- The Reaction of Superoxide Radical Anion with Dithiothreitol: A Chain Process
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The radical-induced oxidation of dithiothreitiol (DTT) by O2 to 4,5-dihydroxy-1,2-dithiane (ox-DTT) in aqueous solutions of pH 8.7 proceeds via a chain reaction.Radicals such as OH generated by the radiolysis of N2O/O2-saturated aqueous solutions abstract an H atom from DTT.The resulting DTT(-H). radicals cyclize and deprotonate, yielding the disulfide radical anion ox-DTT.-.The latter reacts with O2 (k = 7.1 x 108 dm3 mol-1 s-1) giving rise to ox-DTT and O2.-.The G value of ox-DTT formation increases with decreasing dose rate, displaying a linear yield vs (dose rate)1/2 relationship indicative of a chain reaction.The chain is inhibited by superoxide dismutase, showing that 02.- is a chain carrier.Hydrogen peroxide is not a chain product, from which it is concluded that O2.- does not abstract hydrogen from DTT but rather forms a short lived complex with the DTT anion which then predominantly decomposes into an RSO. radical and an OH- ion, (and to a lesser extent into an OH radical and an RSO- ion).In a second step, the RSO. radical reacts with DTT (probably the anionic form DTT-), thus regenerating DTT(-H)..The resulting sulfenic acid eliminates water and yields the chain product ox-DTT.An overall propagation rate constant of 35 dm3 mol-1 s-1 has been estimated.
- Zhang, Nan,Schuchmann, Heinz-Peter,Sonntag, Clemens von
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- dl-biTOT - A novel building block for electroactive oligomers and polymers in semiconductor applications
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The title compound dl-biTOT (1, dl-2,2′,3,3′-tetrahydro2,2′-bithieno[3,2-b][1,4]oxathiine) was prepared in a five-step synthesis using cheap and readily available starting materials, with an overall yield of 50%. Compound 1 is believed to display interesting and unique properties as a building block in oligomer and polymer applications in the rapidly growing field of organic semiconductors. A new and superior method to oxidize dithiothreitol (Cleland's reagent), that operates rapidly and cleanly on a multigram scale is also reported.
- Von Kieseritzky, Fredrik,Hellberg, Jonas
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- Silica phosphoric acid/NaNO2 as a novel heterogeneous system for the coupling of thiols to their corresponding disulfides
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Silica phosphoric acid was prepared via reaction of silica chloride (I) and phosphoric acid. Thiols can be readily converted to their corresponding thionitrites with a combination of silica phosphoric acid (II), wet SiO 2, and sodium nitrite in dichloromethane at room temperature. Disulfides result from the homolytic cleavage of the sulfur-nitrogen bond of the unstable thionitrite and subsequent coupling of the resultant thiyl radicals.
- Zolfigol, Mohammad Ali,Shirini, Farhad,Zamani, Khosrow,Ghofrani, Efat,Ebrahimi, Satar
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- Radical-induced oxidation of dithiothreitol in acidic oxygenated aqueous solution: A chain reaction
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Sulfur-centered radicals derived from dithiothreitol (DTT) have been generated radiolytically in aqueous solution in the neutral to acid pH range. In the presence of O2, these are eventually transformed by a chain reaction into dihydroxydithiane (ox-DTT) and H2O2. In acid solution, the chain character of the reaction becomes more pronounced with decreasing pH. The radiolytic yield of the products (G value) also depends on the DTT concentration and the dose rate. The HO2· radical carries the chain, abstracting an H atom from the DTT molecule (k = 120 dm3 mol-1 s-1), while its conjugated base, the O2·- radical (pK(a)(HO2·) = 4.8), does not react with DTT. The chain is continued when the DTT-derived radicals react with O2, yielding ox-DTT and HO2· radicals. The self-termination of the HO2·/O2·- radicals breaks the chain.
