2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel artemisinin-based HDAC inhibitors with antitumor and antimalarial activities

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

  • Bioorg Chem. 2025 Apr:157:108312. doi: 10.1016/j.bioorg.2025.108312.
Jin He 1,  Youyou He 2,  Yunan Qian 3,  Shuaibo Du 2,  Ruikang Sun 4,  Yujiao Liu 4,  Jiping Yu 4,  Yi Ding 5,  Siyuan Zhou 6,  Lubin Jiang 7,  Shengzheng Wang 8
Affiliations

Affiliations

  • 1 School of Life Science and Medicine, Northwest University, Xi'an, Shaanxi Province, China; School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi Province, China.
  • 2 Faculty of Pharmacy, School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an, Shaanxi Province, China.
  • 3 Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China.
  • 4 School of Life Science and Medicine, Northwest University, Xi'an, Shaanxi Province, China.
  • 5 Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
  • 6 School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi Province, China. Electronic address: zhousy@fmmu.edu.cn.
  • 7 Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China. Electronic address: lbjiang@ips.ac.cn.
  • 8 School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi Province, China. Electronic address: wangshengzheng001@163.com.
PMID: 40022850 DOI: 10.1016/j.bioorg.2025.108312
Abstract

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 artemisinin-containing 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 μM). 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.

Keywords

Acute myelogenous leukemia; Antimalarial activity; Antitumor activity; Artemisinin derivatives; HDAC inhibitors.

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