RT Journal Article
T1 Copper(II) Cyclopeptides with High ROS-Mediated Cytotoxicity
A1 Boga, Sonia
A1 Bouzada Reboredo, David
A1 López-Blanco, Roi
A1 Sarmiento Fuentes, Axel
A1 Salvadó, Iria
A1 Alvar Gil, David
A1 Brea Floriani, José Manuel
A1 Loza García, María Isabel
A1 Barreiro Piñeiro, Natalia
A1 Martínez Costas, José Manuel
A1 Mena, Silvia
A1 Guirado, Gonzalo
A1 Santoro, Alice
A1 Faller, Peter
A1 Vázquez Sentís, Marco Eugenio
A1 Vázquez López, Miguel
AB 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.
PB American Chemical Society
YR 2025
FD 2025-03-10
LK https://hdl.handle.net/10347/42332
UL https://hdl.handle.net/10347/42332
LA eng
NO Bioconjugate Chem. 2025, 36, 3, 500–509
NO The authors thank grants RTI2018-099877–B-I00, PID2021-127857NB-I00, and PID2021-127702NB-I00 by MCIN/AEI/10.13039/501100011033 and by ERDF A way of making Europe. The authors also thank Xunta de Galicia (grant ED431B 2021/13). This work has received financial support from the Xunta de Galicia (Centro de investigación do Sistema Universitario de Galicia accreditation 2023-2027, ED431G 2023/03) and the European Union (European Regional Development Fund─ERDF).
DS Minerva
RD 3 may 2026