Abstract
Cu(II) coordination complexes are emerging as promising anticancer agents due to their ability to induce oxidative stress through reactive oxygen species (ROS) generation. In this study, we synthesized and characterized two novel Cu(II) metallopeptide systems, 1/Cu(II) and 2/Cu(II), derived from the oligocationic bipyridyl cyclopeptides 1 and 2, and designed to enhance the transport of Cu(II) into cells and increase ROS levels. Spectroscopic and electrochemical analyses confirmed the formation of stable metallopeptide species in aqueous media. Inductively coupled plasma mass spectrometry (ICP-MS) studies demonstrated that both metallopeptides significantly increase intracellular Cu(II) accumulation in NCI/ADR-RES cancer cells, highlighting their role as efficient Cu(II) transporters. Additionally, ROS generation assays revealed that 1/Cu(II) induces a substantial increase in intracellular ROS levels, supporting the hypothesis of oxidative stress-induced cytotoxicity. Cell-viability assays further confirmed that both 1/Cu(II) and 2/Cu(II) exhibit strong anticancer activity in a number of cancer cell lines, with IC50 values significantly lower than those of their free cyclopeptide counterparts or Cu(II) alone, showing an order of activity higher than that of cisplatin. Finally, molecular modeling studies provided further insights into the structural stability and coordination environment of Cu(II) within the metallopeptide complexes. These findings suggest that these Cu(II) cyclometallopeptide systems hold potential as novel metal-based therapeutic agents, leveraging Cu(II) transport and ROS increase as key strategies for cancer treatment.
Reference
Copper(II) Cyclopeptides with High ROS-Mediated Cytotoxicity
Sonia Boga, David Bouzada, Roi Lopez-Blanco, Axel Sarmiento, Iria Salvadó, David Alvar, Gil José Brea, María Isabel Loza, Natalia Barreiro-Piñeiro, José Martínez-Costas, Silvia Mena, Gonzalo Guirado, Alice Santoro, Peter Faller, M. Eugenio Vázquez, and Miguel Vázquez López
Bioconjugate Chemistry, First published: 10 March 2025 – DOI : https://pubs.acs.org/doi/10.1021/acs.bioconjchem.4c00561
Contact
Peter Faller, team BCB (Biométaux et Chimie Biologique, BCB), Institut de Chimie de Strasbourg, UMR7177.
