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Cationic Mn(III) N-alkylpyridyl- or N, N'-dialkylimidazolylporphyrins (MnPs), aimed at clinical development for the treatment of oxidative stress-related diseases must possess high antioxidant potency, lipophilicity, and low toxicity. High antioxidant potency, nearing that of SOD enzymes, has been achieved with ortho isomeric MnPs, such as MnTE-2-PyP5+, MnTDE-2-ImP5+ and MnTnHex-2-PyP5+. They efficiently eliminate O2.-, ONOO-, CO3.-, .NO, peroxyl and alkoxyl radicals and modulate cellular transcriptional activity. Those members of the series with long alkyl chains, such as MnTnHex-2-PyP5+, are lipophilic enough to accumulate in mitochondria (at ~ 90%), and cross the blood brain barrier (BBB). Yet, lipophilic MnPs are also toxic ; at least in part because of their surfactant properties. The cationic charges on pyridyl nitrogens are critical for MnP therapeutic potential as they provide favorable thermodynamics and kinetics in support of its in vivo redox-related activities. Further, the charges and the appropriate lipophilicity are critical for MnP accumulation within mitochondria and transport accross the BBB. We have already shown that introduction of oxygens at the periphery of the butyl and octyl chains markedly decreases toxicity of MnTnBu-2-PyP5+ and MnTnOct-2-PyP5+ ; yet, due to the excessive oxygens solvation, the compounds of reduced lipophilicity were obtained. Much to our surprise, placement of oxygens closer to the pyridyl nitrogens in Mn(III) meso-tetrakis (N-butoxyethylpyridinium-2-yl)porphyrin, MnTnBuOE-2-PyP5+, resulted in a molecule with truly superior properties within a class of cationic alkylpyridylporphyrins. MnTnBuOE-2-PyP5+ (i) has the catalytic rate constant for O2.- dismutation, kcat(O2.-) higher than that of MnTnHex-2-PyP5+ ; (ii) its lipophilicity is higher than that of MnTnHex-2-PyP5+ ; (iii) its toxicity to mice is ~ 5-fold lower than that of MnTnHex-2-PyP5+ ; and (iv) its efficcay in protecting SOD-deficient yeast S. cerevisiae at 0.1 M is much higher than of lipophilic MnTnHex-2-PyP5+. Presence of oxygens buried within the alkyl chains hinders the access of water molecules to the oxygen electron pairs and in turn diminishes greatly oxygen solvation. Further, the placement of oxygens in the close proximity to the porphyrin ring facilitates porphyrin metallation via transient bonding of Mn when it is approaching the pyrrolic nitrogens ; consequently, the metallation happens at room temperature vs at 1000C with MnTnHex-2-PyP5+. Finally, presence of oxygens within otherwise hydrophobic alkyl chains disrupts the surfactant properties and thus supresses the toxicity of this compound relative to hexyl analogue. |
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