Reaction of N-Acetylcysteine with Cu2+: Appearance of Intermediates with High Free Radical Scavenging Activity: Implications for Anti-/Pro-Oxidant Properties of Thiols

Abstract

We studied the kinetics of the reaction of N-acetyl-l-cysteine (NAC or RSH) with cupric ions at an equimolar ratio of the reactants in aqueous acid solution (pH 1.4–2) using UV/Vis absorption and circular dichroism (CD) spectroscopies. Cu2+ showed a strong catalytic effect on the 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonate) radical (ABTSr) consumption and autoxidation of NAC. Difference spectra revealed the formation of intermediates with absorption maxima at 233 and 302 nm (ε302/Cu > 8 × 103 M−1 cm−1) and two positive Cotton effects centered at 284 and 302 nm. These intermediates accumulate during the first, O2-independent, phase of the NAC autoxidation. The autocatalytic production of another chiral intermediate, characterized by two positive Cotton effects at 280 and 333 nm and an intense negative one at 305 nm, was observed in the second reaction phase. The intermediates are rapidly oxidized by added ABTSr; otherwise, they are stable for hours in the reaction solution, undergoing a slow pH- and O2-dependent photosensitive decay. The kinetic and spectral data are consistent with proposed structures of the intermediates as disulfide-bridged dicopper(I) complexes of types cis-/trans-CuI2(RS)2(RSSR) and CuI2(RSSR)2. The electronic transitions observed in the UV/Vis and CD spectra are tentatively attributed to Cu(I) → disulfide charge transfer with an interaction of the transition dipole moments (exciton coupling). The catalytic activity of the intermediates as potential O2 activators via Cu(II) peroxo-complexes is discussed. A mechanism for autocatalytic oxidation of Cu(I)–thiolates promoted by a growing electronically coupled –[CuI2(RSSR)]n– polymer is suggested. The obtained results are in line with other reported observations regarding copper-catalyzed autoxidation of thiols and provide new insight into these complicated, not yet fully understood systems. The proposed hypotheses point to the importance of the Cu(I)–disulfide interaction, which may have a profound impact on biological systems.

Extraintestinal Manifestations in Induced Colitis: Controversial Effects of N-Acetylcysteine on Colon, Liver, and Kidney

“…Unexpectedly, however, consistent with pro-oxidant effect of NAC in others studies [ 32 – 35 ], oral supplementation of NAC caused activation of inflammatory pathways and impaired the anti-inflammatory responses, as evidenced by the increase in TNF- α levels and decrease in IL-10, as well as macroscopic shortening of the colon. In contrast to the findings of the present study, Amrouche-Mekkioui and Djerdjouri [ 40 ] demonstrated that NAC decreased the production of inflammatory and LP markers (MPO and MDA).…”

“…These results in liver and kidney, despite having been obtained in an animal model that mimics UC, shed light on the use of alternative therapies or not in individuals with IBD and who also present associated diseases, such as diabetes, liver, and kidney diseases, since NAC had shown to play a harmful role on markers that reflect metabolic and systemic integrity. This negative effect of NAC had been shown before in others studies [ 32 , 33 ] and can be explained by its pro-oxidant power, and, because of this property, has been tested to induce death in cancer cells [ 34 , 35 ].…”

“…Although NAC and other thiols, such as GSH, are considered excellent antioxidants, the literature reports that under the influence of certain conditions and factors, they can be subjected to thiol oxidation, which generates thiyl radicals. In the presence of oxygen and metals (Cu 2+ and Fe 2+ ), this results in the formation of · OH and the O 2 ·− , thus implying oxidative damage to biological systems [ 11 , 32 ]. A similar effect occurs with the stilbene resveratrol [ 45 , 46 ] and ascorbic acid [ 47 ].…”

Interaction between Cu and Thiols of Biological and Environmental Importance: Case Study Using Combined Spectrophotometric/Bathocuproine Sulfonate Disodium Salt Hydrate (BCS) Assay

“…However, they suggested that GSH release by diatoms may contribute significantly to the Cu-binding ligand pool in marine waters [ 29 ]. Because of the biological and ecological importance of Cu–thiol complexes, Cu interactions with thiols have been of interest for many years, though there are discrepancies in the understanding of the exact reaction mechanisms and Cu oxidation state in such reactions [ 30 ]. Nevertheless, Smith et al reported that the stabilization of the free radical intermediate in Cu-catalyzed thiol oxidation varies as a result of structural differences between thiols affecting the oxidation rate, which is further discussed in their paper [ 31 ].…”

Chain Walking in the AlCl3 Catalyzed Cationic Polymerization of α‐Olefins

“…Consequently, CW can also be considered as a specific part of intermolecular chain transfers. However, its interest is due to the fact that it can lead to (hyper)branched/dendritic hydrocarbon polymers [24] that are tuned depending on the nature of the catalyst, [25,26,27,28,29] leading to stereospecific polymers, [28] or/with the complexity that the process involves the formation of radical species, [30] and this is also called radical ethene polymerization. [31,32,33] In addition, changing parameters such as monomer concentration or temperature can then block copolymerization.…”