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.

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.

• Authors: Chengcheng Fan, Ting Zhong, Huarong Yang, Ying Yang, Daoping Wang, Xiaosheng Yang, Yongnan Xu, Yanhua Fan
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 190 Pg. 112108 (Mar 15 2020) ISSN: 1768-3254 [Electronic] France
• PMID: 32058239 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Benzimidazoles
• Protein Kinase Inhibitors
• Quinazolinones
• AURKA protein, human
• Aurora Kinase A

Topics

• Antineoplastic Agents (chemical synthesis, metabolism, pharmacology)
• Apoptosis (drug effects)
• Aurora Kinase A (antagonists & inhibitors, metabolism)
• Benzimidazoles (chemical synthesis, metabolism, pharmacology)
• Catalytic Domain
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Design
• Drug Screening Assays, Antitumor
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Molecular Docking Simulation
• Protein Binding
• Protein Kinase Inhibitors (chemical synthesis, metabolism, pharmacology)
• Quinazolinones (chemical synthesis, metabolism, pharmacology)