New water soluble pyridyl porphyrins for use as peroxynitrite decomposition catalysts and heme model compounds

Owing to the important roles of porphyrins in biology, major research efforts have been devoted to the development of synthetic porphyrins in the laboratory. Water-soluble pyridyl porphyrins have emerged as one of the most promising classes of such compounds, in part because of the broad diversifiability afforded by the choice of reagent used to tetraalkylate the pyridyl nitrogen. Metalloporphyrins based on this structural motif have found widespread use as enzyme model compounds, oxidation catalysts, and therapeutics. Chapter 2 details the synthesis and evaluation of a new catalyst to decompose the reactive nitrogen species peroxynitrite. The new catalyst, iron(III) chloride meso-tetrakis-2-N-(N-(2-methoxyethyl)acetamido)pyridyl porphyrin (FP23), kinetically outcompetes its predecessor by a factor of two in reaction with peroxynitrite. FP23 was also evaluated in a laboratory model of protein tyrosine nitration, where it reduced the incidence of phenolic nitration by 72%, comparing well to other metalloporphyrin-based peroxynitrite decomposition catalysts. Solventless tetraalkylation of 2-pyridyl porphyrin with 2-bromo-N-(2-methoxyethyl)acetamide proceeded under thermodynamic control, producing the water-soluble ligand as a nearly statistical mixture of rotational isomers.;In Chapter 3, reaction of a series of water-soluble 2-pyridyl and 2-imidazolyl iron(III) porphyrins with excess cyanide resulted in autoreduction to air-stable low-spin bis(cyano)iron(II) porphyrins. The autoreduction reaction proceeded via the initial formation of a low-spin bis(cyano)iron(III) porphyrin of the non-classical low-spin ferric configuration, as shown by 1H NMR spectra with nearly diamagnetic beta-pyrrole resonances. The bis(cyano)ferriheme then underwent homolytic cleavage of an Fe-C(N) bond, as evidenced by the detection of cyanogen by 13C NMR, and this cyanide oxidation was stoichiometric in iron porphyrin. The homolysis yielded a mono(cyano)iron(II) species that was detectable in 13C NMR spectra and as a species with 2 unpaired spins in magnetic susceptibility experiments. In the absence of excess cyanide, the mono(cyano)ferroheme underwent oxidation to a mono(cyano)ferriheme, as evidenced by magnetic susceptibility results showing decay toward a species with only one unpaired spin. In the presence of excess cyanide, a bis(cyano)ferroheme is formed, as evidenced by the disappearance of unpaired spins in magnetic susceptibility experiments.;In Chapter 4, tetraalkylation of 2-pyridyl porphyrin with alpha-bromo- p-toluic acid yielded a conformationally unique tetrabenzylated product, with pi-pi stacking interactions between the carboxybenzyl groups and the porphyrin ring. The tetraalkylation proceeded with a strong thermodynamic bias toward the alphaalphaalphabeta and alphabetaalphabeta rotational isomers, with evidence of a kinetic alphaalphaalphabeta product under more dilute reaction conditions. Iron(III) chloride meso-tetrakis-2-( N-(4-carboxy)benzyl)pyridyl porphyrin (Fe-2-TCBPyP) catalyzed the near complete conversion of cyanide to cyanogen. Fe-2-TCBPyP also reacted with a variety of oxidants to generate a bleaching-resistant oxoiron(IV) species at 5-25°C. Oxidation of Mn-2-TCBPyP with oxone yielded a short-lived oxomanganese(V) complex which decayed through an oxomanganese(IV) intermediate back to the starting manganese(III) porphyrin.