- On N-acetylcysteine. Part I. Experimental and theoretical approaches of the N-acetylcysteine/H2O2 complexation
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The complexation of N-acetylcysteine (RSH) with hydrogen peroxide has been studied experimentally and theoretically. Experimentally we have measured the evolution of RSH, H2O2, and RSSR (N-acetylcystine) as a function of time. Surprisingly, H2O2 decays by a biphasic process, which is not the case for RSH and RSSR. In the first stage of the kinetics, H2O2 disappears without oxidizing the thiol function of RSH. By analogy with glutathione (GSH), the formation of a complex between RSH and H2O2 has been proposed. The thermodynamic equilibrium constant of complex formation has been determined. Theoretical calculations were performed within the SIBFA method to pinpoint the sites of complexation in isolated and hydrated states. A mixed 'discrete-continuum' model was used to evaluate the solvent effect. The two stable complexes found in isolated state have different behaviour under the influence of the solvent. Comparison with complexed GSH is discussed.
- Arroub,Berges,Abedinzadeh,Langlet,Gardes-Albert
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- A kinetic analysis of oxidation of the antioxidant N-acetyl-l-cysteine (NAC) by Pt(IV) complexes
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N-acetyl-l-cysteine (NAC) is an antioxidant and a supplement and has been demonstrated to have protective effects for a variety of toxic effects of heavy metals. Although previous works have shown that NAC can ameliorate the severe toxic effects of cisplatin, there is a lack of understanding of the interactions between NAC and Pt(IV)-based prodrugs. In this work, the oxidation of NAC by a cisplatin prodrug (cis-[Pt(NH3)2Cl4]), by a prototype of Pt(IV) anticancer drug ormaplatin ([Pt(dach)Cl4]) and by a model compound (trans-[PtCl2(CN)4]2-) was characterized in detail. NAC was oxidized to NAC-disulfide as identified by mass spectrometric analysis. Time-resolved spectral and stopped-flow kinetic measurements were carried out over a wide pH range, demonstrating that the oxidation followed overall second-order kinetics. The observed second-order rate constants k′ versus pH profiles were established. A reaction mechanism was deduced, involving three parallel rate-determining steps; conceivable transition states were also proposed for these steps. Rate constants of the rate-determining steps, obtained from the simulations of rate equation to the k′-pH profiles, were largely correlated with the electron density on the sulfur atom in NAC. The Pt(IV) prodrugs can execute oxidative stress in the biological systems of the human body by direct oxidation of relevant molecules, similar to HOCl/OCl- and chloroamines. Instead, the oxidative stress involved in the severe toxic effects of cisplatin is produced via a different mode. NAC could be a chemoprotecting agent also for the Pt(IV) anticancer drugs if recent drug delivery technologies are used.
- You, Daofeng,Ren, Yanli,Huo, Shuying,Dong, Jingran,Ren, Shuguang,Shi, Tiesheng
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- Entropy-Controlled Cu(II)-Catalyzed Oxidation of N-Acetyl-L-Cysteine by Methylene Blue in Acidic Medium
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Kinetics of the oxidation of N-acetyl-L-cysteine (NAC) by methylene blue (MB) catalyzed by Cu(II) have been investigated in presence of HCl. The reaction follows a first order kinetics in MB while the concentration order in NAC is zero. Hydrogen ions retard the rate of reaction. The reaction involves the participation of nanoparticles as revealed by SEM, XRD and FTIR techniques and a gel-like Cu-NAC network acts like the effective catalyst. The reaction conforms to Eley-Rideal mechanism at lower [NAC] while at higher [NAC], the kinetics are explained by extended Eley-Rideal mechanism. The reaction is regulated by the size and morphology of the nanoparticles and is controlled by the entropy of activation.
- Sharma, Ranjana,Pal, Mahender,Mishra
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- Electrochemical Evidence in Mechanism of Toxicity of Mefenamic Acid Overdose in the Presence of Glutathione and N-Acetyl-L-Cysteine
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In this study, the electrochemical oxidation of mefenamic acid was investigated in the presence of glutathione and N-acetyl-L-cysteine. The results revealed that the mefenamic acid was involved in a catalytic reaction with glutathione and N-acetyl-L-cysteine. This investigation presents some electrochemical evidence for the mechanism of action of these compounds in mefenamic acid poisoning.
- Amani, Ameneh,Amooshahi, Parvaneh,Khazalpour, Sadegh
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- Enhanced Cellular Polysulfides Negatively Regulate TLR4 Signaling and Mitigate Lethal Endotoxin Shock
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Cysteine persulfide and cysteine polysulfides are cysteine derivatives having sulfane sulfur atoms bound to cysteine thiol. Accumulating evidence has suggested that cysteine persulfides/polysulfides are abundant in prokaryotes and eukaryotes and play important roles in diverse biological processes such as antioxidant host defense and redox-dependent signal transduction. Here, we show that enhancement of cellular polysulfides by using polysulfide donors developed in this study resulted in marked inhibition of lipopolysaccharide (LPS)-initiated macrophage activation. Polysulfide donor treatment strongly suppressed LPS-induced pro-inflammatory responses in macrophages by inhibiting Toll-like receptor 4 (TLR4) signaling. Other TLR signaling stimulants—including zymosan A-TLR2 and poly(I:C)-TLR3—were also significantly suppressed by polysulfur donor treatment. Administration of polysulfide donors protected mice from lethal endotoxin shock. These data indicate that cellular polysulfides negatively regulate TLR4-mediated pro-inflammatory signaling and hence constitute a potential target for inflammatory disorders. Zhang et al. developed potent persulfide donors consisting of sulfane sulfur atoms stabilized by N-acetyl-L-cysteine (NAC polysulfides) via disulfide bonds at both sides. Strong anti-inflammatory activity of NAC polysulfides was demonstrated in cultured macrophage models and a mouse endotoxin shock model.
