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

Eur J Med Chem. 2022 May 11;238:114420. doi: 10.1016/j.ejmech.2022.114420. Online ahead of print.ABSTRACTBased 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.PMID:35594653 | DOI:10.1016/j.ejmech.2022.114420
Source: European Journal of Medicinal Chemistry - Category: Chemistry Authors: Source Type: research