Benzimidazole-based structure optimization to discover novel anti-gastric cancer agents targeting ROS/MAPK pathway

Area of Science:

• Medicinal Chemistry
• Oncology
• Pharmacology

Background:

• Gastric cancer remains a significant health concern, necessitating the development of effective and low-toxicity targeted therapies.
• The benzimidazole scaffold is a promising structural basis for novel anti-cancer drug discovery.

Purpose of the Study:

• To synthesize and evaluate novel benzimidazole derivatives as potential anti-gastric cancer agents.
• To investigate the mechanism of action and in vivo efficacy of the most potent compound.

Main Methods:

• Structural optimization of benzimidazole compounds.
• In vitro antiproliferative assays using MGC803 gastric cancer cells.
• Cell cycle analysis and apoptosis assays.
• Reactive oxygen species (ROS) and mitogen-activated protein kinase (MAPK) pathway analysis.
• In vivo efficacy and toxicity studies in xenograft mouse models.

Main Results:

• Compound 8f exhibited the most potent antiproliferative activity against MGC803 cells.
• Compound 8f induced G0/G1 cell cycle arrest and apoptosis in MGC803 cells.
• Elevated intracellular ROS levels and activated MAPK signaling were observed.
• Compound 8f demonstrated significant tumor growth inhibition in vivo without apparent toxicity.

Conclusions:

• Compound 8f is a potent inhibitor of gastric cancer cell proliferation and tumor growth.
• The anti-cancer effects of compound 8f involve ROS elevation and MAPK pathway activation.
• Compound 8f represents a promising and safe lead compound for the development of novel anti-gastric cancer therapeutics.