- Zhang, Tianli,Ono, Katsuhiko,Tsutsuki, Hiroyasu,Ihara, Hideshi,Islam, Waliul,Akaike, Takaaki,Sawa, Tomohiro
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- Insights into the reactivity of gold-dithiocarbamato anticancer agents toward model biomolecules by using multinuclear NMR spectroscopy
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Some gold(III)-dithiocarbamato derivatives of either single amino acids or oligopeptides have shown promise as potential anticancer agents, but their capability to interact with biologically relevant macromolecules is still poorly understood. We investigated the affinity of the representative complex [Au IIIBr2(dtc-Sar-OCH3)] (dtc: dithiocarbamate; Sar: sarcosine (N-methylglycine)) with selected model molecules for histidine-, methionine-, and cysteine-rich proteins (that is, 1-methylimidazole, dimethylsulfide, and N-acetyl-L-cysteine, respectively). In particular, detailed mono- and multinuclear NMR studies, in combination with multiple 13C/15N enrichments, allowed interactions to be followed over time and indicated somewhat unexpected reaction pathways. Whereas dimethylsulfide proved to be unreactive, a sudden multistep redox reaction occurred in the presence of the other potential sulfur donor, N-acetyl-L-cysteine (confirmed if glutathione was used instead). On the other hand, 1-methylimidazole underwent an unprecedented acid-base reaction with the gold(III) complex, rather than the expected coordination to the metal center by replacing, for instance, a bromide. Our results are discussed herein and compared with the data available in the literature on related complexes; our findings confirm that the peculiar reactivity of gold(III)-dithiocarbamato complexes can lead to novel reaction pathways and, therefore, to new cytotoxic mechanisms in cancer cells. To react or not to react? Model nitrogen- and sulfur-donor compounds can be treated with a representative gold(III)- dithiocarbamato anticancer agent to evaluate potential reactivity of such anticancer agents toward biomolecules (see figure). Detailed NMR studies show that the interaction with physiologically relevant species can lead to unexpected reaction pathways that may contribute to the novel mechanisms of cytotoxicity observed for this class of complexes. Copyright
- Boscutti, Giulia,Marchio, Luciano,Ronconi, Luca,Fregona, Dolores
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- On N-acetylcysteine. Part II. Oxidation of N-acetylcysteine by hydrogen peroxide: Kinetic study of the overall process
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The oxidation kinetics of N-acetylcysteine (RSH) by hydrogen peroxide has been studied at neutral pH at different concentration ratios from 0.2 to 20 (4 x 10-4 mol L-1 ≤ [RSH]0 ≤ 2 x 10- mol L-1, 10-4 mol L-1 ≤ [H2O2]0 ≤ 10-2 mol L-1). In all the cases studied, N-acetyleystine (RSSR) is the only oxidized product formed. Our kinetic data have focused on the importance of the concentration ratio to reach the stoichiometric oxidation of N-acetylcysteine by hydrogen peroxide. Indeed non-stoichiometric oxidation of RSH occurs at relatively low concentration ratios (R 2.5. Moreover, it has been shown that in the first minutes of the reaction there is the formation of a complex between RSH and H2O2, the stoichiometry of the complex being RSH concentration-dependent for a given R (R > 2.5). Reaction mechanisms have been quantitatively established and the k values of each step determined.
- Abedinzadeh,Arroub,Gardes-Albert
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- Efficient Amino-Sulfhydryl Stapling on Peptides and Proteins Using Bifunctional NHS-Activated Acrylamides
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Widely used reagents in the peptide functionalization toolbox, Michael acceptors and N-hydroxysuccinimide (NHS) activated esters, are combined in NHS-activated acrylamides for efficient chemoselective amino-sulfhydryl stapling on native peptides and proteins. NHS-activated acrylamides allow for a fast functionalization of N-terminal cysteines (k2=1.54±0.18×103 M?1 s?1) under dilute aqueous conditions, enabling selectivity over other nucleophilic amino acids. Additionally, the versatility of these new bioconjugation handles was demonstrated in the cross-linking of in-chain or C-terminal cysteines with nearby lysine residues. NHS-activated acrylamides are compatible with the use of other cysteine selective reagents, allowing for orthogonal dual-modifications. This strategy was successfully applied to the late-stage functionalization of peptides and proteins with a PEG unit, fluorescent probe, and cytotoxic agent. The level of molecular control offered by NHS-activated acrylamides is expected to promote amino-sulfhydryl stapling technology as a powerful strategy to design functional bioconjugates.
- Silva, Maria J. S. A.,Faustino, Hélio,Coelho, Jaime A. S.,Pinto, Maria V.,Fernandes, Adelaide,Compa?ón, Ismael,Corzana, Francisco,Gasser, Gilles,Gois, Pedro M. P.
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supporting information
p. 10850 - 10857
(2021/04/15)
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- PROCESS OF MAKING N,N'-DIACETYL-L-CYSTINE
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An effective process of making Ν,Ν'-diacetyl-L-Cystine ( NDAC ), which process is fast, green, does not require labor-intensive isolation or purification of the product, by yielding products in desired ratio, and has improved yield and purity. The process comprising the steps of Forming a reaction mixture, starting with a cystine derivative di-tert- butyl-L-cystine as the dihydrochloride form; Acetylating said di-tert-butyl-L-cystine to obtain Ν,Ν'-diacetyl-di-tert- butyl-L-cystine; followed by Removing said tert- butyl groups from said Ν,Ν'-diacetyl-di-tert-butyl- L-cystine to obtain Ν,Ν'-diacetyl-L-cystine product; and Isolating said Ν,Ν'-diacetyl-L-Cystine product from said reaction mixture; wherein said acetylating agent is acetic anhydride.
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Page/Page column 16-17
(2021/11/06)
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- Bacterial flavoprotein monooxygenase YxeK salvages toxic S-(2-succino)-adducts via oxygenolytic C–S bond cleavage
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Thiol-containing nucleophiles such as cysteine react spontaneously with the citric acid cycle intermediate fumarate to form S-(2-succino)-adducts. In Bacillus subtilis, a salvaging pathway encoded by the yxe operon has recently been identified for the detoxification and exploitation of these compounds as sulfur sources. This route involves acetylation of S-(2-succino)cysteine to N-acetyl-2-succinocysteine, which is presumably converted to oxaloacetate and N-acetylcysteine, before a final deacetylation step affords cysteine. The critical oxidative cleavage of the C–S bond of N-acetyl-S-(2-succino)cysteine was proposed to depend on the predicted flavoprotein monooxygenase YxeK. Here, we characterize YxeK and verify its role in S-(2-succino)-adduct detoxification and sulfur metabolism. Detailed biochemical and mechanistic investigation of YxeK including 18O-isotope-labeling experiments, homology modeling, substrate specificity tests, site-directed mutagenesis, and (pre-)steady-state kinetics provides insight into the enzyme’s mechanism of action, which may involve a noncanonical flavin-N5-peroxide species for C–S bond oxygenolysis.
