82 - Nitroxide Radical Production from Hydroxamic Acids and Carcinogenic Halogenated Quinones via an Unexpected Nitrogen-centered Radical Intermediate Pathway

Abstract

We have found previously that a nitroxide radical could be produced from desferrioxamine (DFO) with tetrachloro-hydroquinone (TCHQ, the major genotoxic metabolite of the widely used wood preservative pentachlorophenol). However, the underlying molecular mechanism remains unclear. In this study, N-methyl acetohydroxamic acid (N-MeAHA) was used as a simple model compound for DFO for further mechanistic study. As expected, the N-MeAHA-nitroxide radical (N-MeAHA-O•) was found to be produced during the reaction between N-MeAHA and TCHQ by direct ESR. Interestingly and unexpectedly, when TCHQ was substituted by tetrachloro-1,4-benzoquinone (TCBQ), N-MeAHA-O• was also observed, but no tetrachlorosemiquinone anion radical (TCSQ•—) or TCHQ was detected, suggesting the formation of N-MeAHA-O• is not a direct redox reaction between N-MeAHA and TCBQ (or TCSQ•—). To detect whether other radical intermediates were formed during the reaction of N-MeAHA and TCBQ, ESR spin-trapping method was used with 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as trapping agent. We found, surprisingly, that a new nitrogen-centered radical was produced, which was identified as Ac-(CH3)N• by HPLC-MS and the high resolution FTICR-MS. Taken together, we propose the production of nitroxide radical from N-MeAHA and TCHQ is via an unexpected new pathway via H-abstraction from the N-OH group by the novel nitrogen-centered radical intermediate.