Gang Jia, Yuanying Wang, Jikuan Wang, Bingxin Yu, Haiyang Zhao, Ze Zhao, Wenming Zhao, Ya Gao, Bo Wang, Zhiyu Song
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引用次数: 0
摘要
鉴于胃癌的恶性程度,开发高效低毒的靶向药物对于延长患者生存期和改善患者预后至关重要。在本研究中,我们基于苯并咪唑支架进行了结构优化。值得注意的是,化合物 8 f 在 MGC803 细胞中具有最强的抗增殖活性,并能诱导细胞周期停滞在 G0/G1 期。进一步的机理研究表明,化合物 8 f 通过提高细胞内活性氧(ROS)水平、激活丝裂原活化蛋白激酶(MAPK)信号通路以及相应的标志物变化,导致 MGC803 细胞凋亡。此外,体内研究还验证了化合物 8 f 对 MGC803 细胞异种移植模型中肿瘤生长的抑制作用,且无明显毒性。我们的研究表明,化合物 8 f 有望成为开发抗胃癌药物的一种潜在而安全的先导化合物。
Benzimidazole-based structure optimization to discover novel anti-gastric cancer agents targeting ROS/MAPK pathway
Given the malignancy of gastric cancer, developing highly effective and low-toxic targeted drugs is essential to prolong patient survival and improve patient outcomes. In this study, we conducted structural optimizations based on the benzimidazole scaffold. Notably, compound 8 f presented the most potent antiproliferative activity in MGC803 cells and induced cell cycle arrest at the G0/G1 phase. Further mechanistic studies demonstrated that compound 8 f caused the apoptosis of MGC803 cells by elevating intracellular reactive oxygen species (ROS) levels and activating the mitogen-activated protein kinase (MAPK) signaling pathway, accompanied by corresponding markers change. In vivo investigations additionally validated the inhibitory effect of compound 8 f on tumor growth in xenograft models bearing MGC803 cells without obvious toxicity. Our studies suggest that compound 8 f holds promise as a potential and safe lead compound for developing anti-gastric cancer agents.
期刊介绍:
The Journal of Biochemical and Molecular Toxicology is an international journal that contains original research papers, rapid communications, mini-reviews, and book reviews, all focusing on the molecular mechanisms of action and detoxication of exogenous and endogenous chemicals and toxic agents. The scope includes effects on the organism at all stages of development, on organ systems, tissues, and cells as well as on enzymes, receptors, hormones, and genes. The biochemical and molecular aspects of uptake, transport, storage, excretion, lactivation and detoxication of drugs, agricultural, industrial and environmental chemicals, natural products and food additives are all subjects suitable for publication. Of particular interest are aspects of molecular biology related to biochemical toxicology. These include studies of the expression of genes related to detoxication and activation enzymes, toxicants with modes of action involving effects on nucleic acids, gene expression and protein synthesis, and the toxicity of products derived from biotechnology.