Ines Batinic-Haberle

Electrostatic Contribution in the Catalysis of O Dismutation by Superoxide Dismutase Mimics MnIIITE-2-PyP5+ VERSUSMnIIIBr8T-2-PyP+

The Mn(III)meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnIIITE-2-PyP5+) is a potent superoxide dismutase (SOD) mimic in vitro and was beneficial in rodent models of oxidative stress pathologies. Its high activity has been ascribed to both the favorable redox potential of its metal center and to the electrostatic facilitation assured by the four positive charges encircling the metal center. Its comparison with the non-alkylated, singly charged analogue Mn(III) beta-octabromomeso-tetrakis(2-pyridyl)porphyrin (MnIIIBr8T-2-PyP+) enabled us to evaluate the electrostatic contribution to the catalysis of O 2 · _ dismutation. Both compounds exhibit nearly identical metal-centered redox potential for MnIII/MnII redox couple: +228 mV for MnIIITE-2-PyP5+ and +219 mVversus NHE for MnIIIBr8T-2-PyP+. The eight electron-withdrawing beta pyrrolic bromines contribute equally to the redox properties of the parent MnIIIT-2-PyP+ as do four quaternized cationicmeso ortho pyridyl nitrogens. However, the SOD-like activity of the highly charged MnIIITE-2-PyP5+is >100-fold higher (log k cat = 7.76) than that of the singly charged MnIIIBr8T-2-PyP+ (logk cat = 5.63). The kinetic salt effect showed that the catalytic rate constants of the MnIIITE-2-PyP5+ and of its methyl analogue, MnIIITM-2-PyP5+, are exactly 5-fold more sensitive to ionic strength than is the k cat of MnIIIBr8T-2-PyP+, which parallels the charge ratio of these compounds. Interestingly, only a small effect of ionic strength on the rate constant was found in the case of penta-charged para(MnIIITM-4-PyP5+) and meta isomers (MnIIITM-3-PyP5+), indicating that the placement of the positive charges in the close proximity of the metal center (ortho position) is essential for the electrostatic facilitation of O 2 · _ dismutation.