engleski

Lipophilicity of Potent Mn Porphyrin-based SOD and Peroxynitrite Reductase Mimics is Redox Modulated

Cationic Mn(III) N-alkylpyridylporphyrins display electrostatic and thermodynamic facilitation for the dismutation of superoxide and reduction of peroxynitrite. Some members of the series are among the most potent catalytic scavengers of these reactive species. Mn(III) porphyrins, such as MnTE-2-PyP5+ (AOEL10113), MnTnHex-2-PyP5+, and MnTDE-2-ImP5+ (AEOL10150), effectively attenuate oxidative stress in animal models of cancer, central nervous system disorders, radiation injury, diabetes, morphine tolerance, ischemia/reperfusion injuries etc. Recent data, however, has hinted that factors other than redox-based antioxidant potency, such as lipophilicity, size, and the overall geometry and conformational flexibility of the Mn porphyrins play also a significant role in their design and activity. We show here that redox status controls the lipophilicity of Mn porphyrins and, therefore, their bioavailability and in vivo efficacy. In the presence of superoxide and/or cellular reductants, such as ascorbate, cationic Mn(III) N-alkylpyridylporphyrins, Mn(III)P5+, can be reduced to the corresponding Mn(II) porphyrin, Mn(II)P4+, which are about 1 (meta series) or 2 (ortho series) orders of magnitude more lipophilic than the Mn(III) counterparts. The lipophilicity of Mn(II)P4+ is similar to that of the metal-free ligands (H2P4+), which suggests that lipophilicity may be controlled by the overall charge of the species. The distribution of the Mn(III) and Mn(II) species of the ortho and meta series of cationic Mn porphyrins was investigated in vivo in the O2 •–-specific, SODdeficient E. coli model. Despite the high hydrophilicity of MnIIITE- 2-PyP5+, we have shown that it reaches mouse heart mitochondria and is effective in ameliorating CNS disorders. As the lipophilicity of MnIIITE-2-PyP5+ is increased by >2 orders of magnitude upon reduction, it is likely that the mechanism by which this Mn porphyrin and its congeners get into the brain and spinal cord may involve the in situ reduction to Mn(II) porphyrins. Worth noting is that the reduction to Mn(II) does not affect the SOD activity of these complexes, which normally redox cycle between the Mn(III) and Mn(II) oxidation states during dismutation. The redox status of cells and tissues modulates, thus, the oxidation state of the Mn porphyrins, their overall charge, and consequently, their lipophilicity and bioavailability

Mn(III)porfirini; lipofilnost; peroksinitit reduktaza; SOD

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