Copper(II) Pyridyl Aminophenolates: Hypoxia-Selective, Nucleus-Targeting Cytotoxins, and Magnetic Resonance Probes

Targeting the low-oxygen (hypoxic) environments found in many tumours by using redox-active metal complexes is a strategy that can enhance efficacy and reduce the side effects of chemotherapies. We have developed a series of Cu-II complexes with tridentate pyridine aminophenolate-based ligands for preferential activation in the reduction window provided by hypoxic tissues. Furthermore, ligand functionalization with a pendant CF3 group provides a F-19 spectroscopic handle for magnetic-resonance studies of redox processes at the metal centre and behaviour in cellular environments. The phenol group in the ligand backbone was substituted at the para position with H, Cl, and NO2 to modulate the reduction potential of the Cu-II centre, giving a range of values below the window expected for hypoxic tissues. The NO2-substituted complex, which has the highest reduction potential, showed enhanced cytotoxic selectivity towards HeLa cells grown under hypoxic conditions. Cell death occurs by apoptosis, as determined by analysis of the cell morphology. A combination of F-19 NMR and ICP-OES indicates localization of the NO2 complex in HeLa cell nuclei and increased cellular accumulation under hypoxia. This correlates with DNA nuclease activity being the likely origin of cytotoxic activity, as demonstrated by cleavage of DNA plasmids in the presence of the Cu-II nitro complex and a reducing agent. Selective detection of the paramagnetic Cu-II complexes and their diamagnetic ligands by F-19 MRI suggests hypoxia-targeting theranostic applications by redox activation.

Automated summary

The development of Cu-II complexes with preferential activation in the reduction window provided by hypoxic tissues, particularly the NO2-substituted complex, shows enhanced cytotoxic selectivity and cellular accumulation under hypoxia. The localization in HeLa cell nuclei and DNA nuclease activity suggest potential therapeutic applications by redox activation. Selective detection by F-19 MRI indicates promising hypoxia-targeting theranostic applications.