engleski

Structural Modification Diminishes Toxicity of Lipophilic Longer Mn(III) N-alkylpyridyl porphyrin-based Powerful SOD Mimics: Synthesis, Characterization and SOD-deficient E. coli and S. cerevisiae studies

Oxidative stress is implicated in numerous diseases such as injuries of central nervous system, cancer, diabetes, radiation, ischemia/reperfusion injuries etc. Thus synthetic and natural compounds that could reduce oxidative stress have been actively sought. The structure-activity relationship guided us to successfully develop the ortho cationic Mn(III) Nalkylpyridylporphyrins ; some of them have kcat (O2 •–) as high as of SOD enzymes. Their ability to dismute O2 •– parallels their ability to scavenge ONOO– and suppress cellular redox-based transcriptional activity via inhibition of activation of transcription factors such as NF-κB, HIF-1α and AP-1. Our ongoing in vitro and in vivo studies have helped us to understand how much the type of substituents, the charge, lipophilicity, size, shape, and bulkiness of Mn porphyrins contribute to their therapeutic potency. For example, the 10-fold higher lipophilicity of meta ethyl, MnTE- 3-PyP5+relative to ortho analog, MnTE-2-PyP5+ outbalances its inferior SOD-like activity ; consequently in a SOD-deficient E. coli model of oxidative stress both isomers were equally efficacious. Analog with longer hydrophobic hexyl chains, MnTnHex-2-PyP5+is 13, 500-fold more lipophilic than ethyl porphyrin, MnTE-2-PyP5+, and thus crosses the blood brain barrier at levels enough to make it superior in rodent models of stroke and hemorrhage. However, it possesses strong micellar character which contributes to its higher toxicity relative to shorter ethyl compound, MnTE-2-PyP5+. We herein modified the isomeric hexyl porphyrins, MnTnHex-2(or 3 or 4)-PyP5+ to diminish their toxicity, while maintaining their SOD-like activity. We disrupted their surfactant character by introducing oxygen atom into each of the four alkyl chains. We tested such Mn(III) N-methoxyhexylpyridylporphyrins on efficacy and toxicity in eukaryotic (SOD-deficient yeast S. cerevisiae), and prokaryotic system (SOD-deficient E. coli). While their high SODlike activity was preserved relative to hexyl analogs, the toxicity was dramatically reduced. Whereas 1 μM MnTnHex-3-PyP5+ was already toxic to E. coli, 5 μM methoxyhexyl analog was fully protective. The diminished toxicity of methoxyhexyl relative to hexyl analogs was also found in yeast study. Thus, oxygenmodified Mn(III) N-alkylpyridylporphyrins are strong candidates for clinical development.

Mn porphyrin; SOD mimic; peroxynitrite scavenger

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