Antiproliferative hydrogen sulfide releasing evodiamine derivatives and their apoptosis inducing properties

To explore antitumor agents with high efficiency and selectivity, two series of 16 H₂S donating evodiamine derivatives 8-12 were synthesized and characterized by ¹H NMR, ¹³C NMR and HRMS. Their antiproliferative activities were tested against five cancer cell lines (Bel-7402, MCF-7, SGC-7901, Caco-2 and HL-60) and human normal peripheral blood mononuclear cells. Among them, compound 12c showed the most potent inhibitory activities against human leukemia HL-60 and epithelial colorectal adenocarcinoma Caco-2 cells with IC₅₀ values of 0.58 and 2.02 μM, respectively. Additionally, high selectivity was also observed between human normal peripheral blood mononuclear cells and human leukemia HL-60 cells. Further mechanism studies confirmed that 12c could induce apoptosis, arrest cell cycle at the G₂/M phase and lead to mitochondrial dysfunction in HL-60 cells. Furthermore, western blot assay demonstrated that 12c induced the intrinsic apoptotic mitochondrial pathway by upregulating protein expression of Bax, cytochrome c, caspase-3, -9 and p53, and downregulating the relative levels of Bcl-2. The levels of cell cycle related proteins cyclin B1 and cdc2 were also downregulated in which G₂/M phase arrest was confirmed. Overall, 12c possessed immense potential for the discovery of antitumor candidates with high efficiency and selectivity.