40055-98-9Relevant articles and documents
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.
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.
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.
