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

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 deproto nated PMA- framework is ligated to the metal center through five nitro gens located in the primary and secondary amines, pyrimidine and imida zole rings, and the amide moiety. The sixth coordination site on iron in these complexes is occupied by a solvent molecule that is easily re placeable. Similarities in spectral and chemical behaviors of these tw o model complexes with those of the Fe(II) and Fe(III) complexes of BL M 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 reversi ble manner, and the spectral parameters of the adducts are very simila r to those for the corresponding adducts of Fe(II)-BLM. Most notably, brief exposure of a methanolic solution of 4 to dioxygen generates [(P MA)Fe(III)-O-OH]+, a low-spin iron(III)-hydroperoxy species which exhi bits 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 D NA in the presence of sodium ascorbate and O2 while 5 causes strand sc ission in the presence of H2O2. Longer incubation leads to digestion o f DNA with the formation of base propenals. Interestingly, Fe-BLMs and the model complexes exhibit the same sequence specificity (5'-G-pyrim idine-3') in the DNA cleavage reactions. This fact clearly indicates t hat the primary determinant of the DNA sequence specificity of Fe-BLMs is the metal-binding domain of the metallodrug. The two model complex es also promote rapid oxo transfer to olefinic substrates in stereospe cific manner and their oxo transfer capabilities approach those of the Fe-BLMs (and [Fe(TPP)]Cl (TPP = tetraphenylporphyrinato)) under simil ar experimental conditions. The monooxygenase activity of 4 and 5 is e specially noteworthy, since these two are the first examples of mononu clear 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 ex ample 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.