- Syntheses and Structural Characterization of Water-Soluble Selenium Reagents for the Redox Control of Protein Disulfide Bonds
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A new class of water-soluble redox reagents (1-4) that contain selenium as the active site was developed for the purpose of the redox control of protein structures. The X-ray crystallographic analyses revealed that trans-3,4-dihydroxy-1-selenolane (DHSred) (1) and its Se-oxide (DHSox) (2) have two axial hydroxy groups on the selenolane five-membered ring, whereas trans-1,2-diselenane-4,5-diol (DSTox) (3), a selenium analog of oxidized dithiotreiotol (DDTox), has two equatorial hydroxy groups on the diselenane six-membered ring. According to the vicinal 3JHH coupling constants observed for 1-3, it was suggested that they adopt similar structures in solution to those in the solid state. Diselenothreitol (DSTred (4), a selenium analog of dithiothreitol (DTTred), was also synthesized, but it was too air sensitive to be isolated. The reactions of 1-4 with DTTox and DTTred indicated that the oxidizing power of DHSox (2) exceeds by far that of DTTox, while the reducing power of DSTred (4) exceeds that of DTTred.
- Iwaoka, Michio,Takahashi, Taro,Tomoda, Shuji
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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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- Charge Accumulation and Multi-Electron Photoredox Chemistry with a Sensitizer–Catalyst–Sensitizer Triad
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Photoinduced electron transfer in donor–sensitizer–acceptor compounds usually leads to simple electron–hole pairs, and photoredox catalysis typically relies on single-electron transfer (SET) events. This work reports on a molecular triad able to accumulate two electrons on a central dibenzo[1,2]dithiin moiety flanked by two peripheral RuII photosensitizers. Under continuous illumination, the doubly reduced form of the dibenzo[1,2]dithiin undergoes thiolate–disulfide exchange with an aliphatic disulfide substrate, thereby acting as a two-electron catalyst after two initial SET events with triethylamine at the RuII sensitizers. The use of a relatively simple triad for coupling two separate SET processes to a subsequent two-electron reduction is an important conceptual advance from photoinduced SET and light-driven charge accumulation towards multi-electron photoredox catalysis. This is relevant for artificial photosynthesis and light-driven multi-electron chemistry in general.
- Nomrowski, Julia,Guo, Xingwei,Wenger, Oliver S.
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p. 14084 - 14087
(2018/09/11)
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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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p. 4114 - 4117
(2015/11/03)
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- Thiols and selenols as electron-relay catalysts for disulfide-bond reduction
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Pass them on! Dithiobutylamine immobilized on a resin is a useful reagent for the reduction of disulfide bonds. Its ability to reduce a disulfide bond in a protein is enhanced greatly if used along with a soluble strained cyclic disulfide or mixed diselenide that relays electrons from the resin to the protein. This electron-relay catalysis system provides distinct advantages over the use of excess soluble reducing agent alone. Copyright
- Lukesh III, John C.,VanVeller, Brett,Raines, Ronald T.
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supporting information
p. 12901 - 12904
(2014/01/06)
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- METHOD FOR THE PRODUCTION OF BISEPOXIDES AND DITHIOLS
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The invention relates to a method for the production of bisepoxides, characterised in that a conjugated diene of formula (I) is reacted with at least one peroxide with the application of up to 4 equivalents of peroxide per C-C double bond, where R1 is selected from hydrogen and C1-C12 alkyl, unsubstituted or substituted with one or several SH or OH groups, in the presence of a catalyst, obtained by the bringing into contact of at least one manganese compound, selected from A2MnX4, AMnX3, MnY, MnX2 and MnX3 with at least one ligand L, of general formula (II), whereby the variables have the following definitions: X may be the same or different and is selected from monovalent anions, Y is a divalent anion, A is selected from alkali metals and optionally alkylated ammonium, R2 may be different or preferably the same and selected from C1-C20 alkyl and at least one co-ligand, derived from monocarboxylic acids, di- or poly-carboxylic acids or diamines.
