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

Targeting of low-oxygen (hypoxic) environments found in many tumors using redox-active metal complexes is a strategy that can enhance efficacy and reduce 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 CF3 pendant group provides a 19F 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 in hypoxic conditions. Cell death occurs via apoptosis, as determined by cell morphology analysis. A combination of 19F 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 through 19F MRI suggests hypoxia targeting theranostic applications via redox activation.