%0 Journal Article
%T Design, synthesis and antitumour activity of novel 5(6)-amino-benzimidazolequinones containing a fused morpholine.
%A Wang H
%A Meng Y
%A Yang J
%A Huang H
%A Zhao Y
%A Zhu C
%A Wang C
%A Liu FW
%A Wang H
%A Meng Y
%A Yang J
%A Huang H
%A Zhao Y
%A Zhu C
%A Wang C
%A Liu FW
%J Eur J Med Chem
%V 238
%N 0
%D Aug 2022 5
%M 35594653
%F 7.088
%R 10.1016/j.ejmech.2022.114420
%X 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.