2. Academic Validation
  3. Design, synthesis and antitumour activity of novel 5(6)-amino-benzimidazolequinones containing a fused morpholine

Design, synthesis and antitumour activity of novel 5(6)-amino-benzimidazolequinones containing a fused morpholine

  • Eur J Med Chem. 2022 Aug 5:238:114420. doi: 10.1016/j.ejmech.2022.114420.
Haixia Wang 1,  Yao Meng 1,  Jing Yang 1,  Hao Huang 1,  Yifan Zhao 1,  Chuantao Zhu 1,  Cong Wang 2,  Feng-Wu Liu 3
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Research, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
  • 2 Institute of Pharmaceutical Research, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou, 450001, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, 450001, China. Electronic address: wangcong@zzu.edu.cn.
  • 3 Institute of Pharmaceutical Research, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou, 450001, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, 450001, China. Electronic address: fwliu@zzu.edu.cn.
PMID: 35594653 DOI: 10.1016/j.ejmech.2022.114420
Abstract

Based on the previous synthesis of tetracyclic and tricyclic benzimidazoles starting from 1,4:3,6-dianhydro-d-fructose and o-phenylenediamines, a series of 5(6)-amino substituted tetracyclic and tricyclic benzimidazolequinones were obtained through the oxidation of 4,7-dimethoxy-benzimidazole analogues with bis(trifluoroacetoxy)iodobenzene (PIFA) and subsequent substitution with various aliphatic and aromatic amines. Biological evaluations of the target benzimidazolequinones indicated that all the arylamino-substituted benzimidazolequinones possess potent antitumour activity against human gastric Cancer cells (MGC-803), especially compound a21-2. Furthermore, compound a21-2 inhibits gastric Cancer cells proliferation and cell colony formation. Mechanistic investigations showed that compound a21-2 induces ROS production, which subsequently causes DNA damage and activation of ATM/Chk2, leading to G2/M phase arrest. ROS activates the c-Jun N-terminal kinase (JNK) pathway to induce mitochondrial-mediated Apoptosis. In vivo studies showed that compound a21-2 inhibits the growth of tumours in nude mice without significant systemic toxicity. These findings suggest that compound a21-2 represents a promising candidate antitumour drug.

Keywords

1,4:3,6-dianhydro-d-fructose; Antitumour activity; Benzimidazolequinone; Fused morpholine; ROS generation.

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