40055-98-9Relevant academic research and scientific papers
Alkylamine-Substituted Perthiocarbamates: Dual Precursors to Hydropersulfide and Carbonyl Sulfide with Cardioprotective Actions
Khodade, Vinayak S.,Pharoah, Blaze M.,Paolocci, Nazareno,Toscano, John P.
supporting information, p. 4309 - 4316 (2020/03/05)
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.
Identification and characterization of the first ovothiol biosynthetic Enzyme
Braunshausen, Andrea,Seebeck, Florian P.
supporting information; scheme or table, p. 1757 - 1759 (2011/04/15)
Ovothiols are histidine-derived thiols that were first isolated from marine invertebrates. We have identified a 5-histidylcysteine sulfoxide synthase (OvoA) as the first ovothiol biosynthetic enzyme and characterized OvoAs from Erwinia tasmaniensis and Trypanosoma cruzi. Homologous enzymes are encoded in more than 80 genomes ranging from proteobacteria to animalia.
Reaction of N-acyloxy-N-alkoxyamides with biological thiol groups
Glover, Stephen A.,Adams, Meredith
experimental part, p. 443 - 453 (2011/10/09)
Mutagenic N-acyloxy-N-alkoxyamides 1 react with thiols by an SN2 process at nitrogen with displacement of carboxylate. They react with glutathione 4 in [D6]DMSO/D2O and methyl and ethyl esters of cysteine hydrochloride, 11 and 12, in [D4]methanol but the intermediate N-alkoxy-N-(alkylthio)amides undergo a rapid substitution reaction at sulfur by a second thiol molecule to give hydroxamic esters and disulfides. Arrhenius activation energies and entropies of activation obtained for a series of different N-benzyloxy-N-(4-substitutedbenzoyloxy)benzamides 13-17 were similar to those found for the SN2 reaction of the same series with N-methylaniline. Entropies of activation were strongly negative in keeping with polar separation and attendant solvation in the transition state, and in keeping with this, bimolecular reaction rate constants at 298K correlated with Hammett σ constants with a positive ρ-value of 1.1. The structure of model N-methoxy-N-(methylthio)acetamide has been computed at the B3LYP/6-31G(d) level and exhibits properties atypical of other anomeric amides with more electronegative atoms at nitrogen. Relative to N,N-bisoxyl substitution, the combination of a sulfur and an oxygen atom at the amide nitrogen results in a relatively small reduction in amide resonance.
Fast cleavage of a diselenide induced by a platinum(II)-methionine complex and its biological implications
Liu, Qin,Wang, Xiaoyong,Yang, Xiaoliang,Liang, Xiao,Guo, Zijian
experimental part, p. 1178 - 1184 (2011/12/21)
Platinum-based anticancer drugs such as cisplatin induce increased oxidative stress and oxidative damage of DNA and other cellular components, while selenium plays an important role in the antioxidant defense system. In this study, the interaction between a platinum(II) methionine (Met) complex [Pt(Met)Cl2] and a diselenide compound selenocystine [(Sec)2] was studied by electrospray ionization mass spectrometry, high performance liquid chromatography mass spectrometry, and 1H NMR spectroscopy. The results demonstrate that the diselenide bond in (Sec)2 can readily and quickly be cleaved by the platinum complex. Formation of the selenocysteine (Sec) bridged dinuclear complex [Pt2(Met-S,N)2(μ-Sec-Se,Cl)]3+ and Sec chelated species [Pt(Met-S,N)(Sec-Se,N)]2+ was identified at neutral and acidic media, which seems to result from the intermediate [Pt(Met-S,N)(Sec-Se)Cl]+. An accelerated formation of S-Se and S-S bonds was also observed when (Sec)2 reacted with excessive glutathione in the presence of [Pt(Met)Cl2]. These results imply that the mechanism of activity and toxicity of platinum drugs may be related to their fast reaction with seleno-containing biomolecules, and the chemoprotective property of selenium agents against cisplatin-induced toxicity could also be connected with such reactions.
Reaction of ascorbic acid with S-nitrosothiols: Clear evidence for two distinct reaction pathways
Holmes, Anthony J.,Williams, D. Lyn H.
, p. 1639 - 1644 (2007/10/03)
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.
Kinetics and mechanism for reduction of the anticancer prodrug trans,trans,trans-[PtCl2(OH)2(c-C6H11NH2)(NH3)] (JM335) by thiols.
Lemma,Shi,Elding
, p. 1728 - 1734 (2008/10/08)
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.
Kinetic study of the oxidation mechanism of glutathione by hydrogen peroxide in neutral aqueous medium
Abedinzadeh, Z.,Gardes-Albert M.,Ferradini, C.
