Copper(II) Cyclopeptides with High ROS-Mediated Cytotoxicity.

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, /Cu(II) and /Cu(II), derived from the oligocationic bipyridyl cyclopeptides and 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 /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 /Cu(II) and /Cu(II) exhibit strong anticancer activity in a number of cancer cell lines, with IC 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.