The Glutathione/Metallothionein System Challenges the Design of Efficient O2-Activating Copper Complexes

Copper complexes are of medicinal and biological interest, including as anticancer drugs designed to cleave intracellular biomolecules by O₂ activation. To exhibit such activity, the copper complex must be redox active and resistant to dissociation. Metallothioneins (MTs) and glutathione (GSH) are abundant in the cytosol and nucleus. Because they are thiol-rich reducing molecules with high Cu^I affinity, they are potential competitors for a copper ion bound in a copper drug. Herein, we report the investigation of a panel of Cu^I/Cu^II complexes often used as drugs, with diverse coordination chemistries and redox potentials. We evaluated their catalytic activity in ascorbate oxidation based on redox cycling between Cu^I and Cu^II, as well as their resistance to dissociation or inactivation under cytosolically relevant concentrations of GSH and MT. O₂-activating Cu^I/Cu^II complexes for cytosolic/nuclear targets are generally not stable against the GSH/MT system, which creates a challenge for their future design.