LIPID-PEROXIDATION BY SYNTHETIC ANALOGS OF IRON BLEOMYCIN - POSSIBLE ROLE OF A LOW-SPIN (HYDROPEROXO)IRON(III) INTERMEDIATE IN LIPID-PEROXIDATION INDUCED BY BLEOMYCIN

The iron complexes [Fe(PMA)](n+) (n = 1, 2) of a designed ligand PMAH (H is a dissociable amide H) that mimics the metal-binding portion of the antitumor drug bleomycin (BLM) promote facile lipid peroxidation in the presence of O-2 or H2O2. These peroxidation reactions are not induced by singlet oxygen or (OH)-O-. radical. The active intermediate, detected spectroscopically, is a low-spin {hydroperoxo}iron(III) species formulated as [(PMA)Fe-III-O-OH](+). This highly oxidizing intermediate causes H atom abstraction from a variety of organic substrates including lipids. With linoleic acid and arachidonic acid as the substrates, the two model complexes mainly afford the 13-OOH and the 15-OOH positional isomers, respectively. The same predominant products, albeit in higher yields, are obtained in enzymatic peroxidation with soybean lipoxygenase. The Fe chelates of BLM also induce lipid peroxidation, a reaction that could be responsible for the lung damage observed during BLM therapy. Similarities in the overall characteristics of the peroxidation reactions suggest that a low-spin {hydroperoxo}iron(III) intermediate could be involved in lipid peroxidations by the Fe-BLMs.