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

Abstract

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-richr educing molecules with high Cu I affinity,t hey are potential competitors for ac opper ion bound in ac opper drug. Herein, we report the investigation of apanel of Cu I /Cu II complexes often used as drugs,w ith diverse coordination chemistries and redox potentials.W ee valuated their catalytic activity in ascorbate oxidation based on redox cycling between Cu I and Cu II ,a sw ell 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, whichcreates achallenge for their future design.

Cancer Cell Resistance Against the Clinically Investigated Thiosemicarbazone COTI-2 Is Based on Formation of Intracellular Copper Complex Glutathione Adducts and ABCC1-Mediated Efflux

“…This can be explained by the formation of a mixed-ligand complex with GSH via the coordination of the thiolate at the fourth coordination site of the copper(II), as also reported for similar complexes. 6 , 42 , 43 For Cu-COTI-2, this was also proven by mass spectrometry measurements, clearly indicating the respective GSH-Cu-COTI-2 complex at m/z = 735 ( Figure S6 ). This GSH-adduct formation was similar for all copper(II) complexes, but over time, a very different behavior was observed.…”

Designed Metal-ATCUN Derivatives: Redox- and Non-redox-Based Applications Relevant for Chemistry, Biology, and Medicine

“…Recently, Santoro et al. have reported that Cu I and Cu II oxidation states of Cu-catalysts during O 2 activation under ascorbate are unstable against GSH/MT system ( Santoro et al., 2020 ). Therefore, intercellular Cu-trafficking proteins are a challenge for the design of Cu-ATCUN complexes as oxidative cleavage catalysts in cells.…”

Insight into the Anticancer Activity of Copper(II) 5-Methylenetrimethylammonium-Thiosemicarbazonates and Their Interaction with Organic Cation Transporters

“…Although the production of ROS by redox reactions has been recently challenged [ 78 ], the generation of ROS via thiol-mediated reduction of copper(II) to copper(I) has been assumed as the major mechanism of anticancer activity of many copper(II) TSC complexes [ 62 ]. The presence of reducing agents such as biologically relevant GSH is crucial for the redox reactivity of copper(II) TSC complexes [ 62 ].…”