Relationship among redox potentials, proton dissociation constants of pyrrolic nitrogens, and in vivo and in vitro superoxide dismutating activities of manganese(III) and iron(III) water-soluble porphyrins

The log k(cat) values for the dismutation of O-2(.-) by a series of monohyd roxoiron(III) and aquamanganese(III) porphyrins, including ortho, meta, and para isomers of 5,10,15,20-tetrakis(N-alkylpyridiniumyl) were found to var y linearly with the metal-centered redox potentials (E-1/2) for the M(III)/ M(II) couple. Each 120 mV increase in E-1/2 imparted a 10-fold increase in k(cat). The observed behavior is in accord with the Marcus equation for out er-sphere electron-transfer reactions, suggesting that the same mechanism i s operative for iron and manganese porphyrins. The Marcus plot enabled us t o estimate the self-exchange late constants of monohydroxoiron porphyrins t o be similar to 1 order of magnitude higher than those of aquamanganese por phyrins. Furthermore, E-1/2 values for all of the metalloporhyrins investig ated were linearly related to the acid dissociation constants (pK(a3)) of t he pyrrolic nitrogen of the metal-free porphyrins, indicating that either E 1/2, or the more readily measured pK(a3), may be useful in predicting SOD a ctivity in vitro. The most potent compounds investigated, with respect to S OD activity, are those of the ortho N-alkylpyridiniumyl series. Ortho N-alk ylpyridiniumyl groups are more electron withdrawing than are the meta or pa ra groups, thus imparting a more positive redox potential and a correspondi ngly higher SOD activity. Sufficiently positive potentials, or sufficiently low pK(a3) values, are necessary for useful SOD activity, but so is the ab sence of toxicity. Despite their favorable redox potentials and SOD activit ies, all Fe(III) porphyrins investigated were toxic to Escherichia coli und er both aerobic and anaerobic conditions and to both SOD-deficient and SOD- proficient strains. Only the ortho and meta manganese isomers of the N-alky lpyridiniumyl series (Mn-III-TE-2-PyP5+, (MnTM)-T-III-2-PyP5+ and (MnTM)-T- III-3-PyP5+) significantly protected SOD-deficient E. coli and allowed grow th in an aerobic minimal medium. In previous work, we established that the lower toxicity of these compounds is due to diminished ability to bind to n ucleic acids. The Mn(III) complexes are preferable to the Fe(III) complexes for SOD mimics possibly due to a lower tendency for axial ligation. We pro pose E-1/2 greater than or equal to +0.05 V vs NHE and/or pK(a3) less than or equal to 2.0 as necessary requirements for Mn porphyrins to be considere d useful SOD mimics.