- Ellis, Holly R.,Kammerer, Bernd,Lagies, Simon,Matthews, Arne,Sch?nfelder, Julia,Schleicher, Erik,Stull, Frederick,Teufel, Robin
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- Thiol-based michael-type addition. A systematic evaluation of its controlling factors
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This paper is about the factors controlling kinetics and product stability of this popular bioconjugation reaction. We demonstrate that a) thiol pKa, i.e. the amount of thiolates, is the only determinant of the reaction kinetics for the nucleophile; b) product degradation occurs primarily via hydrolysis (not thiol exchange), and is more prominent for the most rapidly reacting electrophiles. In terms of molecular design, acrylamides and low pKa thiols appear as the reaction partners that provide the best compromise for stability and reaction rate.
- Francini, Nora,Gennari, Arianna,Lallana, Enrique,Tirelli, Nicola,Wedgwood, Jennifer
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supporting information
(2020/10/19)
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- Alkylamine-Substituted Perthiocarbamates: Dual Precursors to Hydropersulfide and Carbonyl Sulfide with Cardioprotective Actions
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The recent discovery of hydropersulfides (RSSH) in mammalian systems suggests their potential roles in cell signaling. However, the exploration of RSSH biological significance is challenging due to their instability under physiological conditions. Herein, we report the preparation, RSSH-releasing properties, and cytoprotective nature of alkylamine-substituted perthiocarbamates. Triggered by a base-sensitive, self-immolative moiety, these precursors show efficient RSSH release and also demonstrate the ability to generate carbonyl sulfide (COS) in the presence of thiols. Using this dually reactive alkylamine-substituted perthiocarbamate platform, the generation of both RSSH and COS is tunable with respect to half-life, pH, and availability of thiols. Importantly, these precursors exhibit cytoprotective effects against hydrogen peroxide-mediated toxicity in H9c2 cells and cardioprotective effects against myocardial ischemic/reperfusion injury, indicating their potential application as new RSSH- and/or COS-releasing therapeutics.
- Khodade, Vinayak S.,Pharoah, Blaze M.,Paolocci, Nazareno,Toscano, John P.
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supporting information
p. 4309 - 4316
(2020/03/05)
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- Crystal-facet-dependent denitrosylation: Modulation of NO release from S-nitrosothiols by Cu2O polymorphs
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Nitric oxide (NO), a gaseous small molecule generated by the nitric oxide synthase (NOS) enzymes, plays key roles in signal transduction. The thiol groups present in many proteins and small molecules undergo nitrosylation to form the corresponding S-nitrosothiols. The release of NO from S-nitrosothiols is a key strategy to maintain the NO levels in biological systems. However, the controlled release of NO from the nitrosylated compounds at physiological pH remains a challenge. In this paper, we describe the synthesis and NO releasing ability of Cu2O nanomaterials and provide the first experimental evidence that the nanocrystals having different crystal facets within the same crystal system exhibit different activities toward S-nitrosothiols. We used various imaging techniques and time-dependent spectroscopic measurements to understand the nature of catalytically active species involved in the surface reactions. The denitrosylation reactions by Cu2O can be carried out multiple times without affecting the catalytic activity.
- Ghosh, Sourav,Roy, Punarbasu,Prasad, Sanjay,Mugesh, Govindasamy
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p. 5308 - 5318
(2019/05/29)
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- Reducing Holomycin Thiosulfonate to its Disulfide with Thiols
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The dithiolopyrrolone (DTP) natural products contain a unique ene-disulfide that is essential for their antimicrobial and anticancer activities. The ene-disulfide in some DTPs is oxidized to a cyclic thiosulfonate, but it is unknown how the DTP thiosulfonates react with biomolecules. We studied the reactivity of the thiosulfonate derivative of the DTP holomycin, oxo-holomycin, and discovered a unique redox reaction: Oxo-holomycin is reduced to its parent disulfide, while oxidizing small molecule and protein thiols to disulfides. Our work reveals that the DTP core is a privileged scaffold that undergoes unusual redox chemistry. The redox chemistry of the DTP natural products may contribute to their mechanism of action.
- Chan, Andrew N.,Massolo, Elisabetta,Li, Bo,Wever, Walter J.,Allen, Scott E.
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p. 400 - 404
(2019/04/16)
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- An Organodiselenide with Dual Mimic Function of Sulfhydryl Oxidases and Glutathione Peroxidases: Aerial Oxidation of Organothiols to Organodisulfides
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A novel organodiselenide, which mimics sulfhydryl oxidases and glutathione peroxidase (GPx) enzymes for oxidation of thiols by oxygen and hydrogen peroxide, respectively, into disulfides has been presented. The developed catalyst oxidizes an array of organothiols into respective disulfides in practical yields by using aerial O2 to avoid any reagents/additives, base, and light source. The synthesized diselenide also catalyzes the reduction of hydrogen peroxide into water by following the GPx enzymatic catalytic cycle with a reduction rate of 49.65 ± 3.7 μM·min-1.
- Rathore, Vandana,Upadhyay, Aditya,Kumar, Sangit
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supporting information
p. 6274 - 6278
(2018/10/05)
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- Organic oxidations promoted in vortex driven thin films under continuous flow
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With increasing concerns for the environmental impact of chemical manufacturing, reagents and processes that align with the principles of green chemistry are essential. The fundamental oxidation of organic substrates is no exception and in this report three distinct modes of green oxidation are demonstrated in a vortex fluidic device (VFD) under continuous flow: aerobic oxidation, oxidation using chlorine bleach, and oxidation using hydrogen peroxide. The VFD, which is a thin film microfluidic platform, revealed clear advantages in these oxidations in comparison to traditional batch reactor processing: Efficient mass transfer of gases in the dynamic thin film increased the rate of aerobic oxidations, and the intense micromixing allowed multi-phase oxidations to proceed efficiently, obviating the need for organic solvents and phase transfer catalysts. In addition, the rapid dissipation of heat in the VFD also improved the safety profile and stereoselectivity for exothermic oxidations.
- Pye, Scott J.,Dalgarno, Scott J.,Chalker, Justin M.,Raston, Colin L.
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supporting information
p. 118 - 124
(2018/01/17)
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- Reaction Kinetics Direct a Rational Synthesis of an HIV-1 Inactivator of Nucleocapsid Protein 7 and Provide Mechanistic Insight into Cellular Metabolism and Antiviral Activity
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Mercaptobenzamide thioester SAMT-247 is a non-toxic, mutation-resistant HIV-1 maturation inhibitor with a unique mechanism of antiviral activity. NMR spectroscopic analyses of model reactions that mimic the cellular environment answered fundamental questions about the antiviral mechanism and inspired a high-yielding (64 % overall), scalable (75 mmol), and cost-effective ($4 mmol?1) three-step synthesis that will enable additional preclinical evaluation.
