Redox modulation of oxidative stress by Mn porphyrin-based therapeutics: the effect of charge distribution.

We evaluate herein the impact of positive charge distribution on the in vitro and in vivo properties of Mn porphyrins as redox modulators possessing the same overall 5+ charge and of minimal stericity demand: Mn(III) meso-tetrakis(trimethylanilinium-4-yl)porphyrin (MnTTriMAP(5+)), Mn(III) meso-tetrakis(N,N'-dimethylpyrazolium-4-yl)porphyrin (MnTDM-4-PzP(5+)), Mn(III) meso-tetrakis(N,N'-dimethylimidazolium-2-yl)porphyrin (MnTDM-2-ImP(5+)), and the ortho and para methylpyridinium complexes Mn(III) meso-tetrakis(N-methylpyridinium-4-yl)porphyrin (MnTM-4-PyP(5+)) and Mn(III) meso-tetrakis(N-methylpyridinium-2-yl)porphyrin (MnTM-2-PyP(5+)). Both Mn(III)/Mn(II) reduction potential and SOD activity within the series follow the order: MnTTriMAP(5+)<MnTDM-4-PzP(5+)<MnTM-4-PyP(5+)<MnTM-2-PyP(5+)<MnTDM-2-ImP(5+). The kinetic salt effect (KSE) on the catalytic rate constant for superoxide dismutation (k(cat)) indicates that the electrostatic contribution to the O(2)*(-) dismutation is the greatest with MnTM-2-PyP(5+) and follows the order: MnTM-4-PyP(5+)<MnTDM-4-PzP(5+) approximately MnTDM-2-ImP(5+)<MnTM-2-PyP(5+). The KSE observed on k(cat) suggests that the charges are relatively confined within specific regions of the aryl rings. Whereas the charges in imidazolium, pyrazolium, and MnTM-4-PyP(5+) compounds are distributed in-plane with the porphyrin ring, the charges of MnTM-2-PyP(5+) are either above or below the plane, which channels the negatively-charged superoxide toward the axial positions of the Mn porphyrin more efficiently, and leads to the highest KSE. This mimics the tunneling effect observed in the SOD enzymes themselves. The modulation of the reactivity of the Mn center by the electronic perturbations caused by the meso-aryl substituent could be explained by DFT calculation, whereby a correlation between the Mn(III)/Mn(II) reduction potential (and/or SOD activity) and meso-aryl fragment softness descriptors for nucleophilic (s(f)(+)) and radical (s(f)(o)) attacks was observed. MnTDM-4-PzP(5+) and MnTM-4-PyP(5+) did not protect SOD-deficient E. coli grown aerobically, which is in agreement with their low k(cat). MnTM-2-PyP(5+) and MnTDM-2-ImP(5+) have similar high k(cat), but MnTDM-2-ImP(5+) was significantly less protective to E. coli, probably due to its bulkier size, decreased cellular uptake, and/or observed toxicity. The placement of charges closer to the metal center and spatial charge localization increases both the in vitro and the in vivo SOD activity of the compound.