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.
摘要：
基于先前从1,4：3,6-二脱水-d-果糖和邻苯二胺开始的四环和三环苯并咪唑的合成，通过用双（三氟乙酰氧基）碘苯（PIFA）氧化4,7-二甲氧基-苯并咪唑类似物，然后用各种脂肪胺和芳香族胺取代，获得了一系列5（6）-氨基取代的四环和三环苯并咪唑酮。目标苯并咪唑醌的生物学评估表明，所有芳基氨基取代的苯并咪唑醌都具有对人胃癌细胞（MGC-803）的有效抗肿瘤活性，尤其是化合物a21-2。此外，化合物a21-2抑制胃癌细胞增殖和细胞集落形成。机制研究表明，化合物a21-2诱导ROS产生，这随后引起DNA损伤和ATM/Chk2的激活,导致G2/M期停滞。ROS激活c-JunN末端激酶(JNK)途径以诱导线粒体介导的细胞凋亡。体内研究表明,化合物a21-2抑制裸鼠中肿瘤的生长,而没有显著的全身毒性。这些发现表明化合物a21-2代表有希望的候选抗肿瘤药物。
