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We investigated the reaction between glutathionylcobalamin (GSCbl), a tight complex of cobalamin with glutathione (GSH), and nitroxyl (HNO) produced upon decomposition of Angeli's salt using ultraviolet-visible spectroscopy and 1H NMR. The reaction in neutral and alkaline media leads to formation of nitrosylcobalamin (NOCbl). Simulation of the kinetic traces using the ChemMech program package suggested that the mechanism of the process involves complexation between HNO and GSCbl and further decomposition of the complex into the products. The complex participates in an acid-base equilibrium (pKa = 8.9), and the deprotonated form decomposes to NOCbl more rapidly than the protonated species. At pH 7.4, the reaction of HNO with GSCbl proceeds ca.103-times more slowly than with free GSH. GSCbl can react directly with the monoprotonated anion of Angeli's salt (HN2O3−) to produce nitrocobalamin (NO2Cbl). The reaction between GSCbl and HN2O3− is insignificant in an alkaline medium and is accelerated upon acidification of the medium. The critical step of the process is the complexation between GSCbl and HN2O3−. The produced complex is involved in an acid-base equilibrium (pKa = 8.1): the protonated form can be transformed to NO2Cbl and GSNHO−, whereas the deprotonated species decompose to initial reactants. [ABSTRACT FROM AUTHOR]

[Display omitted] • Efficient synthesis methods for meso-brominated aquacyanocobinamide and aquahydroxocobinamide. • meso-Bromination alters the aerobic stability of NOCbi in the presence of ligands. • Slower NO release from the meso-brominated NOCbi suggests milder hypotensive effects. • meso-Modification represents a valuable tool for modifying the properties of corrinoids as NO donors. This study explores the modification of nitrosylcobinamide, explicitly focusing on meso-bromination, and its impact on the dissociation rate of nitric oxide (NO). meso-Brominated aquahydroxocobinamide was efficiently synthesized from meso-brominated cyanocobalamin via hydrolysis, followed by decyanation step. Its reaction with Angeli's salt produces meso-brominated nitrosylcobinamide (NOCbi-Br). NOCbi-Br exhibits stability in the presence of dioxygen comparable to that of the unmodified NOCbi in neutral aqueous solutions. However, in the presence of L-histidine the oxidation of NOCbi-Br by dioxygen is significantly slower than unmodified NOCbi, indicating potential differences in ligand affinities. Furthermore, the rate constant for NO release from NOCbi-Br was lower than that of unmodified NOCbi, suggesting that meso-bromination strengthens the Co(II)–NO bond. These findings underscore the utility of meso-modification in tailoring the properties of corrinoids as nitric oxide donors, with potential implications for therapeutic applications. [ABSTRACT FROM AUTHOR]

Nitrosylcobinamide (NOCbi) is a tight complex between Co(II)-form of cobinamide, a nucleotide-free analog of cobalamin (vitamin B12), and nitric oxide (NO). Here, we report that NOCbi exhibits high resistance toward aerobic oxidation in comparison with nitrosylcobalamin. NOCbi slowly degrades in the presence of hydrogen peroxide and undergoes a more rapid oxidation by H2O2/peroxidase (viz. horseradish or lactoperoxidase) mixture to nitrocobinamide. Aerobic oxidation of NOCbi is accelerated by addition of ligands (i.e., imidazole, cyanide, and others). The mechanism of NOCbi oxidation in the presence of these ligands can be represented by two parallel routes: the axial ligand binding on NOCbi (i) results in the elongation of Co(II)-NO bond, leading to acceleration of NO-dissociation and further NO reaction with O2 to give NO2, and Cbi(II) oxidation by NO2, and (ii) facilitates reaction of the NO-motif with O2 to give peroxynitrite intermediate decomposing to nitrite and dioxygen. Decrease in aerobic stability of NOCbi may occur in vivo upon reaction with side chains of extracellular proteins, that was indicated using bovine serum albumin. [ABSTRACT FROM AUTHOR]