Lipophilicity of potent porphyrin-based antioxidants: Comparison of ortho and meta isomers of Mn(III) N-alkylpyridylporphyrins

Mn(III) N-alkylpyridylporphyrins are among the most potent known SOD mimics and catalytic peroxynitrite scavengers and modulators of redox-based cellular transcriptional activity. In addition to their intrinsic antioxidant capacity, bioavailability plays a major role in their in vivo efficacy. Although of identical antioxidant capacity, lipophilic MnTnHex-2-PyP is up to 120-fold more efficient in reducing oxidative stress injuries than hydrophilic MnTE-2-PyP. Owing to limitations of an analytical nature, porphyrin lipophilicity has been often estimated by the thin-layer chromatographic R-f parameter, instead of the standard n-octanol/water partition coefficient, P-OW. Herein we used a new methodological approach to finally describe the MnP lipophilicity, using the conventional log P-OW means, for a series of biologically active ortho and meta isomers of Mn(III) N-alkylpyridylporphyrins. Three new porphyrins (MnTnBu-3-PyP, MnTnHex-3-PyP, and MnTnHep-2-PyP) were synthesized to strengthen the conclusions. The log P-OW was linearly related to R-f and to the number of carbons in the alkyl chain (n(C)) for both isomer series, the meta isomers being 10-fold more lipophilic than the analogous ortho porphyrins. Increasing the length of the alkyl chain by one carbon atom increases the log P-OW value similar to 1 log unit with both isomers. Dramatic similar to 4 and similar to 5 orders of magnitude increases in the lipophilicity of the ortho isomers, by extending the pyridyl alkyl chains from two (MnTE-2-PyP, log P-OW=-6.89) to six (MnTnHex-2-PyP, log P-OW=-2.76) and eight carbon atoms (MnTnOct-2-PyP, log P-OW=-1.24), parallels the increased efficacy in several oxidative-stress injury models, particularly those of the central nervous system, in which transport across the blood-brain barrier is critical. Although meta isomers are only slightly less potent SOD mimics and antioxidants than their ortho analogues, their higher lipophilicity and smaller bulkiness may lead to a higher cellular uptake and overall similar effectiveness in vivo. (C) 2009 Elsevier Inc. All rights reserved.