- Lal, Manohar,Rao, Raghavendra,Fang, Xingwang,Schuchmann, Heinz-Peter,Von Sonntag, Clemens
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- Selective, Modular Probes for Thioredoxins Enabled by Rational Tuning of a Unique Disulfide Structure Motif
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Specialized cellular networks of oxidoreductases coordinate the dithiol/disulfide-exchange reactions that control metabolism, protein regulation, and redox homeostasis. For probes to be selective for redox enzymes and effector proteins (nM to μM concentrations), they must also be able to resist non-specific triggering by the ca. 50 mM background of non-catalytic cellular monothiols. However, no such selective reduction-sensing systems have yet been established. Here, we used rational structural design to independently vary thermodynamic and kinetic aspects of disulfide stability, creating a series of unusual disulfide reduction trigger units designed for stability to monothiols. We integrated the motifs into modular series of fluorogenic probes that release and activate an arbitrary chemical cargo upon reduction, and compared their performance to that of the literature-known disulfides. The probes were comprehensively screened for biological stability and selectivity against a range of redox effector proteins and enzymes. This design process delivered the first disulfide probes with excellent stability to monothiols yet high selectivity for the key redox-Active protein effector, thioredoxin. We anticipate that further applications of these novel disulfide triggers will deliver unique probes targeting cellular thioredoxins. We also anticipate that further tuning following this design paradigm will enable redox probes for other important dithiol-manifold redox proteins, that will be useful in revealing the hitherto hidden dynamics of endogenous cellular redox systems.
- Becker, Katja,Busker, Sander,Felber, Jan G.,Maier, Martin S.,Poczka, Lena,Scholzen, Karoline,Theisen, Ulrike,Thorn-Seshold, Julia,Thorn-Seshold, Oliver,Zeisel, Lukas,Arnér, Elias S. J.,Brandst?dter, Christina
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supporting information
p. 8791 - 8803
(2021/06/27)
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- Oxidative Formation of Disulfide Bonds by a Chemiluminescent 1,2-Dioxetane under Mild Conditions
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The oxidation of alkyl thiols to disulfides has been achieved under mild conditions using a chemiluminescent 1,2-dioxetane as a stoichiometric oxidant. Besides the mild and biocompatible reaction conditions, this approach offers the possibility to monitor the presence of thiols through oxidation and chemiluminescence of the remaining dioxetane.
- Sauer, Caroline S.,K?ckenberger, Johannes,Heinrich, Markus R.
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p. 9331 - 9338
(2020/08/14)
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- Syntheses of prodrug-type phosphotriester oligonucleotides responsive to intracellular reducing environment for improvement of cell membrane permeability and nuclease resistance
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We synthesized prodrug-type phosphotriester (PTE) oligonucleotides containing the six-membered cyclic disulfide moiety by using phosphoramidite chemistry. Prodrug-type oligonucleotides named “Reducing-Environment-Dependent Uncatalyzed Chemical Transforming (REDUCT) PTE oligonucleotides” were converted into natural oligonucleotides under cytosol-mimetic reductive condition. Furthermore, the REDUCT PTE oligonucleotides were robust to nuclease digestion and exhibited good cell membrane permeability.
- Hayashi, Junsuke,Samezawa, Yusuke,Ochi, Yosuke,Wada, Shun-ichi,Urata, Hidehito
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p. 3135 - 3138
(2017/06/13)
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- Hydrogen Bonding-Assisted Enhancement of the Reaction Rate and Selectivity in the Kinetic Resolution of d,l-1,2-Diols with Chiral Nucleophilic Catalysts
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An extremely efficient acylative kinetic resolution of d,l-1,2-diols in the presence of only 0.5 mol% of binaphthyl-based chiral N,N-4-dimethylaminopyridine was developed (selectivity factor of up to 180). Several key experiments revealed that hydrogen bonding between the tert-alcohol unit(s) of the catalyst and the 1,2-diol unit of the substrate is critical for accelerating the rate of monoacylation and achieving high enantioselectivity. This catalytic system can be applied to a wide range of substrates involving racemic acyclic and cyclic 1,2-diols with high selectivity factors. The kinetic resolution of d,l-hydrobenzoin and trans-1,2-cyclohexanediol on a multigram scale (10 g) also proceeded with high selectivity and under moderate reaction conditions: (i) very low catalyst loading (0.1 mol%); (ii) an easily achievable low reaction temperature (0 °C); (iii) high substrate concentration (1.0 M); and (iv) short reaction time (30 min). (Figure presented.).
