A novel matrine derivative exerts antitumor effects against hepatocellular carcinoma by inducing oxidative stress and DNA damage.

DNA has long been a major target in the development of anticancer drugs. Natural products, as an important source of antitumor agents, play a key role in cancer prevention and treatment. Matrine is a natural quinoline alkaloid isolated from the medicinal plant Sophora flavescens. In this study, using matrine as a lead compound, we designed and synthesized 25 novel matrine derivatives containing a naphthalimide moiety based on a molecular hybridization strategy. The antiproliferative activities of these derivatives were evaluated against several human cancer cell lines (Hela, A549, HepG2 and MHCC97H) and a normal human hepatocyte line (LO2). Results showed that most derivatives exhibited significantly enhanced antiproliferative activity compared to matrine. Among them, compound 15 h demonstrated the most potent effect, with an IC₅₀ value of 4.92 ± 0.33 µM against MHCC97H cells. Further mechanistic studies revealed that 15 h can effectively intercalate into and bind to DNA, significantly inhibit colony formation and migration of tumor cells, arrest the cell cycle at the G0/G1 phase, and induce apoptosis in a dose-dependent manner. In addition, 15 h promoted the accumulation of intracellular reactive oxygen species (ROS). Upregulation of γ-H2AX, a key DNA damage marker, was confirmed by both immunofluorescence and Western blot analysis, indicating that the antitumor activity of 15 h is closely associated with the induction of DNA damage. In conclusion, compound 15 h effectively suppresses tumor cell proliferation and induces apoptosis through ROS-mediated DNA damage, demonstrating promising potential for development as a novel DNA-targeting anticancer agent.