Abstract
The dynamics of hydrogen peroxide reactions with metal carbonyls have received little attention. Given reports that therapeutic levels of carbon monoxide are released in hypoxic tumour cells upon manganese carbonyls reactions with endogenous H2O2, it is critical to assess the underlying CO release mechanism(s). In this context, a quantitative mechanistic investigation of the H2O2 oxidation of the water-soluble model complex fac-[Mn(CO)3(Br)(bpCO2)]2–, (A, bpCO22– = 2,2′-bipyridine-4,4′-dicarboxylate dianion) was undertaken under physiologically relevant conditions. Characterizing such pathways is essential to evaluating the viability of redox-mediated CO release as an anti-cancer strategy. The present experimental studies demonstrate that approximately 2.5 equivalents of CO are released upon H2O2 oxidation of A via pH-dependent kinetics that are first-order both in [A] and in [H2O2]. Density functional calculations were used to evaluate the key intermediates in the proposed reaction mechanisms. These pathways are discussed in terms of their relevance to physiological CO delivery by carbon monoxide releasing moieties.
Highlights
The present investigation was triggered by reports that carbon monoxide can be released in tumour cells via the reaction of manganese carbonyl complexes with endogenous hydrogen peroxide [1,2,3,4]
Given that hypoxic tumours have significantly higher H2O2 concentrations than normal tissues [11,12,13,14,15,16], and that H2O2 and other reactive oxygen species may accumulate in certain cellular locations, CO releasing moieties (CORMs) reactivity with H2O2 has the potential of enhancing targeted CO delivery
The results described here clearly point to the importance of intracellular pH as a potent factor for controlling the location and rate of redox-mediated CO release from a metal-based CORM
Summary
The present investigation was triggered by reports that carbon monoxide can be released in tumour cells via the reaction of manganese carbonyl complexes with endogenous hydrogen peroxide [1,2,3,4]. Similar activation of metal carbonyl-based CORMs has been noted with other tissues subject to oxidative stress [17,18]. This type of CORM activation has likely application in treating other inflammation sites, such as those infected by antibiotic-resistant bacteria [18,19,20,21,22,23,24]. Overall, unravelling the reaction mechanisms of metal CORMs, and the consequent CO release in cells under oxidative stress, is essential to understanding and controlling the observed physiological effects
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