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

Abstract

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 approximately 1 log unit with both isomers. Dramatic approximately 4 and approximately 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.

Figure 1

Structures of ortho and meta isomers of Mn(III) N-alkylpyridylporphyrins.

Figure 2

The relationship between R_f obtained on TLC plastic-backed silica gel plates (R_f(Plastic)) and on TLC aluminum-backed silica gel plates (R_f(Al)) in acetonitrile: KNO₃-saturated H₂O:H₂O = 8:1:1. The ortho porphyrins are presented as squares (from methyl to octyl) and meta as triangles (from methyl to hexyl). The relationship is described with equation R_f(plastic) = 0.91 x R_f(Al) + 0.01, R² = 0.9609.

Figure 3

Relationship between the log P_OW and the number of carbon atoms (nC) for the series of ortho and meta Mn(III) N-alkylpyridylporphyrins. Full squares (ortho isomers) and triangles (meta isomers) present experimental values (determined in water/n-butanol system and converted to water/n-octanol system using equation 2) while empty squares and triangles present predicted values, respectively. The porphyrins are from bottom to top: MnTM-2,3-PyP, MnTE-2,3-PyP, MnTPr-2,3-PyP, MnTnBu-2,3-PyP, MnTnHex-2,3-PyP, MnTnHep-2-PyP, MnTnOct-2,3-PyP.

Figure 4

Relationship between the thin-chromatographic parameter, R_f and log P_OW for the series of ortho and meta Mn(III) N-alkylpyridylporphyrins. R_f values refer to those calculated using plastic-backed TLC plates (R_f(Plastic)). Full squares (ortho isomers) and triangles (meta isomers) present experimental values (determined in n-butanol/water system and converted to n-octanol/water system using equation 2) while empty squares and triangles present predicted values, respectively. The porphyrins are from bottom to top: MnTM-2,3-PyP (2,3-Me), MnTE-2,3-PyP (2,3-Et), MnTPr-2,3-PyP (2,3-Pr), MnTnBu-2,3-PyP (2,3-Bu), MnTnHex-2,3-PyP (2,3-Hex), MnTnHep-2,3-PyP (2,3-Hep), MnTnOct-2,3-PyP (R_f value was determined on silica gel plates with plastic base in acetonitrile: KNO₃-saturated H₂O:H₂O = 8:1:1.) Equations for ortho series is log P_OW = 12.69 x R_f - 7.59 (R² = 0.9672) and for meta series is log P_OW = 8.89 x R_f - 6.70 (R² = 0.9316).