Design, synthesis and in vitro and in vivo biological evaluation of matrine derivatives as efficient anticancer agents with the characteristics of endoplasmic reticulum stress induction and apoptosis activation.

Natural products have made significant contributions to the prevention and treatment of malignant tumors. However, natural products often suffer from low efficacy and potential toxicity. Therefore, modifying and optimizing lead compounds derived from natural products is a crucial strategy in drug development. In this study, we used matrine as an ideal lead compound and synthesized 27 matrine derivatives by incorporating indole structures with known antitumor activity. The antiproliferative effects of these derivatives were evaluated against human cancer cell lines (A549, HeLa, and Huh-7) and normal human liver cells (LO2). Compared to matrine, most of the derivatives exhibited superior antiproliferative activity. Notably, compound 9q showed significant antiproliferative activity against HeLa cells, with an IC50 value of 4.48 μM, demonstrating approximately 1500-fold greater potency than matrine (IC50 = 6756 μM). Further mechanistic studies revealed that compound 9q inhibited HeLa cell proliferation by modulating the expression of PI3K/AKT and Activating transcription factor 4 (ATF4) proteins. The upregulation of ATF4 promoted the expression of the key endoplasmic reticulum stress (ER stress) protein C/EBP homologous protein (CHOP). In the HeLa xenograft mouse model, compound 9q demonstrated significant anticancer efficacy. Therefore, compound 9q holds promise as a potential lead compound for the development of novel anticancer drugs.