Angew. Chem. Int. Ed. [BCB]

Abstract:

Copper-complexes are of medicinal and biological interest, including as anticancer drugs designed to cleave intracellular biomolecules via 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 also are thiol-rich reducing molecules with high Cu^I-affinity, they are potential competitors for copper ion bound in a copper drug. Here, we investigated a panel of Cu^I/ Cu^II-complexes often used as drugs, from various classes, 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. Our findings show that 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.

Graphical Abstract:

 

Reference:

Santoro A, Calvo JS, Peris-Díaz MD, Krężel A, Meloni G, Faller P.

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

Angew Chem Int Ed Engl. 2020 Feb - DOI: 10.1002/anie.201916316

Contact:

Alice Santoro & Peter Faller, équipe BCB, Institut de Chimie (UMR 7177).