Design, synthesis, and mechanistic insights of quinoline-1(3H)-one derivatives as selective DNA intercalating agent targeting triple-negative breast cancer.

Triple negative breast cancer remains one of the most aggressive malignancies with limited targeted therapies and poor survival outcomes. Although DNA-intercalating agents, including natural products exhibit anti-cancer potential by disrupting various cellular processes that rely on DNA-protein interactions, their therapeutic application is limited by poor tumor selectivity and high cytotoxicity to normal cells. Here, through rational design, synthesis and optimization, we have developed a series of novel Quinoline-1(3H)-one derivatives aimed at enhancing selectivity towards TNBC. While several synthesized molecules demonstrated promising anticancer activity across multiple cancer cell lines, compound 4l emerged as the most potent and selective DNA-binding agent, exhibiting low IC50 values in TNBC (IC50 = 2.08 ± 0.67 μM) with minimal cytotoxicity to WI-38 (CC50 = ≥60 μM) a normal lung fibroblasts cell. Importantly, comparative analyses revealed substantially higher selectivity index of compound 4l than the clinical DNA-binding drug doxorubicin. Further in vitro, studies demonstrated that Compound 4l induced G2/M cell cycle arrest and robust, caspase-3 dependent apoptosis. This response was driven by marked intracellular and mitochondrial ROS generation, loss of mitochondrial membrane potential, and non-intercalative electrostatic DNA binding. Collectively, these results highlight compound 4l as a promising, selective anticancer candidate with improved therapeutic potential for TNBC.