Design, synthesis and anti-hepatocarcinoma activity of benzimidazole-fused carbazole derivatives by inducing PANoptosis.

PANoptosis, a combination of apoptosis, pyroptosis, and necroptosis, plays a key role in the occurrence and development of tumors. In this article, a series of benzimidazole-carbazole-based compounds were developed, which exhibited broad cytotoxicity against eight different cancer cell lines, with significant activity against HepG2 cells. Among them, 3m shows the strongest antiproliferative by preventing HepG2 cells in the G2/M stage. Moreover, 3m can effectively inhibit cell colony formation and migration. Mechanistically, 3m induce PANoptosis in HepG2 cells by upregulating of NLRP3, BAX/BCL2, and cleaved caspase3 expressions, along with the cleavage of gasdermin E (GSDME) into its N-terminal fragment (GSDME-N) and increasing phosphorylation level of MLKL. Additionally, 3m responds to pH/Viscosity. The present study describes a novel therapeutic 3m for the treatment of cancer, providing valuable insights into understanding the anticancer properties of these compounds.