Anti-tumor Effects of Artemisinin-Based Oligomers: From Monomer to Trimer as a Novel Drug-Enhancing Strategy

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.