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. Derived from benzimidazole scaffold-based structural optimization, compound 8 f effectively inhibited MGC-803 cells (IC50 = 2.12 mu M). Compound 8 f induced apoptosis in MGC-803 cells by elevating intracellular ROS levels and activating the MAPK signaling pathway. Compound 8 f effectively suppressed tumor growth in xenograft models without causing noticeable toxicity. image