- Nikolayevskiy, Herman,Scerba, Michael T.,Deschamps, Jeffrey R.,Appella, Daniel H.
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supporting information
p. 9485 - 9489
(2018/05/30)
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- Constitutional self-selection from dynamic combinatorial libraries in aqueous solution through supramolecular interactions
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We describe the predominant formation of a specific constitution arising from the combination of building blocks with different topologies through disulphide chemistry in a Dynamic Combinatorial Library (DCL). The supramolecular interactions established by a zwitterionic cysteine moiety are responsible for the self-selection of one product from all the virtual members of a large library. the Partner Organisations 2014.
- Sola, Jordi,Lafuente, Maria,Atcher, Joan,Alfonso, Ignacio
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supporting information
p. 4564 - 4566
(2014/05/06)
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- Iodate oxidation of n-acetyl l-cysteine: Application in drug determination and characterization of its oxidation and degradation product by mass spectrometry
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A kinetic spectrophotometric method based on the initial rate measurement has been developed for the determination of N-acetyl L-cysteine. The developed method is based on the oxidation of N-acetyl L-cysteine with iodate. The reaction product was studied and characterized using the mass spectrometry and the structure of the product was proposed. From the mass spectrometric studies it was concluded that the oxidation of the drug resulted in the formation of a disulfide. The developed method was validated as per the guidelines of international conference on harmonization. The developed initial rate method was found to be linear in the concentration range of 1.25-30 μg ml-1. The detection and quantitation limits were found to be 0.018 and 0.056 μg ml-1. In the current study, the degradation product of N-acetyl L cysteine was also prepared and identified using mass spectrometry.
- Siddiqui, Masoom Raza,Wabaidur, Saikh Mohammad,Alothman, Zied A.,Rahman, Habibur,Alam, Md.Sarfaraz,Ali, Md.Sajid
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p. 2303 - 2307
(2014/07/22)
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- Rapid high-yield N-acylation of aminothiols: N-acetylglutathione and N-acetylhomocysteine and their thiol pKa values
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Methodology for the rapid N-acylation of aminothiols in aqueous solution using procedures commonly employed in biochemical studies is described here. Glutathione disulfide (GSSG) and homocystine were diN-acetylated in ~100% yield in 0.1M aqueous NaHCO3 (pH 8.5) at room temperature by 2.5equiv of the activated ester, N-hydroxysulfosuccinimidyl acetate, an efficient water-soluble acetylating reagent. Following acetone precipitation, diN-acetylGSSG was further purified and desalted on a strong anion-exchange (SAX) cartridge. DiN-acetylhomocystine was simultaneously purified and desalted on a C18 cartridge. The N-acetylated aminothiols were generated using gel-immobilized tris(2-carboxyethyl)phosphine as a reductant, which obviated the need for further purification. Alternatively, disulfide exchange with dissolved dithiothreitol yielded N-acetylglutathione, which was purified on the SAX cartridge. pH titrations of N-acetylglutathione (8.99) and N-acetylhomocysteine (9.66) as well as those of commercially available N-acetylcysteine (9.53) and N-acetylpenicillamine (10.21) yielded pKa(SH) values of importance for biological studies.
- Shen, Biao,Bazin, Cynthia,English, Ann M.
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p. 263 - 267
(2013/07/05)
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- Aerobic oxidation of thiols to disulfides catalyzed by diaryl tellurides under photosensitized conditions
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Aerobic oxidation of thiols is efficiently catalyzed by diaryl tellurides such as bis(4-methoxyphenyl) telluride under photosensitized conditions to give the corresponding disulfides in good to excellent yields. In this catalytic system, the tellurone oligomer, produced by the reaction of a telluride with singlet oxygen, is assumed to be the active species and is capable of oxidizing 4 equiv of a thiol.
- Oba, Makoto,Tanaka, Kazuhito,Nishiyama, Kozaburo,Ando, Wataru
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experimental part
p. 4173 - 4177
(2011/06/26)
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- Electrochemical evidences in oxidation of acetaminophen in the presence of glutathione and N-acetylcysteine
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Electrochemical oxidation of acetaminophen has been studied in the presence of glutathione and acetylcysteine. Our results indicate that N-acetyl-p-benzoquinone-imine (NAPQI) participates in a catalytic reaction with glutathione and N-acetylcysteine. Also, the observed homogeneous rate constants of the reaction of NAPQI with glutathione and acetylcysteine were estimated.
- Shayani-Jam, Hasan,Nematollahi, Davood
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supporting information; experimental part
p. 409 - 411
(2010/04/04)
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- Myoglobin modification by enzyme-generated dopamine reactive species
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The generation of reactive quinone species (DAQ) from oxidation of dopamine (DA) is involved in neurodegenerative pathologies like Parkinson's disease (A. Borta, G. U. Hoeglinger, J. Neurochem. 2007, 100, 587-595). The oxidation of DA to DAQ can occur either in a single two-electron process or in two consecutive one-electron steps, through semiquinone radicals, giving rise to different patterns of reactions. The former type of reaction can be promoted by tyrosinase, the latter by peroxidases in the presence of H2O 2, which can be formed under oxidative stress conditions. Both enzymes were employed for the characterization of the thiol-catechol adducts formed by reaction of DA and cysteine or glutathione, and for the identification of specific amino acid residues modified by DAQs in two representative target proteins, human and horse heart myoglobin. Our results indicate that the cysteinyl-DA adducts are formed from the same quinone intermediate independently of the mechanism of DA oxidation, and that the hallmark of a radical mechanism is the formation of the cystine dimer. The reactivity of quinone species also controls the DA-promoted derivatization of histidine residues in proteins. However, for the modification of the cysteine residue in human myoglobin, a radical intramolecular mechanism has been proposed, in which the protein acts both as the catalyst and target of the reaction. Most importantly, the modification of myoglobins through DAQ linkages, and in particular by DA oligomers, has dramatic effects on their stability, as it induces protein unfolding and incorporation into insoluble melanic precipitates.
