Potent Biological Activity by a Synthetic Cu(I) Cationophore Redistributing Intracellular Copper Pools
Nathan Renier1, Gianluca Weyckmans Mele1,2, Pierre Lelièvre3,4
1Université libre de Bruxelles (ULB), Engineering of Molecular NanoSystems, Ecole Polytechnique De Bruxelles, Avenue F. Roosevelt 50, CP165/64, 1050 Brussels, Belgium.
Journal of the American Chemical Society
|December 23, 2025
Summary
Researchers developed novel lipophilic compounds that act as copper(I) ionophores. These compounds show potent anticancer activity by disrupting cellular copper distribution, suggesting a new therapeutic strategy.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Cell Biology
Background:
- Copper is essential but toxic; homeostasis is critical.
- Disrupting copper balance is a potential anticancer strategy.
- Copper(I) (Cu(I)) transport proteins like Ctr1 regulate cellular copper.
Purpose of the Study:
- To design and synthesize novel biomimetic Cu(I) ionophores.
- To evaluate their ability to transport copper across membranes.
- To assess their anticancer activity in hepatocarcinoma cells.
Main Methods:
- Synthesis of lipophilic compounds with coordinating (benz)imidazole groups.
- Liposome-based assays with fluorescent probes to demonstrate Cu(I) transport.
- Yeast cell growth assays to confirm cellular copper transport.
- In vitro anticancer activity assays in hepatocarcinoma cells.
- Synchrotron X-ray fluorescence microscopy to study subcellular copper distribution.
Main Results:
- Developed lipophilic ionophores that bind and transport Cu(I).
- Demonstrated Cu(I) transport in liposomes and yeast cells.
- Identified four potent anticancer ionophores with IC50 values of 3-5 μM.
- Found optimal activity within a specific lipophilicity range (cLogP = 7-9.2).
- Cuphoralix induced metal stress and altered subcellular copper distribution without increasing total intracellular copper.
Conclusions:
- Novel Cu(I) ionophores exhibit significant anticancer activity.
- Lipophilicity is crucial for the efficacy of these ionophores.
- Altered subcellular copper distribution, not increased intracellular levels, drives cytotoxicity.
- These findings support further investigation of Cu(I) ionophores as anticancer agents.
