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  3. Anti-tumor effects of artemisinin-based oligomers: From monomer to trimer as a novel drug-enhancing strategy

Anti-tumor effects of artemisinin-based oligomers: From monomer to trimer as a novel drug-enhancing strategy

  • Eur J Med Chem. 2025 Apr 5:287:117313. doi: 10.1016/j.ejmech.2025.117313.
Bingying Jiang 1,  Jiaoying Wang 2,  Lin Yue 3,  Zejin Zhang 2,  Jiagang Lv 2,  Jianping Chen 4,  Jianguo Cao 5,  Fujiang Guo 6,  Qingjie Zhao 7
Affiliations

Affiliations

  • 1 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai Frontiers Science Center for TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China.
  • 2 Shanghai Frontiers Science Center for TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China.
  • 3 Shanghai Frontiers Science Center for TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China; College of Life Sciences, Shanghai Normal University, Shanghai, 200234, China.
  • 4 Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 5 College of Life Sciences, Shanghai Normal University, Shanghai, 200234, China. Electronic address: cao101@shnu.edu.cn.
  • 6 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: gfj@shutcm.edu.cn.
  • 7 Shanghai Frontiers Science Center for TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China. Electronic address: zhaoqingjie@shutcm.edu.cn.
PMID: 39914142 DOI: 10.1016/j.ejmech.2025.117313
Abstract

Artemisinin and its derivatives (ARTs) are being studied for their potential anti-tumor activity. Dimerization of artemisinin has been proposed as a promising means of enhancing drug efficacy. However, the sequential progression from monomers to dimers and trimers, retaining a consistent β-configuration, has not been previously investigated in terms of its effect on compound activity. To investigate the effect of various oligomeric forms on drug potency, we synthesized β-configuration-based ARTs, namely a monomer, dimer, and trimer, and rigorously characterized their structure. We evaluated the antitumor efficacy of these compounds against MCF-7 breast Cancer cells. The artemisinin trimer 6a (β, β, β) exerted a stronger cytotoxic effects against MCF-7 breast Cancer cells, with an IC50 value of 0.09 ± 0.03 μM, than did the monomer (β) or dimer (β, β), which had IC50 values of >50 and 3.14 ± 0.54 μM, respectively. This specific configuration induced alterations in nuclear morphology, inhibited colony formation, and facilitated Cancer cell death. Mechanistic studies revealed that 6a (β, β, β) promoted Apoptosis by modulating the Bax-caspase 3 signaling pathway and induced Ferroptosis by regulating key signaling molecules, including GPX4. This study introduces an innovative methodology-a stepwise synthesis strategy progressing from monomers to dimers and trimers-to explore the relationship between oligomeric structure and drug activity. These findings provide novel insight into the architecture-activity relationship of ART derivatives, offering a foundation for advancing drug design and improving clinical applications.

Keywords

Anti-tumor activity; Anti-tumor mechanism; Artemisinin polymeric derivatives; β configuration.

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