35 - Redox Properties of Therapeutic Cu Bis(Thiosemicarbazone) Complexes in a Biomimetic Environment

Abstract

Cu II complexes of bis-thiosemicarbazones (btsc) are under active investigation as copper delivery agents in vivo, where they have been successfully used as radioimaging agents and are currently being adapted for potential use as antimicrobial and antitumoricidal agents, as well as therapeutic agents for treatment of neurodegenerative diseases. In ongoing studies, we have found that several of these compounds are extremely effective in treating ALS in mice. Their general mode of action is thought to involve passive diffuse into cells followed by metal-centered reduction and release of Cu(I); alternatively, copper loss is conceivably a consequence of ligand oxidative degradation. Critical to identifying this process are the redox potentials of the Cu-btsc analogs, which vary widely with substituent identity; these potentials, in turn, appear to be primary determiners of the so-called “hypoxic selectivity” of the complexes wherein cells possessing lowered redox poise are preferentially targeted. However, the limited aqueous solubility of the complexes severely hinders determination of their reactivity characteristics in biologically relevant media. In this study, we overcome this limitation by utilizing an aqueous SDS micellar environment as a cytosolic model; in this environment, it becomes possible to directly measure the reducing capacity and dynamics of various biological compounds toward the microphase-bound complexes, as well as the nature of oxidative reactions with ROS. Ligand substitution dynamics, including Cu-Zn transmetallation, are also investigated, as are direct determination of the binding of Zn(II) (which is isoelectronic with Cu(I)) to the btsc ligands. Collectively, these data provide a marked improvement in our understanding of the underlying intracellular delivery mechanisms for copper and zinc.