- Nicolis, Stefania,Zucchelli, Matteo,Monzani, Enrico,Casella, Luigi
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experimental part
p. 8661 - 8673
(2009/11/30)
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- A study of the glutathione metaboloma peptides by energy-resolved mass spectrometry as a tool to investigate into the interference of toxic heavy metals with their metabolic processes
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To better understand the fragmentation processes of the metal-biothiol conjugates and their possible significance in biological terms, an energy-resolved mass spectrometric study of the glutathione conjugates of heavy metals, of several thiols and disulfides of the glutathione metaboloma has been carried out. The main fragmentation process of γ-glutamyl compounds, whether in the thiol, disulfide, thioether or metal-bis-thiolate form, is the loss of the γ-glutamyl residue, a process which ERMS data showed to be hardly influenced by the sulfur substitution. However, loss of the γ-glutamyl residue from the mono-S-glutathionyl-mercury (II) cation is a much more energetic process, possibly pointing at a strong coordination of the carboxylic group to the metal. Moreover, loss of neutral mercury from ions containing the γ-glutamyl residue to yield a sulfenium cation was a much more energetic process than those not containing them, suggesting that the redox potential of the thiol/disulfide system plays a role in the formal reduction of the mercury dication in the gas phase. Occurrence of complementary sulfenium and protonated thiol fragments in the spectra of protonated disulfides of the glutathione metaboloma mirrors the thiol/disulfide redox process of biological importance. The intensity ratio of the fragments is proportional to the reduction potential in solution of the corresponding redox pairs. This finding has allowed the calculation of the previously unreported reduction potentials for the disulfide/thiol pair of cysteinylglycine, thereby confirming the decomposition scheme of bis- and mono-S-glutathionyl-mercury (II) ions. Finally, on the sole basis of the mass spectrometric fragmentation of the glutathione-mercury conjugates, and supported by independent literature evidence, an unprecedented mechanism for mercury ion-induced cellular oxidative stress could be proposed, based on the depletion of the glutathione pool by a catalytic mechanism acting on the metal (II)-thiol conjugates and involving as a necessary step the enzymatic removal of the glutamic acid residue to yield a mercury (II)-cysteinyl-glycine conjugate capable of regenerating neutral mercury through the oxidation of glutathione thiols to the corresponding disulfides. Copyright
- Rubino, Federico Maria,Pitton, Marco,Brambilla, Gabri,Colombi, Antonio
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p. 1578 - 1593
(2007/10/03)
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- Characterization of the disulfides of bio-thiols by electrospray ionization and triple-quadrupole tandem mass spectrometry
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Glutathione and other intracellular low molecular mass thiols act both as the major endogenous antioxidant and redox buffer system and, as recently highlighted, as an important regulator of cellular homeostasis. Such cellular functions are mediated by protein thiolation, a newly recognized post-translational modification which involves the formation of mixed disulfides between GSH and key disulfide-linked Cys residues in the native protein structure. It is also well known that thiol-seeking heavy metals, such as mercury, cadmium and lead, may interfere in this regulatory system, thus disrupting the cellular functioning. To identify such mixed disulfides in order to investigate their biological role, 15 homo- and heterodimeric disulfides were prepared by air oxidation of binary mixtures containing cysteine, homocysteine, penicillamine, N-acetylcysteine, N-acetylpenicillamine and glutathione and their protonated molecules were characterized by mass spectrometry. Collisionally activated unimolecular decomposition of protonated homo- and heterodimeric disulfides generated by electrospray ionization gives rise to fission of the disulfide system both between the two sulfur atoms and across the C-S bonds, to yield structurally specific fragments which allow one to define the structure of the compounds and to discriminate between isomeric compounds. Fission between the sulfur atoms yields a pair of R-S? ions and, in some cases, also the complementary fragments corresponding to the protonated amino acids. Fission across the C-S bonds mainly occurs in the disulfides of N-acetylcysteine and N-acetylpenicillamine and gives rise to non-S-containing fragments formally similar to those obtained from some mercapturic acids. The complementary fragments, formally connected as R-S-S+ ions are also observed. Fragmentation of glutathione disulfides mainly shows the characteristic loss of the terminal γ-linked glutamic acid and little, if any, fragmentation of the disulfide system. Copyright
- Rubino, Federico Maria,Verduci, Cinzia,Giampiccolo, Rosario,Pulvirenti, Salvatore,Brambilla, Gabri,Colombi, Antonio
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p. 1408 - 1416
(2007/10/03)
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- Reaction of hydroxyl radicals with S-nitrosothiols: Determination of rate constants and end product analysis
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The reaction of the hydroxyl radical (OH) with S-nitroso derivatives of cysteine, acetylcysteine and glutathione was studied at neutral and acidic pH. The second-order rate constants were determined by a competition kinetic method using a deoxyribose-thiobarbituric acid assay. The rate constants were diffusion controlled and were 2.27, 1.94 and 1.46 × 1010 dm3 mol-1 s-1, for S-nitrosocysteine, S-nitrosoacetylcysteine and S-nitrosoglutathione respectively, at neutral pH. The major products of the degradation induced by OH were found to be the corresponding disulfide (-S-S-) and nitrite (NO2-) at neutral pH as well as at pH 3. Simultaneous proton formation has also been observed. A plausible mechanism based on the formation of an intermediate thiol radical (RS), as a result of electron transfer from the S-nitrosothiols (RSNOs) to OH, is proposed for the formation of disulfide and nitrite at both pHs. The high rate constant values and the degradation of these compounds demonstrate the potential role of OH in RSNO metabolism under physiological conditions.
- Manoj, Veleeparambil M.,Aravindakumar, Charuvila T.
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p. 1171 - 1175
(2007/10/03)
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- Oxidation of proximal protein sulfhydryls by phenanthraquinone, a component of diesel exhaust particles
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Diesel exhaust particles (DEP) contain quinones that are capable of catalyzing the generation of reactive oxygen species in biological systems, resulting in induction of oxidative stress. In the present study, we explored sulfhydryl oxidation by phenanthraquinone, a component of DEP, using thiol compounds and protein preparations. Phenanthraquinone reacted readily with dithiol compounds such as dithiothreitol (DTT), 2,3-dimercapto-1-propanol (BAL), and 2,3-dimercapto-1-propanesulfonic acid (DMPS), resulting in modification of the thiol groups, whereas minimal reactivities of this quinone with monothiol compounds such as GSH, 2-mercaptoethanol, and N-acetyl-L-cysteine were seen. The modification of DTT dithiol caused by phenanthraquinone proceeded under anaerobic conditions but was accelerated by molecular oxygen. Phenanthraquinone was also capable of modifying thiol groups in pulmonary microsomes from rats and total membrane preparation isolated from bovine aortic endothelial cells (BAEC), but not bovine serum albumin (BSA), which has a Cys34 as a reactive monothiol group. A comparison of the thiol alkylating agent N-ethylmaleimide (NEM) with that of phenanthraquinone indicates that the two mechanisms of thiol modification are distinct. Studies revealed that thiyl radical intermediates and reactive oxygen species were generated during interaction of phenanthraquinone with DTT. From these findings, it is suggested that phenanthraquinone-mediated destruction of protein sulfhydryls appears to involve the oxidation of presumably proximal thiols and the reduction of molecular oxygen.
