Fe porphyrins Revisited: Synthesis, Characterization and the Effects of Ortho and Meta Fe(III) N-Alkylpyridylporphyrins Upon the Growth of E. Coli in the Presence and Absence of Ascorbate

Abstract

Fe porphyrins Revisited: Synthesis, Characterization and the Effects of Ortho and Meta Fe(III) NAlkylpyridylporphyrins Upon the Growth of E. Coli in the Presence and Absence of Ascorbate Artak Tovmasyan, Tin Weitner, Ivan Spasojevic, Zrinka Rajic, Ludmil Benov, and Ines Batinic-Haberle Duke University Medical Center, USA, Faculty of Medicine, Kuwait School of Medicine, Kuwait Earlier studies indicated that at concentrations where Mn porphyrins (MnPs) are protective to SOD-deficient E. coli, Fe porphyrins (FePs) were toxic. Given the possible release of iron from FeP, and subsequent Fenton chemistry-directed OH radical production, over years we concentrated on MnPs only. However recent intriguing data tempted us to revisit FePs. Series of ortho and meta Fe(III) N-alkylpyridylporphyrins (alkyl = methyl, ethyl, butyl, hexyl, octyl) were synthesized and characterized. Metalcentered reduction potentials of ortho isomers, E1/2 are more positive than of their respective meta analogs. Similar “ortho” effect, already observed for analogous MnPs was attributed to stronger electron-withdrawing properties of the pyridyl nitrogens situated closer to the metal center. Large negative shift of E1/2 upon the increase of pH from 2 to 7.8 was observed for all complexes, and is associated with the predominance of FeP(OH) complexes in neutral solutions. Electrochemical data allow us to calculate the size of the ionic cavity formed by FePs where reactions of interest occur. the kcat (O2), obtained at pH 7.8, are higher with both ortho and meta FePs than with isomeric MnPs. Under same conditions, E1/2 values are somewhat lower for ortho FePs, but nearly twice higher for meta FePs, when compared to analogous MnPs. Consequently, the difference in kcat between ortho and meta FePs is smaller than between isomeric MnPs. the relationship between E1/2 for the FeP/FeP redox couple and kcat shows a behavior different from the one established for MnPs and is related to the differences in the type of axial ligands; at pH 7.8 there is hydroxo ligand at the Fe site and aqua ligand at the Mn site. FeP(OH) lacks positive charge at the metal site, but trans-effect makes it more reactive than MnP(H2O). With MnPs, the kcat decreases from methyl to butyl (as the steric hindrance of O2 approach increases), and increases beyond butyl as the continuous increase in E1/2 outbalances the unfavorable steric effects. With FePs though, kcat continuously decreases as the alkyl chains lengthen; the increase in E1/2 from butyl to hexyl is too small to overcome the unfavorable hindrance exerted by long alkyl chains. the results show that the differences in the axial coordination of the metal site play critical role in the thermodynamics and kinetics of O2 catalysis. Preliminary E. coli data show an intriguing behavior of FePs. Their toxicity to wild type and SOD-deficient strains is reverted in the presence of ascorbate; under identical conditions, ascorbate makes MnPs toxic. This effect may be also attributed to the differences in the Fe and Mn coordination chemistry. Studies are in progress to evaluate the therapeutic potential of FePs.