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
I. Batinic-haberle et al., 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, INORG CHEM, 38(18), 1999, pp. 4011-4022
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.