TitleOxidative Release of Copper from Pharmacologic Copper Bis(thiosemicarbazonato) Compounds.
Publication TypeJournal Article
Year of Publication2018
AuthorsSirois JJ, Padgitt-Cobb L, Gallegos MA, Beckman JS, Beaudry CM, Hurst JK
JournalInorg Chem
Date Published2018 Aug 06
KeywordsCoordination Complexes, Copper, Horseradish Peroxidase, Hydrogen Peroxide, Hypochlorous Acid, Ligands, Oxidation-Reduction, Peroxidase, Peroxynitrous Acid, Thiosemicarbazones

Intracellular delivery of therapeutic or analytic copper from copper bis-thiosemicabazonato complexes is generally described in terms of mechanisms involving one-electron reduction to the Cu(I) analogue by endogenous reductants, thereby rendering the metal ion labile and less strongly coordinating to the bis-thiosemicarbazone (btsc) ligand. However, electrochemical and spectroscopic studies described herein indicate that one-electron oxidation of Cu(btsc) and ZnATSM (btsc = diacetyl-bis(4-methylthiosemicarbazonato)) complexes occurs within the range of physiological oxidants, leading to the likelihood that unrecognized oxidative pathways for copper release also exist. Oxidations of Cu(btsc) by HO catalyzed by either myeloperoxidase or horseradish peroxidase, by HOCl and taurine chloramine (which are chlorinating agents generated primarily in activated neutrophils from MPO-catalyzed reactions), and by peroxynitrite species (ONOOH, ONOOCO) that can form under certain conditions of oxidative stress are demonstrated. Unlike reduction, the oxidative reactions proceed by irreversible ligand oxidation, culminating in release of Cu(II). 2-Pyridylazoresorcinol complexation was used to demonstrate that Cu(II) release by reaction with peroxynitrite species involved rate-limiting homolysis of the peroxy O-O bond to generate secondary oxidizing radicals (NO, OH, and CO). Because the potentials for Cu(btsc) oxidation and reduction are ligand-dependent, varying by as much as 200 mV, it is clearly advantageous in designing therapeutic methodologies for specific treatments to identify the operative Cu-release pathway.

Alternate JournalInorg Chem
PubMed ID29979041