- Kumagai, Yoshito,Koide, Sachie,Taguchi, Keiko,Endo, Akiko,Nakai, Yumi,Yoshikawa, Toshikazu,Shimojo, Nobuhiro
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p. 483 - 489
(2007/10/03)
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- Polyethylene glycol matrix reduces the rates of photochemical and thermal release of nitric oxide from S-nitroso-N-acetylcysteine
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S-nitrosothiols have many biological activities and may act as nitric oxide (NO) carriers and donors, prolonging NO half-life in vivo. In spite of their great potential as therapeutic agents, most S-nitrosothiols are too unstable to isolate. We have shown that the S-nitroso adduct of N-acetylcysteine (SNAC) can be synthesized directly in aqueous and polyethylene glycol (PEG) 400 matrix by using a reactive gaseous (NO/O2) mixture. Spectral monitoring of the S-N bond cleavage showed that SNAC, synthesized by this method, is relatively stable in nonbuffered aqueous solution at 25°C in the dark and that its stability is greatly increased in PEG matrix, resulting in a 28-fold decrease in its initial rate of thermal decomposition. Irradiation with UV light (λ = 333 nm) accelerated the rate of decomposition of SNAC to NO in both matrices, indicating that SNAC may find use for the photogeneration of NO. The quantum yield for SNAC decomposition decreased from 0.65 ± 0.15 in aqueous solution to 0.047 ± 0.005 in PEG 400 matrix. This increased stability in PEG matrix was assigned to a cage effect promoted by the PEG microenvironment that increases the rate of geminated radical pair recombination in the homolytic S-N bond cleavage process. This effect allowed for the storage of SNAC in PEG at -20°C in the dark for more than 10 weeks with negligible decomposition. Such stabilization may represent a viable option for the synthesis, storage and handling of S-nitrosothiol solutions for biomedical applications.
- Shishido, Silvia Mika,De Oliveira, Marcelo Ganzarolli
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p. 273 - 280
(2007/10/03)
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- Kinetics and mechanism for reduction of the anticancer prodrug trans,trans,trans-[PtCl2(OH)2(c-C6H11NH2)(NH3)] (JM335) by thiols.
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The reduction of the platinum(IV) prodrug trans,trans,trans-[PtCl2(OH)2(c-C6H11NH2)(NH3)] (JM335) by L-cysteine, DL-penicillamine, DL-homocysteine, N-acetyl-L-cysteine, 2-mercaptopropanoic acid, 2-mercaptosuccinic acid, and glutathione has been investigated at 25 degrees C in a 1.0 M aqueous perchlorate medium with 6.8 a reductive elimination process through an attack by sulfur at one of the mutually trans chloride ligands, yielding trans-[Pt(OH)2(c-C6H11NH2)(NH3)] and RSSR as the reaction products, as confirmed by 1H NMR. Second-order rate constants for the reduction of JM335 by the various protolytic species of the thiols span more than 3 orders of magnitude. Reduction with RS- is approximately 30-2000 times faster than with RSH. The linear correlation log(kRS) = (0.52 +/- 0.06)-pKRSH--(2.8 +/- 0.5) is observed, where kRS denotes the second-order rate constant for reduction of JM335 by a particular thiolate RS- and KRSH is the acid dissociation constant for the corresponding thiol RSH. The slope of the linear correlation indicates that the reactivity of the various thiolate species is governed by their proton basicity, and no significant steric effects are observed. The half-life for reduction of JM335 by 6 mM glutathione (40-fold excess) at physiologically relevant conditions of 37 degrees C and pH 7.30 is 23 s. This implies that JM335, in clinical use, is likely to undergo in vivo reduction by intracellular reducing agents such as glutathione prior to binding to DNA. Reduction results in the immediate formation of a highly reactive platinum(II) species, i.e., the bishydroxo complex in rapid protolytic equilibrium with its aqua form.
- Lemma,Shi,Elding
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p. 1728 - 1734
(2008/10/08)
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- Reaction of ascorbic acid with S-nitrosothiols: Clear evidence for two distinct reaction pathways
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Ascorbate reacts with S-nitrosothiols generally, in the pH range 3-13 by way of two distinct pathways, (a) at low [ascorbate], typically below ~1 × 10-4 mol dm-3 which leads to the formation of NO and the disulfide, and (b) at higher [ascorbate] when the products are the thiol and NO. Reaction (a) is Cu2+-dependent, and is completely cut out in the presence of EDTA, whereas reaction (b) is totally independent of [Cu2+] and takes place readily whether EDTA is present or not. For S-nitrosoglutathione (GSNO) the two reactions can be made quite separate, although for some reactants the two reactions overlap. In reaction (a), ascorbate acts as a reducing agent, generating Cu+ from Cu2+, which in turn reacts with RSNO forming initially NO, Cu2+ and RS-. The latter can then play the role of reducing agent for Cu2+, leading to disulfide formation. Ascorbate will initiate reaction when the free thiolate has initially been reduced to a very low level by the synthesis of RSNO from a large excess of nitrous acid over the thiol. Reaction (b) is interpreted in terms of nucleophilic attack by ascorbate at the nitroso-nitrogen atom, leading to thiol and O-nitrosoascorbate which breaks up, by a free-radical pathway, to give dehydroascorbic acid and NO. A similar pathway is the accepted mechanism in the literature for the nitrosation of ascorbate by nitrous acid and alkyl nitrites. The rate constant for the Cu2+-independent pathway increases sharply with pH and analysis of the variation of the rate constant with pH identifies a reaction pathway via both the mono- and di-anion forms of ascorbate, with the latter being the more reactive. As expected the entropy of activation is large and negative. Some aspects of structure-reactivity trends are discussed.
- Holmes, Anthony J.,Williams, D. Lyn H.
