020.112108.
Chengcheng Fan 1,  Ting Zhong 2,  Huarong Yang 3,  Ying Yang 2,  Daoping Wang 2,  Xiaosheng Yang 2,  Yongnan Xu 4,  Yanhua Fan 5
Affiliations

Affiliations

  • 1 The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, China; Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2 State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, China.
  • 3 The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, China.
  • 4 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: ynxu@syphu.edu.cn.
  • 5 State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, China. Electronic address: fanyhkyem@163.com.
PMID: 32058239 DOI: 10.1016/j.ejmech.2020.112108
Abstract

Aurora A kinase, a member of the Aurora Kinase family, is frequently overexpressed in various human cancers. In addition, Overexpression of Aurora A kinase is associated with drug resistance and poor prognosis in many cancers including breast Cancer. Therefore, Aurora A kinase has been considered as an attractive Anticancer target for the treatment of human cancers. Herein, A series of 6-(2-amino-1H-benzo[d]imidazole-6-yl)quinazolin-4(3H)-one derivatives were designed, synthesized, and evaluated as Aurora A kinase inhibitors. The cell-based cytotoxicity assays showed that compound 16h was the most potent cytotoxic agent against all tested Cancer cells and had a lower IC50 value than ENMD-2076 against MDA-MB-231 cells. Meanwhile, Aurora A kinase assay and Western blot analysis showed that 16h inhibited Aurora A kinase with an IC50 value of 21.94 nM and suppressed the phosphorylation of Histone H3 on Ser10 and Aurora A kinase on Thr288, which were consistent with the activation of Aurora A kinase. Accordingly, 16h caused aberrant mitotic phenotypes and obvious G2/M phase arrest in MDA-MB-231 cells and induced caspase-dependent Apoptosis in MDA-MB-231 cells. These results demonstrated that 16h is a potential candidate for the development of Anticancer agents targeting Aurora A kinase.

Keywords

6-(1H-benzo[d]imidazole-6-yl)quinazolin-4(3H)-one derivatives; Aurora A kinase; Cell apoptosis; Cell cycle arrest.

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