To model the mononuclear FeIII-OOH species identified in the catalytic cycle of the anticancer drug bleomycin, the iron chemistry of the pentadentate ligand N-[bis(2-pyridylmethyl)aminoethyl]pyridine-2-carboxamide (H-PaPy3) has been investigated. The complex [Fe III(PaPy3)OCH3](ClO4) was reacted with H2O2 to form a red species (λ max=480 nm, ε=1800 M-1 cm-1) with an S=1/ 2 EPR signal at g=2.25, 2.17, and 1.95. This species has been identified by electrospray ionization mass spectrometry as [FeIII(PaPy 3)OOH](ClO4) and further characterized by resonance Raman and EXAFS analysis. The decomposition of this intermediate leads to the modification of the ligand, as revealed by 1H NMR. One hydrogen atom is substituted by a solvent-derived methoxy group. The substitution at this site is a result of the two-electron oxidation of the ligand following the heterolytic cleavage of the O-O bond of the FeIII-OOH species. This is a plausible mechanism to rationalize related ligand modifications that have been proposed in the decay of activated bleomycin.
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Acknowledgements This work was supported by the National Institutes of Health grant GM33162 (to L.Q.). K.D.K. acknowledges support from the National Institutes of Health Chemistry Biology Interface Training grant GM08700. We thank Dr. Tom Krick at the Mass Spectrometry Consortium for the Life Sciences at the University of Minnesota, St. Paul, Minnesota for his assistance with mass spectroscopy. XAS data were collected on beam line X9B at the National Synchrotron Light Source, which is supported by the U.S. Department of Energy and the NIH Research Resource program.
- Iron-hydroperoxo intermediate
- Ligand modification