[FE(PMA)]N+ (N = 1, 2) - GOOD MODELS OF FE-BLEOMYCINS AND EXAMPLES OF MONONUCLEAR NONHEME IRON COMPLEXES WITH SIGNIFICANT O2-ACTIVATION CAPABILITIES

The Fe(II) and Fe(III) complexes of a designed ligand PMAH that mimics the metal-binding portion of the antitumor drug bleomycin (BLM) have been isolated and characterized by spectroscopic techniques. In both [Fe(II)(PMA)]Cl.MeOH (4) and [Fe(III)(PMA)](NO3)2.DMSO (5), the deprotonated PMA- framework is ligated to the metal center through five nitrogens located in the primary and secondary amines, pyrimidine and imidazole rings, and the amide moiety. The sixth coordination site on iron in these complexes is occupied by a solvent molecule that is easily replaceable. Similarities in spectral and chemical behaviors of these two model complexes with those of the Fe(II) and Fe(III) complexes of BLM strongly suggest that the drug employs the same set of donor centers to bind iron. For example, 4 binds CO and NO, the former in a reversible manner, and the spectral parameters of the adducts are very similar to those for the corresponding adducts of Fe(II)-BLM. Most notably, brief exposure of a methanolic solution of 4 to dioxygen generates [(PMA)Fe(III)-O-OH]+, a low-spin iron(III)-hydroperoxy species which exhibits an EPR spectrum (g = 2.27, 2.18, and 1.93) that is identical with the spectrum of ''activated bleomycin''. Reaction of 5 with H2O2 also affords this species. Like the Fe-BLMs, 4 inflicts strand breaks in DNA in the presence of sodium ascorbate and O2 while 5 causes strand scission in the presence of H2O2. Longer incubation leads to digestion of DNA with the formation of base propenals. Interestingly, Fe-BLMs and the model complexes exhibit the same sequence specificity (5'-G-pyrimidine-3') in the DNA cleavage reactions. This fact clearly indicates that the primary determinant of the DNA sequence specificity of Fe-BLMs is the metal-binding domain of the metallodrug. The two model complexes also promote rapid oxo transfer to olefinic substrates in stereospecific manner and their oxo transfer capabilities approach those of the Fe-BLMs (and [Fe(TPP)]Cl (TPP = tetraphenylporphyrinato)) under similar experimental conditions. The monooxygenase activity of 4 and 5 is especially noteworthy, since these two are the first examples of mononuclear non-heme iron complexes capable of O2 activation. Reaction of 5 with PhIO in basic media gives rise to [(PMA)Fe(III)-O-OH]+, a rare example of O-O bond formation at the iron center. Taken together, these results indicate that {hydroperoxo}iron(III) species could be involved in O2 activation by non-heme iron complexes in general.