Synthesis and Biological Evaluation of Matrine Derivatives as Anticancer Agents

Abstract Matrine, a quinoline alkaloid, was extracted and isolated from the dried roots, fruits, and other plant parts of Sophora flavescens Aiton. Although it exhibits moderate antitumor activity, associated toxicity limits its clinical application. Using matrine as a lead compound, we designed, synthesized, and evaluated a series of novel matrine‐derived hybrid compounds for in vitro cytotoxicity. The preliminary screening revealed that most synthesized compounds showed improved inhibitory activity against four cancer cell lines (SGC‐7901, MCF‐7, HepG2, and A549) compared to matrine. Notably, compound 4k demonstrated significant potency against HepG2 cells, exhibiting an IC₅₀ value of 16.80 ± 0.49 µM. This compound induced dose‐dependent cell cycle arrest at the G₀/G₁ phase, triggering apoptosis in HepG2 cells. qRT‐PCR analysis showed that compound 4k downregulated Bcl‐2 expression while upregulating p53, Bax, caspase‐3, and caspase‐9. Western blot analysis further confirmed that compound 4k significantly reduced Bcl‐2 levels and increased the expression of caspase‐3 and caspase‐9. Molecular docking simulations indicated that compound 4k displayed a strong binding affinity for the anti‐apoptotic protein Bcl‐2, suggesting a potential mechanism of action through regulation of the Bcl‐2 signaling pathway. Thus, the novel matrine derivative compound 4k represents a promising candidate for developing anti‐cancer agents targeting human hepatoma.