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p. 1639 - 1644
(2007/10/03)
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- Novel Water-Soluble Diorganyl Tellurides with Thiol Peroxidase and Antioxidant Activity
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Novel water-soluble diaryl tellurides, alkyl aryl tellurides, and dialkyl tellurides carrying sulfopropyl groups were prepared and found to possess potent peroxide decomposing and chain-breaking antioxidative capacity. The dilithium, disodium, dipotassium, and bis-tetramethylammonium salts of bis(4-hydroxyphenyl) telluride (4) were treated with 2.3 equiv of 1,3-propanesultone in aqueous tert-butyl alcohol to give the corresponding salts 5 of bis-O-sulfopropylated diaryl telluride. A variety of diaryl ditellurides were reduced with sodium borohydride in ethanol. Upon addition of propanesultone to the resulting sodium arenetellurolates, the corresponding 3-aryltellurenylpropanesulfonic acid sodium salts 8 were precipitated. Diphenyl diselenide and dibutyl ditelluride reacted similarly to afford the sodium salts of 3-benzeneselenenylpropanesulfonic acid (9) and 4-telluraoctanesulfonic acid (10), respectively. The glutathione peroxidase-like activity of the water-soluble compounds was assessed at pH = 7.4 by using the coupled GSSG reductase assay. Dialkyl telluride 10 turned out to be the most efficient catalyst. Several alkyl aryl tellurides 8 were also more efficient than any of the previously tested organotellurium compounds in this model. Bulky and electron-withdrawing aryl substituents seemed to reduce activity, whereas electron-donating groups enhanced it. Alkyl aryl selenide 9 was void of any catalytic activity. The novel compounds were also assessed by 1H NMR spectroscopy for their capacity to catalyze the hydrogen peroxide oxidation of N-acetylcysteine in D2O under acidic conditions. In the presence of 0.01 mol % of the organotellurium catalyst, the thiol concentration was reduced to 50% within 12 min for the most active catalyst (compound 5b). Although many of the compounds showed high catalytic activity, it was not possible to rationalize their relative efficiency. The capacity of the novel organotellurium compounds to act as a scavengers of 1,1-diphenyl-2-picrylhydrazyl (DPPH) was also investigated. The organotelluriums seem to act primarily as electron donors in their reaction with DPPH. Compounds 8d, 10, and 8b were the most effective scavengers. Bulky or electron-withdrawing aryl substituents caused a reduction in activity, whereas electron-donating ones enhanced it. None of the compounds could match vitamin E in their scavanging capacity.
- Kanda, Takahiro,Engman, Lars,Cotgreave, Ian A.,Powis, Garth
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p. 8161 - 8169
(2007/10/03)
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- Disulfide-bridge formation through solvent-free oxidation of thiol amino acids catalysed by peroxidase or hemin on mineral supports
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Air oxidation of hydrophilic thiols to disulfides was performed in neutral conditions on mineral supports activated by hemin or peroxidase. The Royal Society of Chemistry 1999.
- Guibe-Jampel, Eryka,Therisod, Michel
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p. 3067 - 3068
(2007/10/03)
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- The reaction of S-nitrosothiols with thiols at high thiol concentration
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Reactions of S-nitrosothiols (RSNO) with their corresponding thiols (RSH) present in a large excess (>20-fold) proceed readily to give the disulfide. Ammonia is formed together with some nitrite anion, and these constitute >90% of the 'nitrogen' products. This is in marked contrast with the reaction at low thiol concentration, where nitric oxide is the major initial 'nitrogen' product, which is rapidly converted in the presence of oxygen in water to nitrite anion. Also in marked contrast to the 'low thiol concentration' reaction, the reaction at high thiol concentration is not affected by added Cu2+, nor by the metal-ion scavenger EDTA. Kinetically all reactions were excellent first-order processes, and the reactions were also strictly first order in thiol concentration. A large range of nitrosothiols were studied and the generality of the reaction established. Some reactions of RSNO with other thiols (R'SH) were examined and the results readily interpreted in terms of a prior rapid equilibrium transnitrosation. The pH dependence for the reaction of S-nitrosocysteine with cysteine clearly showed that the reactive species is the cysteine thiolate anion. The results are discussed along with those of two other recent reports of these reactions, in terms of thiolate attack initially at the nitroso nitrogen atom, and subsequently at sulfur atoms, eliminating RSSR and yielding hydroxylamine, which is rapidly reduced by thiolate ion to ammonia. The results are also discussed in connection with the release of NO from nitrosothiols and with the important biological consequences, both for the in vivo reactions of NO and for the potential of nitrosothiols as NO-releasing drags for medical use.
- Dicks, Andrew P.,Li,Munro, Andrew P.,Swift, Helen R.,Williams, D. Lyn H.
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p. 789 - 794
(2007/10/03)
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- Radiolysis study of N-acetylcystein radical reactions in an ethanol-water mixture
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The study of model peroxyl radicals and superoxide anions scavenging by N-acetylcystein (NASH) has been performed in aerated ethanol (70%)/water (30%) mixtures using the steady state radiolysis method. The obtained dilution curves have allowed to propose a reactional mechanism which fits a part of the experimental results.
- Gres,Jore,Gardes-Albert
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p. 271 - 276
(2007/10/03)
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- Thiol oxidation by 1,2,3-oxadiazolinium ions, presumed carcinogens
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3-Alkyl-1,2,3-oxadiazolinium ions 1 have been proposed as reactive intermediates in the activation of (2-hydroxyethyl)nitrosamines. The reaction of 3-methyl-1,2,3-oxadiazolinium tosylate (1a), 2-ethyl-1-methoxy-2- phenyldiazenium tetrafluoroborate (3), and 3-phenyl-1,2,3- oxadiazolinium triflate (1b) with thiols was investigated to determine the behavior of these compounds toward typical 'cellular nucleophiles'. Each of these substances oxidizes benzenethiol to diphenyl disulfide. The reaction aqueous buffer at pH 7.4 is rapid. Reaction of 1b with benzenethiol gives, in addition to the disulfide, benzene, biphenyl, azobenzene, diphenylsulfide, aniline, and glycolaldehyde. Similar products are obtained from 3. Phenyldiazene is postulated as an intermediate in this process, and its generation from phenyldiazoformate in the presence of benzenethiol gives similar products. Diazenes are presumed to arise by proton abstraction from the CH adjacent to N. The kinetic reaction of 1a with N-acetylcysteine to give the corresponding disulfide show first order dependence on each reactant and base catalysis. The data from these model chemical experiments suggests that 1,2,3- oxadiazolinium ions could react with abundant thiols in cells to lead to either their detoxification or radical processes emanating from diazenes. The occurrence of thiol-oxadiazolinium ion redox transformations could modulate the alkylation chemistry of these substances as well.
