Design, synthesis, and biological evaluation of novel artemisinin-based HDAC inhibitors with antitumor and antimalarial activities

In addition to the clinical applications as antimalarial agents, artemisinin and its derivatives have demonstrated significant potential in antitumor drug discovery. To enhance antitumor activity, a novel series of artemisinincontaining histone deacetylase (HDAC) inhibitors was designed using a hybrid strategy that fused the artemisinin moiety with HDAC inhibitory functionality. A triazole ring was incorporated into the linker region to improve water solubility. Among these derivatives, compound Hj-9 exhibited broad spectrum and especially potent antitumor activity against acute myelogenous leukemia cells MV4-11 (IC50 = 0.38 mu M). Mechanism studies revealed that Hj-9 effectively arrests the cancer cell cycle at the G0/G1 phase and exhibits significant antiangiogenic activity. Further investigation demonstrated that Hj-9 induces cell autophagy, apoptosis, and mitochondrial membrane potential changes. Enzyme inhibitory activities against HDAC isoforms indicated that Hj-9 broadly inhibits multiple HDAC subtypes, especially showing particularly good inhibition of HDAC6. Furthermore, the antimalarial evaluation revealed derivatives Hj-1, Hj-2 and Hj-9 showed good antimalarial activity.