Synthesis and evaluation of cytotoxic activities of artemisinin derivatives.

Artemisinin is a naturally occurring antimalarial agent which has shown potent anticancer activity. In this work, new artemisinin derivatives with the piperazine group were synthesized. The cytotoxic activities of derivatives 5a- 5d were evaluated by MTT assay against ten cell lines. The results showed that 5a- 5d were more effective in inhibiting cancer cell growth than artemisinin. 5d was the most active against HepG2 and PLC- PRF-5 cells and presented no cytotoxicity on L-02 cells. Hoechst 33342 staining and flow cytometry experiment revealed that 5d could induce HepG2 and PLC- PRF-5 cell apoptosis. Flow cytometry analysis showed that 5d induced the loss of mitochondrial membrane potential ( MMP) and increased the levels of intracellular free calcium and reactive oxygen species. 5d also induced cell cycle arrest in G2/M phase in HepG2 cells. According to the results of Western blotting and caspase-3 kit, 5d could significantly increase the content of p53, bax, Apaf-1, and caspase-3 and decrease the protein level of bcl-2, pro-caspase-9, and pro-caspase-3 in HepG2 cells. These findings indicate that 5d activates the mitochondria-mediated apoptotic pathway in HepG2 cells and may merit further investigation as a potential therapeutic agent for hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]