- Loeppky,Srinivasan
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p. 817 - 820
(2007/10/03)
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- Analysis of acetylcysteine by capillary electrophoresis (CE). Part 2: Determination of side components
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The purity of N-acetyl-L-cysteine was tested by capillary electrophoresis (CE). The efficiency was optimized up to a theoretical plate number N of several hundred thousand. The most important impurities, N,N-diacetylcystine and cystine were detectable in amounts below 0.05%. These and other possible by-products were synthesized and their identity was confirmed by NMR spectroscopy. All these compounds could be separated.
- Watzig,Dette,Aigner,Wilschowitz
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p. 249 - 252
(2007/10/02)
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- Action des radicaux OH* ou N3* sur la N-acetylcysteine
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Interaction of OH* or N3* radicals with N-acetylcysteine (RSH) have been studied in neutral aqueous solutions using steady-state radiolysis.Initial G values of disappearance of RSH have been determined for a range of RSH concentrations between 3 x 10-5 and 10-3 mol l-1.The OH* or N3* radicals react quantitatively with N-acetylcysteine.A reaction scheme is proposed.
- Charif, A.,Abedinzadeh, Z.,Gardes-Albert, M.,Ferradini, C.
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p. 907 - 916
(2007/10/02)
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- Capillary zone electrophoretic detection of biological thiols and their S-nitrosated derivatives
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Reduced thiols (RSH) react with certain oxides of nitrogen to yield S-nitroso thiols (RSNO) possessing smooth muscle relaxant and platelet inhibitory properties. Nitrosated derivatives of the biological thiols - glutathione, cysteine, and homocysteine - have therefore been considered as bioactive intermediates in the metabolism of organic nitrates and the endothelium-derived relaxing factor with properties of nitric oxide. As yet, however, there is no established chemical method for identifying the biological S-nitroso thiols and, consequently, litttle is known of their distinguishing chemical characteristics or biochemistry. In this study, we demonstrate for the first time a simple, rapid, and reproducible method for separating these thiols from their S-nitrosated derivatives using capillary zone electrophoresis. Cysteine, homocysteine, and glutathione were separated from one another and from their corresponding disulfides in 0.01 M phosphate buffer, pH 2.5, by capillary zone electrophoresis and absorbance detection at 200 nm with measured elution times of 5.92-16.15 min; corresponding S-nitroso thiols were selectively detected at 320 nm and eluted at 2.50-18.20 min. These data support the specificity and reproducibility of this technique for separation and identification of thiols, disulfides, and S-nitroso thiol derivatives.
- Stamler, Jonathan S.,Loscalzo, Joseph
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p. 779 - 785
(2007/10/02)
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- Thiol peroxidase activity of diaryl ditellurides as determined by a 1H NMR method
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A 1H NMR method was developed for the assessment of the glutathione peroxidase-like activity of synthetic compounds. In this assay, thiols (N-acetylcysteine, tert-butyl mercaptan and 1-octyl mercaptan) were oxidized to the corresponding disulfides in CD3OD or CD3OD/D2O in the presence of hydrogen peroxide and the catalyst to be evaluated. The time required to reduce the thiol concentration with 50%, t50, was determined as a measure of the thiol peroxidase activity of the catalyst. Several diaryl ditellurides were efficient catalysts when present in low concentrations (0.3 mol %), whereas compounds with well-documented glutathione peroxidase-like activity in other assays were inactive (Ebselen, diaryl diselenides). The glutathione peroxidase-like activity of diaryl ditellurides was also assessed by using the classical coupled reductase assay. A mechanistic study showed that diaryl ditellurides, in the presence of hydrogen peroxide and a thiol, were rapidly converted to tellurosulfides. These species were stable enough to be isolated in some cases. The tellurosulfides reacted very slowly with added thiol, but in the presence of thiol/hydrogen peroxide the thiol was rapidly converted to its corresponding disulfide. On the basis of these observations, a mechanism involving a tellurinic acid thiol ester was proposed for the thiol peroxidase reaction of ditellurides. In contrast to tellurosulfides, selenosulfides, obtained either from diphenyl diselenide/hydrogen peroxide/1-octyl mercaptan or from Ebselen and 1-octyl mercaptan, were found to react very slowly with thiols in the presence of hydrogen peroxide.
- Engman, Lars,Stern, David,Cotgreave, Ian A.,Andersson, Carl M.
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p. 9737 - 9743
(2007/10/02)
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- Coenzyme Models. 48. Novel Diastereo-Differentiating Hydrogen Transfer and "Rope-Skipping" Racemization in Chiral Flavinophanes and 5-Deazaflavinophanes
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Cyclic flavins and 5-deazaflavins with planar chirality and their noncyclic analogues were optically resolved for the first time by a liquid chromatographic method.They did not racemize below 40 deg C, but Fl(n) and dFl(n) with a long strap (n >/= 10) racemized invariably when they were reduced to the 1,5-dihydro forms.This novel redox-induced "rope-skipping" racemization occurs because the flat (5-deaza)isoalloxazine plane is folded along a line through N(5) and N(10) like butterfly wings in the reduced forms, and thus, rope-skipping racemization is facilitated.A similar racemization took place via the formation of sulfite adducts at N(5) or C(5), indicating that the adducts also employ the folded conformation.These chiral (5-deaza)flavinophanes could oxidize optically active thiols (62.8percent enantiomeric excess) and NADH model compounds (60.0percent enantiomeric excess) in an asymmetric manner.When dFl(n) were reduced to dFlred(n), 1H NMR gave a pair of doublets for the two C(5) protons.This indicates that the central ring in the reduced isoalloxazine employs a boat form and that the flip-flop motion is significantly suppressed by the ring structure.By use of the nuclear Overhauser effect, the two 1H NMR peaks were assigned to axial proton (higher magnetic field) and equatorial proton (lower magnetic field).The tracer experiments using dFl(n) established for the first time that the hydrogen transfer to dFl(n) and from dFlred(n) occurs exclusively at the "axial" C(5) position.These novel results were found owing to unique characteristics of cyclic (5-deaza)flavins.Furthermore, the high asymmetric discrimination suggests that planar chirality is a promising approach to the design of new flavoenzyme model systems.
- Shinkai, Seiji,Yamaguchi, Toshiro,Kawase, Akito,Manabe, Osamu,Kellogg, Richard M.
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p. 4935 - 4940
(2007/10/02)
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