P-227 - An unexpected double radical homolysis mechanism for the reactions between the pyridinium aldoxime nerve agent antidotes and polyhalogenated quinones under normal physiological conditions

Abstract

We have recently shown that the pyridinium aldoximes, best-known as therapeutic antidotes for chemical warfare nerve-agents, could markedly detoxify the carcinogenic tetrachloro-1,4-benzoquinone (TCBQ) via an unusual double Beckmann fragmentation mechanism. However, it remains not clear why pralidoxime (2-PAM) cannot provide full protection against TCBQ-induced biological damage even when 2-PAM was in excess. Here we show, unexpectedly, that TCBQ can also activate pralidoxime to generate a reactive iminyl radical intermediate in two-consecutive steps, which was detected and unequivocally characterized by the complementary application of ESR spin-trapping, HPLC/MS and nitrogen-15 2-PAM isotope-labeling studies. The end product of iminyl radical was isolated and identified as its corresponding reactive and toxic aldehyde. We proposed that the reaction of 2-PAM and TCBQ might be via the following two competing mechanisms: double Beckmann fragmentation vs double radical homolysis. This study represents the first detection and identification of reactive iminyl radical intermediates produced under normal physiological conditions, which provides direct experimental evidence to explain the potential side-toxic effects induced by 2-PAM and other pyridinium aldoxime nerve-agent antidotes.