- Fujii, Kazuki,Mitsudo, Koichi,Mandai, Hiroki,Suga, Seiji
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supporting information
p. 2778 - 2788
(2017/08/23)
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- Tris(3-hydroxypropyl)phosphine (THPP): A mild, air-stable reagent for the rapid, reductive cleavage of small-molecule disulfides
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Tris(3-hydroxypropyl)phosphine (THPP) is demonstrated to be a versatile, water-soluble and air-stable reducing agent, allowing for the rapid, irreversible reductive cleavage of disulfide bonds in both aqueous and buffered aqueous-organic media. The reagent shows exceptional stability at biological pH under which condition it permits the rapid reduction of a wide range of differentially functionalized small-molecule disulfides.
- McNulty, James,Krishnamoorthy, Venkatesan,Amoroso, Dino,Moser, Michael
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supporting information
p. 4114 - 4117
(2015/11/03)
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- A potent, versatile disulfide-reducing agent from aspartic acid
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Dithiothreitol (DTT) is the standard reagent for reducing disulfide bonds between and within biological molecules. At neutral pH, however, >99% of DTT thiol groups are protonated and thus unreactive. Herein, we report on (2S)-2-amino-1,4-dimercaptobutane (dithiobutylamine or DTBA), a dithiol that can be synthesized from l-aspartic acid in a few high-yielding steps that are amenable to a large-scale process. DTBA has thiol pKa values that are ~1 unit lower than those of DTT and forms a disulfide with a similar E o′ value. DTBA reduces disulfide bonds in both small molecules and proteins faster than does DTT. The amino group of DTBA enables its isolation by cation-exchange and facilitates its conjugation. These attributes indicate that DTBA is a superior reagent for reducing disulfide bonds in aqueous solution.
- Lukesh III, John C.,Palte, Michael J.,Raines, Ronald T.
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supporting information; experimental part
p. 4057 - 4059
(2012/04/10)
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- 1,3-Dibromo-5,5-dimethylhydantoin [DBDMH] as an efficient and selective agent for the oxidation of thiols to Disulfides in solution or under solvent-free conditions
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A useful method for oxidation of various thiols to their corresponding disulfides with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) in very short reaction times and mild conditions under both solution and solvent-free conditions is described.
- Khazaei, Ardeshir,Zolfigol, Mohammad Ali,Rostami, Amin
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p. 2959 - 2961
(2007/10/03)
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- Oxidation of thiols to disulfides with molecular bromine on hydrated silica gel support
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Results of oxidation of thiols to disulfides with molecular bromine on silica gel solid support are reported. The procedure utilizes organic media and does not require a base to neutralize HBr by-products to suppress acid promoted side reactions. Utilization of silica gel support simplifies work up and product isolation.
- Ali, Mohammed Hashmat,McDermott, Mario
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p. 6271 - 6273
(2007/10/03)
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- Synthesis of Dithiols as Reducing Agents for Disulfides in Neutral Aqueous Solution and Comparison of Reduction Potentials
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Several dithiols have been prepared that are useful for the reduction of disulfides in aqueous solution.The reduction potential of these thiols have been determined from the measurement of the equilibrium constant of thiol/disulfide interchange with oxidized dithiothreitol using a 1H NMR assay.The values of pKa of some of the dithiols were measured to estimate their rate of reduction of disulfides.Bis(2-mercaptoethyl) sulfone (2), N,N'-dimethyl-N,N'-bis(mercaptoacetyl)hydrazine (5), and meso-2,5-dimercapto-N,N,N',N'-tetramethyladipamide (6) are especially interesting as alternatives to dithiothreitol for the reduction of disulfides.
- Lamoureux, Guy V.,Whitesides, George M.
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p. 633 - 641
(2007/10/02)
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- Equilibrium Constants for Thiol-Disulfide Interchange Reactions: A Coherent, Corrected Set
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Equilibrium constants (Keq) for the thiol-disulfide interchange reactions between dithiothreitol (DTT) and lipoic acid (14.2 +/- 0.7), lipoic acid (Lip) and mercaptoethanol (13.3 M +/- 1.0 M), and mercaptoethanol (ME) and glutathione (GSH or GSSG) (1.20 +/- 0.10) were measured in D2O at pD 7.0 by 1H NMR spectroscopy.Two of these equilibrium constants were also measured in D2O/CD3OD.These values are compared with those obtained by other methods.A coherent set of values for the equilibrium constants between DTT or ME and thiols having a range of structures was assembled (Table III).The recommended value for the equilibrium constant between DTT and GSH is 210 M (Keq = ox>2/(red>)).
