- Reactions of Thiols and Disulfides with Phosphite Radicals. A Chain Mechanism and RS*/PO32-* Equilibrium
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Thiyl and phosphite radicals exist in equilibrium, PO32-* + RSH = RS* + HPO32-, with equilibrium constants of 800 where RSH is ethyl mercaptan and 1500 where RSH is penicillamine.Rate constants for the respective forward reactions are 3.0E8 M-1s-1 for both compounds, and for the back reeactions, 2.0E5 and 3.8E5 M-1s-1.In solutions containing both phosphite and disulfide an SH2 reaction, PO32-* + RSSR ---> RSPO32- + RS*, yields phosphate thioester and thiyl radicals.At higher phosphite concentrations, a chain reaction mechanism is established, based on re-formation of PO32-* radicals in the reverse reaction of the above equilibrium.G values of up to about 30 are observed for thiol formation and disulfide destruction in these systems.One of the factors controlling the extent of the chain mechanism seems to be the thiyl/phosphite radical equilibrium.
- Schaefer, K.,Asmus, K.-D.
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- Quinoxalinyl macrocyclic hepatitis C serine protease inhibitors
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The present invention relates to compounds of Formula I or II, or a pharmaceutically acceptable salt, ester, or prodrug, thereof: which inhibit serine protease activity, particularly the activity of hepatitis C virus (HCV) NS3-NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.
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Page/Page column 56
(2008/06/13)
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- Reactivity of sulfur nucleophiles towards S-nitrosothiols
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Rate constants have been measured for the reactions of a range of S-nitrosothiols with the following sulfur-centred nucleophiles: sulfite ion, thiourea, thiocyanate ion, thiosulfate ion, thiomethoxide ion and sulfide ion. Many of the reactions were very fast and were followed in a stopped-flow spectrophotometer. For the sulfite reaction the reactive species over the pH range 4-8 was shown to be exclusively SO32-. For two RSNO species the reactivity sequence was established as: SO32- > MeS- > S2O32- ? SC(NH2)2 SCN-. The reaction with sulfide ion was also rapid and generated a fairly stable yellow species (λmax 410 nm), which was probably the nitrosodisulfide ion ONSS-, but the absorbance-time data were too complex for a simple kinetic analysis. This reaction could have some potential as an analytical procedure for the determination of RSNO species. The kinetic results are discussed in terms of the factors affecting nucleophilicity and are compared with the corresponding reactions of other nitrosating species.
- Munro, Andrew P.,Williams, D. Lyn H.
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p. 1794 - 1797
(2007/10/03)
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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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- Thiol/disulfide exchange reactions of captopril and penicillamine with arginine vasopressin and oxytocin
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The kinetics and equilibria of the reaction of the thiol-containing drugs captopril (D-3-mercapto-2-methylpropanoyl-L-proline, CpSH) and penicillamine (β, β-dimethylcysteine, PSH) with the disulfide bonds of the neurohypophyseal peptide hormones arginine vasopressin (AVP) and oxytocin (OT) have been characterized. CpSH reacts with AVP and OT by thiol/disulfide interchange to form two peptide-CpSH mixed disulfides, which in turn react with another molecule of CpSH to form the reduced peptide and CpSSCp. Forward and reverse rate constants and the equilibrium constant are reported for both steps in the reaction of CpSH with AVP and OT at pH 7.00. The rate constant for the first step (k1) is much larger than that for the second step (k2). Also, once formed, the peptide-CpSH mixed disulfides rapidly undergo intramolecular thiol/disulfide interchange with reformation of the cyclic peptide and CpSH. PSH reacts with AVP and OT by the same two-step reaction sequence; however, the rate of the second step is very slow due to steric hindrance from the methyl groups of PSH and the PSH moiety of the peptide-PSH mixed disulfides. Using rate constants determined in this study and PSH levels in the plasma of patients on PSH therapy, it is predicted that in vivo reduction of the disulfide bonds of AVP and OT by PSH and CpSH has little effect on the plasma half-lives of AVP or OT.
- Rabenstein, Dallas L.,Yeo, Pauline L.
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p. 109 - 118
(2007/10/02)
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- Reduction Potential of the .CO2- Radical Anion in Aqueous Solution
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The reduction potential for the .CO2- radical anion has been determined by equilibration of formate with sulfhydryl radicals of β-mercaptoethanol, penicillamine, and lipoamide in aqueous solutions at pH 3-6.The reaction .CO2- + e- + H+ = HCO2- yields the value E09 = 1.49 V with an uncertainty of +/-0.06 V.On the basis of this value and the known free energies of CO2(aq) and HCO2-(aq), E019 for CO2 + e- = .CO2- was found to be -1.85 V.
- Surdhar, Parminder S.,Mezyk, Stephen P.,Armstrong, David A.
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p. 3360 - 3363
(2007/10/02)
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- Reduction Potentials and Exchange Reactions of Thiyl Radicals and Disulfide Anion Radicals
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Redox equilibria between RS. and -S-S-- radicals, and between these types of radical and phenoxyl and chlorpromazine (ClPz.2+) radicals, have been investigated in aqueous solutions at pHs over the range 6-10 to obtain a self-consistent set of redox potentials for the reactions PhO. + H+ + e- = PhOH (4), RSS.R + 2H+ + e- = 2RSH (11), and RS. + H+ + e- = RSH (18), in sulfur systems with alkyl R groups.Absolute standard potentials were calculated on the of E0 = 0.83 V for the chlorpromazine couple.The results for E04 (=1.35 +/- 0.02 V) and E018 (=1.33 +/- 0.02 V) were in agreement with values calculated from thermodynamic data within the known uncertainties.E018 was found to exhibit a falloff when electron-rich groups, such as the two methyls of penicillamine or the CO2- of β-mercaptoacetic acid, were present on the carbon adjacent to the S atom.However, the effect was relatively small (ca. 10-14 mV).E011 was 1.72 +/- 0.02 V for β-mercaptoethanol.The corresponding potentials for the cyclic anions of dithiothreitol, dithioerythritol, and lipoamide were the same within experimental error, but the uncertainties were larger (+/- 0.04 V).For the reaction e- + -S-S- = -S-S-- (22), the magnitude of E022 was calculated to be -1.60 V, showing that only strongly reducing species could donate electrons to disulfide.Rate constants for several of the forward and backward reactions in the equilibria were also determined.
- Surdhar, Parminder S.,Armstrong, David A.
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p. 6532 - 6537
(2007/10/02)
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- A Kinetic Analysis of the Acidic Degradation of Penicillin G and Confirmation of Penicillamine as a Degradation Product
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Two recently proposed degradation pathways for the acidic degradation of penicillin G were examined by calculating the theoretical time course based on each pathway and examining the fit of the theoretical predictions to the experimental data.A substantial difference in the goodness of fit was observed.The degradation pathway which provided the best fit included penicillamine as a terminal degradation product.This pathway is therefore favoured since penicillamine was also identified as a degradation product of penicillin G by both reversed-phase high pressure liquid chromatrography and differential pulse polarography.
- Kessler, David P.,Ghebre-Sellassie, Isaac,Knevel, Adelbert M.,Hem, Stanley L.
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p. 1247 - 1251
(2007/10/02)
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