, p. 1247 - 1256 (2007/10/02)
The oxidation kinetics of glutathione (GSH) by hydrogen peroxide has been studied at neutral pH for different concentration ratios 0 between 0.2 and 2(5 * 10-4 M 0 -3 M; 4 * 10-4 M 0 -3 M).In all cases studied, glutathione disulfide GSSG is the main product formed via two different oxidation ways, each of them contributing respectively to 80-85 percent and 10-15 percent.Our kinetic data indicate that an important fraction of hydrogen peroxide disappears without oxidizing the thiol function.This can be attributed to a combination between GSH and H2O2 protecting the sulfide group.Chemical evidences of the existence of a peroxide bond with GSSG are described.In our experimental conditions, the overall oxidation equation is 2 mol GSH reacting with 2 mol H2O2 giving 1 mol GSSG.It is very different from the usually accepted stoichiometric reaction: .A kinetic scheme is proposed and the corresponding rate constants are determined.Key words: glutathione, hydrogen peroxide, kinetic mechanism, glutathione disulfide.
Transvesicular Reactions of Thiols with Ellman's Reagent
Moss, Robert A.,Swarup, Shanti
, p. 5860 - 5866 (2007/10/02)
The cleavage of Ellman's reagent , 1, to chromophoric anion 2 by various thiols has been studied in pH 8 buffer, micellar cetyltrimethylammonium bromide (4), and vesicular dihexa-decyldimethylammonium bromide (5) or dioctadecyldimethylammonium chloride (6) solutions.The thiols included thiocholesterol, thiophenol, 2-thionaphthol, DL-cysteine, glutathione, 1-butanethiol, and 1-octanethiol.Vesicles of 6 at 25 deg C sequester 1 in distinct exovesicular and endovesicular binding sites, where reactions with added thiols are kinetically differentiated.Differences in thiol acidity and structure influence their rates of permeation and reaction with vesicle-bound 1.Small quantities of covesicallized 1-hexanol (0.2 wt percent) lower the gel to liquid crystalline transition temperature of vesicular 1 (from ca. 39 deg C to 24 deg C), enhance vesicular fluidity, accelerate the thiol/1 reactions, and destroy the kinetic distinction between the exovesicular and endovesicular reactions.
Oxidation of Thiols by Nitric Oxide and Nitrogen Dioxide: Synthetic Utility and Toxicological Implications
Pryor, William A.,Church, Daniel F.,Govindan, C. K.,Crank, George
, p. 156 - 159 (2007/10/02)
Thiols are readily oxidized to disulfides by either nitric oxide or nitrogen dioxide.Reaction conditions are mild, and quantitative yields can be obtained.The reactions are useful for preparative purposes and may have toxicological significance.
Rate Constants and Equilibrium Constants for Thiol-Disulphide Interchange Reactions Involving Oxidized Glutathione
Szajewski, Richard P.,Whitesides, George M.
, p. 2011 - 2026 (2007/10/02)
The rate of reduction of oxidized glutathione (GSSG) to glutathione (GSH) by thiolate (RS-) follows a Broensted relation in pKas of the conjugate thiols (RSH): βnuc ca. 0.5.This value is similar to that for reduction of Ellman's reagent: βnuc ca. 0.4 - 0.5.Analysis of a number of rate and equilibrium data, taken both from this work and from the literature, indicates that rate constants, k, for a range of thiolate-disulphide interchange reactions are correlated well by equations of the form log k = C + βnucpKanuc + βcpKac + βlgpKalg ( nuc = nucleophile, c = central, and lg = leaving group sulfur): eq 36 - 38 give representative values of the Broensted coefficients.The values of these Bronsted coefficients are not sharply defined by the available experimental data, although eq 36 - 38 provide useful kinetic models for rates of thiolate-disulfide interchange reactions.The uncertainty in these parameters is such that their detailed mechanistic interpretation is not worthwhile, but their qualitative interpretation - that all three sulphur atoms experience a significant effective negative charge in the transition state, but that the charge is concentrated on the terminal sulfurs - is justified.Equilibrium constants for reduction of GSSG using α,ω-dithiols have been measured.The reducing potential of the dithiol is strongly influenced by the size of the cyclic disulfide formed on its oxidation: the most strongly reducing dithiols are those which can form six-membered cyclic disulfides.Separate equilibrium constants for thiolate anion-disulphide interchange (KS-) and for thiol-disufide interchange (KSH) have been estimated from literature data: KS- is roughly proportional to 2ΔpKa is the difference between the pKas of the two thiols involved in the interchange.The contributions of thiol pKa values to the observed equilibrium constants for reduction of GSSG with α,ω-dithiols appear to be much smaller than those ascribable to the influence of structure on intramolecular ring formation.These equilibrium and rate constants are helpful in choosing dithiols for use as antioxidants in solutions containing proteines: dithiothreitol (DTT), 1,3-dimercapto-2-propanol (DMP), and 2-mercaptoethanol have especially useful properties.