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Page/Page column 17; 18
(2008/06/13)
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- Micellar systems
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A complex is described that is deliverable to a cell comprising inserting a nucleic acid or other cargo into a reverse micelle. The reverse micelle has the property to compact the nucleic acid for easier delivery.
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- 4-hydroxyquinoline-3-carboxamides and hydrazides as antiviral agents
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The present invention provides 4-hydroxyquinoline-3-carboxamide and hydrazide compounds of formula I These compounds are useful to treat or prevent the herpesviral infections, particularly, human cytomegaloviral infection.
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- Interleukin-2/viral antigen protein chimers
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Disclosed are (1) a fused protein obtained by combining an antigen used for vaccine and a lymphokine by the application of gene engineering, (2) a recombinant DNA containing a nucleotide sequence coding for the above fused protein, (3) a transformant bearing the above recombinant DNA, (4) a method for producing the fused protein which comprises cultivating the above transformant, producing and accumulating the above fused protein in a culture, and collecting the fused protein, and (5) a hybrid protein obtained by chemically combining an antigen used for vaccine with a lymphokine. The resulting fused and hybrid proteins have strong immunogenicity.
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- BIOLOGICALLY ACTIVE COMPOUNDS ISOLATED FROM AEROBIC FERMENTATION OF TRICHODERMA VIRIDE
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This invention relates to compounds of structural formula (I) isolated from an aerobic fermentation of Trichoderma viride MF5628, ATCC 74084: (I) which are squalene synthase inhibitors and thus useful as cholesterol lowering agents. These compounds are also potent antifungal agents. Additionally, they inhibit farnesyl protein transferase and farnesylation of the oncogene protein Ras and are thus useful in treating cancer. This invention also relates to a process for obtaining compounds of structural formula (I)
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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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- 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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- Process for reconfiguring keratin fibre
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A process of recofiguring keratin fibre is disclosed. The process includes rolling, winding, curling, looping lapping, folding, twirling, bending, curving, twisting, coiling, twining, entwining or straightening the keratin fibre or leaving the keratin fibre unchanged. A reducing agent is then applied to the keratin fibre to reduce cystine disulfide linkages and other susceptible linkages in the keratin fibre. An oxidizing agent is applied to the keratin fibre having the reducing agent, to set cystine disulfide linkages in the keratin fibre. The reducing agent and the oxidizing agent are then removed from the keratin fibre by rinsing the keratin fibre.
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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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- Bleomycin conjugates and method
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A bleomycin conjugate for use in targeting a compound to a body tumor. The conjugate includes an oxidized bleomycin/cobalt(III) complex and the compound to be targeted joined to the complex through a monodentate cobalt/sulfur coordinate bond. Also disclosed are methods for preparing the conjugate, and for targeting the compound to a body tumor, for purposes of tumor radioimaging or therapy.
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- Polyfunctional disulfide compounds having S--S exchange reactivity
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A polyfunctional disulfide compound, useful as a cross-linking reagent having S--S exchange reactivity, of the formula STR1 wherein R is 2-benzothiazolyl or 2-pyridyl-N-oxide and X is a spacer group having an alkylene group directly bonded to each S--S group.
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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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- Thiopolymers, their derivatives and methods for their preparation and use
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A method for producing products for separation, ion exchange or as basic material for the preparation of various derivatives designed for separation purposes and adsorption purposes by means of a polymer being activated with a reagent containing at least two bifunctional groups so that at least one of the reactive, functional groups in each molecule is bonded to the polymer while leaving a considerable amount of remaining groups unreacted but still reactive so that the activated polymer can be caused to react with thiosulphate after surplus reagent has been eliminated. The invention also relates to the produced products or their derivatives consisting of a water-soluble hydroxyl group or amino group containing polymer substituted with organic side-chains, each containing one or more thiosulphate groups or derivatives of such groups and the use of the products for purification of water, separation, immobilization of enzymes, etc.
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