Peroxynitrite decomposition catalysis via oxoiron porphyrins

Interactions of iron(III) porphyrins with peracids yield highly oxidized oxoferryl species that play important roles in biology. Water-soluble synthetic iron porphyrins can be useful models of such systems and serve as the basis for therapeutics development. Water-soluble iron porphyrin, Fe(III)TMPS, reacts with peroxynitrite, ONOO-, to generate oxoFe(IV)TMPS and nitrogen dioxide, NO2 (k1 = 1.3 x 10 5M-1s-1). Subsequent recombination of these species (k3 = 1.7 x 107M-1 s-1) yields ferric porphyrin and nitrate, completing the catalytic cycle. The full mechanism by which FeTMPS catalyzes decomposition of peroxynitrite (kcat = 0.6 x 105M -1s-1) has been elucidated through kinetic measurements and computer simulations.;Phenolic nitration is an important cytotoxic process carried out by peroxynitrite. Fluorescein, a highly reactive phenol, was used as a nitration probe to assess the efficacy of several iron and manganese porphyrins as peroxynitrite scavengers. Fe(III)T-2-MPyP and Fe(III)T-4-MpyP show a dose-dependent ability to inhibit phenolic nitration by peroxynitrite. On the other hand, manganese porphyrins, Mn(III)T-2-MPyP and Mn(III)T-4-MpyP exhibit a bell-shaped concentration dependence of their inhibition activity. Mechanistic studies and computer simulations have been used to develop a comprehensive mechanistic understanding of the interactions between porphyrin species, peroxynitrite, and phenolic substrates. The proposed mechanism emphasizes the reaction yield and flux of nitrogen dioxide (the by-product of peroxynitrite decomposition) as the main factor determining the behavior of porphyrin scavengers.;Oxoferryl porphyrin cation radical species are unique in that they play central roles in the action of important enzymes, including cytochrome P450 monooxygenases and peroxidases. Numerous synthetic models of such complexes have been generated and studied at low temperature in organic solvents, but fewer studies of these important intermediates have been carried out in H 2O. Fe(III)TMPS reacts rapidly with meta-chloroperbenzoic acid or sodium hypochlorite to generate an oxoferryl porphyrin cation radical species in aqueous media at room temperature. This complex has been characterized by UV-vis and EPR spectroscopy, its stability and reactions with a wide range of substrates have been explored. OxoFe(IV)TMPS+· rapidly oxidizes thiocyanate and nitrite, but not bromide. It also oxidizes organic substrates by one electron, but is less reactive toward two-electron oxidations of olefins. Its reactivity and electronic properties closely resemble those of lactoperoxidase, making it a useful model for the peroxidase enzyme class.