- Lees, Watson J.,Whitesides, George M.
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p. 642 - 647
(2007/10/02)
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- meso-2,5-Dimercapto-N,N,N',N'-tetramethyladipamide: A Readily Available, Kinetically Rapid Reagent for the Reduction of Disulfides in Aqueous Solution
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meso-2,5-Dimercapto-N,N,N',N'-tetramethyladipamide (meso-DTA) reduces disulfide bonds up to 8 times faster (kinetic) than does dithiothreitol (DTT) in aqueous solution at pH 7.0. meso-DTA is easily synthesized in five steps (39percent overall yield) from adipic acid. meso-DTA, which forms a cyclic disulfide, is less reducing than DTT by approximately 56 mV, but is much more reducing than mercaptoethanol.
- Lees, Watson J.,Singh, Rajeeva,Whitesides, George M.
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p. 7328 - 7331
(2007/10/02)
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- A Reagent for Reduction of Disulfide Bonds in Proteins That Reduces Disulfide Bonds Faster Than Does Dithiothreitol
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We have synthesized a new reagent - N,N'-dimethyl-N,N'-bis(mercaptoacetyl)hydrazine (DMH) - for the reduction of disulfide bonds in proteins.DMH reduces disulfide bonds 7 times faster than does dithiothreitol (DTT) in water at pH 7.DMH reduces mixed disulfides of cysteine proteases (papain and ficin) especially rapidly (30 times faster than DTT).DMH (ε0 = -0.300 V) reduces noncyclic disulfides completely, although it is less strongly reducing than DTT (ε0 = -0.356 V).
- Singh, Rajeeva,Whitesides, George M.
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p. 2332 - 2337
(2007/10/02)
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- Reactions of thiyl radicals with phenothiazines and other antioxidants in aqueous solutions. A pulse radiolysis study.
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Reaction rate constants of thiyl radicals with phenothiazines, promethazine (PMZ), chlorpromazine (CPZ), prochlorperazine (PPZ), trimeperazine tarterate (TPZ), and other antioxidants, e. g., ascorbic acid and 2,2-azinobis(3-ethyl benzthiazoline-6 sulphonate) (ABTS) have been estimated using pulse radiolysis technique.In general they are quite high (108-109 M-1 s-1).The k value of cysteine, cysteamine, mercaptoethanol, and mercaptopropionic acid with similar structures and molecular weights are more or less similar for PMZ, CPZ, and PPZ.Rate constants are lower in value for PenS., DT.T, DT.E and GuS. radicals of phenothiazines showing that they are dependent upon the structure and the molecular weight of the compound. Rate constants are the same whether the thiyl radicals are generated from thiols or their corresponding disulphides.The k values for chlorine-containing phenothiazines, chlorpromazine, and prochlorperazine are higher than those of promothazine.
- Lal, Manohar,Mahal, H. S.
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p. 1376 - 1382
(2007/10/02)
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- Oxidation of Dithiols by Flavopapain
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The redox reactions between flavopapain 1 and various dithiols have been examined under anaerobic conditions.The semisynthetic enzyme is an effective catalyst relative to the model flavin, 7-acetyl-10-methylisoalloxazine (3).Relative rate enhancements, (kcat/Km)/k2model, observed are 3.9, 8.0, and 17.4 for dithiotreitol, d,l-dihydrolipoic acid, and d,l-dihydrolipoamide, respectively.This substrate specificity, also seen in N-alkyl-1,4-dihydronicotinamide series, is explicable in terms of favorable hydrophobic-hydrophobic binding interaction between the substrates and the enzyme active site.Stereospecificity was not observed in the enzymatic reactions of the dithiols.It is demonstrated that the enzyme and model flavin reactions of the dithiols both proceeded via comparable mechanistic pathway.
- Fried, Herbert E.,Kaiser, E. T.
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p. 182 - 184
(2007/10/02)
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- Rate Constants and Equilibrium Constants for Thiol-Disulphide Interchange Reactions Involving Oxidized Glutathione
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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.
- Szajewski, Richard P.,Whitesides, George M.
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p. 2011 - 2026
(2007/10/02)
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