Unique oxidation of imidazolidine nitroxides by potassium ferricyanide: Strategy for designing paramagnetic probes with enhanced sensitivity to oxidative stress

Abstract

Potassium ferricyanide (PF), routinely employed for the oxidation of sterically-hindered hydroxylamines to nitroxides, is considered to be chemically inert towards the latter. In the present study, we report on an unexpected oxidative fragmentation of the imidazolidine nitroxides containing hydrogen atom in the 4-position of the heterocycle (HIMD) by PF resulting in the loss of the EPR signal. The mechanistic EPR, spectrophotometric, electrochemical and HPLC–MS studies support the assumption that the HIMD fragmentation is facilitated by the proton abstraction from the 4-position of the oxoammonium cation formed as a result of the initial one-electron HIMD oxidation. Increase in steric hindrance around the radical fragment by introducing ethyl substituents decreased the rate of ascorbate-induced HIMD reduction by more than 20 times, but did not affect the rate of ferricyanide-induced HIMD oxidation. This preferential sensitivity of HIMDs to oxidative processes has been used to detect peroxyl radicals in the presence of high concentration of the reducing agent, ascorbate. HIMD-based EPR probes capable to discriminate oxidative and reductive processes might find application in biomedicine and related fields for monitoring the oxidative stress and reactive radical species in biological systems.

Keywords::

• nitroxide
• sterically-hindered hydroxylamine
• oxoammonium cation
• electron paramagnetic resonance
• redox probes
• peroxyl radicals

Acknowledgements

The authors thank Dr. I. A. Kirilyuk for the providing of HIMD2 compound, Mr. S.V. Semenov for the assistance with the initial EPR experiments and Dr. F. Villamena for the assistance with the cyclic voltammetric measurements. This work was partially supported by NIH Grants HL089036 and EB014542 - 01A1. M.A.V. thanks the U.S. Department of Energy's Office of Basic Energy Sciences for financial support (Grant DE-FG02 - 02ER15354).

Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.