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

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.