A POTENT SUPEROXIDE-DISMUTASE MIMIC - MANGANESE O-MESO-TETRAKIS-(N-METHYLPYRIDINIUM-4-YL)PORPHYRIN

Variously modified metalloporphyrins offer a promising route to stable and active mimics of superoxide dismutase (SOD). Here we explore brom ination on the pyrroles as a means of increasing the redox potentials and the catalytic activities of the copper and manganese complexes of a cationic porphyrin. Mn(II) and Cu(II) octabrominated 5,10,15,20-tetr akis-(N-methylpyridinium-4-yl) porphyrin, (MnOBTMPyP4+)-O-II, and (CuO BTMPyP4+)-O-II were prepared and characterized. The rate constants for the porphyrin-catalyzed dismutation of O-2(.-) as determined from the inhibition of the cytochrome c reduction are k(cat) = 2.2 x 10(8) and 2.9 x 10(6) M-1 s(-1), i.e., IC50 was calculated to be 12 nM and 0.88 mu M, respectively. The metal-centered half-wave potential was E-1/2 = +0.48 V vs NHE for the manganese compound. (CuOBTMPyP4+)-O-II proved to be extremely stable, while its Mn(II) analog has a moderate stabil ity, log K = 8.08. Nevertheless, slow manganese dissociation from (MnO BTMPyP4+)-O-II enabled the complex to persist and exhibit catalytic ac tivity even at the nanomolar concentration level and at biological pH. The corresponding (MnOBTMPyP5+)-O-III complex exhibited significantly increased stability, i.e., demetallation was not detected in the pres ence of a 400-fold molar excess of EDTA at micromolar porphyrin concen tration and at pH 7.8, The beta-substituted manganese porphyrin facili tated the growth of a SOD-deficient strain of Escherichia coli when pr esent at 0.05 mu M but was toxic at 1.0 mu M The synthetic approach us ed in the case of manganese and copper compounds offers numerous possi bilities whereby the interplay of the type and of the number of beta s ubstituents on the porphyrin ring would hopefully lead to porphyrin co mpounds of increased stability, catalytic activity, and decreased toxi city. (C) 1997 Academic Press.