The glutathione/metallothionein system challenges the design of efficient O2-activating Cu-complexes.

Copper complexes are of medicinal and biological interest, including as anticancer drugs designed to cleave intracellular biomolecules by O-2 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. O-2-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.