EPR spectroscopic reinvestigation of the activation of iron complexes of PMAH as a bleomycin model

The structure and reactivity of iron complexes of PMAH, which contains Liga nds that mimic the metal binding domain of iron bleomycin (FeBLM), have bee n studied using EPR spectroscopy. It had been reported [Guajardo, R. J.; Hu dson, S. E.; Brown, S. J.; Mascharak, P. K. J. Am. Chem. Soc. 1993, 115, 79 71] that iron complexes of PMAH can be activated to a ferric hydroperoxide, a structural analog by activated BLM, by various routes, including reactio n of [Fe(III)PMA](2+) with iodosylbenzene (PhIO), methanol, and base. We sh ow that with or without PhIO, the latter reaction produces the methoxide co mplex of Fe(III)PMA, and not the hydroperoxide, contrary to the previous re port. Thus, O-O bond formation through generation of a ferric hydroperoxide does not occur. The same methoxide complex (g = 2.28, 2.18, 1.93) is gener ated by the addition of organic base and CH3OH, or LiOCH3, to [Fe(III)PMA]( 2+). The formation of this [CH3O-Fe(III)PMA](+) complex is confirmed by EPR titration of [Fe(III)PMA](2+) with -OCH3 and by electrospray mass spectrom etry. In contrast, the hydroperoxy complex of Fe(III)PMA (g = 2.22, 2.17, 1 .94) can be generated by the reaction of I:Fe(III)PMA](2+) with hydrogen pe roxide or during aerobic oxidation of [Fe(II)PMA](+). The present results i llustrate that activation of iron complexes of PMAH occur under conditions that produce activated BLM and further demonstrate that reaction of [Fe(III )PMA](2+) with PhIO and base does not provide a route to either a hypervale nt iron species or a hydroperoxide intermediate. These results agree with t he finding that PhIO cannot: be used to generate activated bleomycin.