Mechanism of S-nitrosation of cysteine derivatives in the pH range 6–12 using N-methyl-N-nitrosotoluene-p-sulphonamide

Abstract

N-Methyl-N-nitrosotoluene-p-sulphonamide (MNTS) reacts readily with the thiolate anion of cysteine and some of its derivatives, in aqueous ethanol, to give the corresponding S-nitroso species. The measured second order rate constant k, increases with pH, and the experimental points lie close to the S-shaped curve calculated for reaction via the thiolate anion. The pK, values for SH ionisation were calculated from the experimental results, and gave figures generally in good agreement with the literature. There is no evidence of reaction via the thiol RSH, or of any reaction, under these conditions, with less powerful nucleophiles including amines, alcohols and an enol. There was no evidence of S-nitrosation of cysteine using dimethylnitrosamine, nitrosoproline or nitrososarcosine. The results are consistent with a direct transfer of the nitroso group to the sulphur atom of the thiolate anion. The results are compared with similar reactions of alkyl nitrites.Many nitroso compounds (both inorganic and organic) can themselves act as nitrosating agents, i.e., they can transfer the nitroso group in an electrophilic sense to a suitable nucleophilic site.' This usually occurs intermolecularly but can, under certain circumstances, take place within the same molecule. In most cases the transfer occurs indirectly; another nucleophile (sometimes the solvent or for example a halide ion) first reacts with the nitroso compound to give a species which is the true nitrosating agent. An example is provided by the nitrosation reactions brought about by alkyl nitrites in aqueous acid. Here, it has been shown' that hydrolysis of the alkyl nitrite occurs first (rapidly and reversibly) liberating nitrous acid (i.e. an 0nitrosation of water) which generates the true nitrosating agent NO+ or H,NO,+. In this case 0-N bond fission is greatly assisted by protonation of the oxygen atom (bound to the alkyl group) in the alkyl nitrite. Nitrosamines behave similarly. However in basic and neutral solution (where hydrolysis is much slower, and in any case yields nitrite ion which is not normally a nitrosating agent) alkyl nitrites act directly as nitrosating agents towards a number of substrates including amines; secondary amines yield nitro~amines.~ This reaction is greatly facilitated by the presence of electron-withdrawing substituents within the alkyl nitrite (see Scheme l), as expected R+O-N<:NHR; 0 No -RO-+ O N~H R ; 3. 1 ROH ONNR; Scheme 1.for an electrophilic It is not known with certainty whether corresponding N-nitroso compounds can act in a similar way, i.e. in a direct reaction, but there are many examples in the literature5 of the indirect reaction where hydrolysis (or reaction with a nucleophile such as halide ion) of nitrosamines in acid solution releases a reactive nitrosating species. There are two reports 6,7 of a somewhat unusual reaction which occurs at high acidity, where the protonated forms of some aromatic nitrosamines react with the protonated form of some aniline derivatives.In this paper we are seeking to establish whet...

Kinetic studies on the influence of micellar aggregates upon the hydrolysis and transnitrosation reactions of N-methyl-N-nitrosotoluene-p-sulphonamide

“…This is probably due to the fact that the two nucleophiles bear the same charge, thus leading to the same electrostatic considerations within the pseudophase model. The results obtained are shown in Figure 4, in which we have also drawn the corresponding linearization in the form of equation (2). From this linearization one can obtain a value of K = 75 & 4 mol-' dm3, which agrees extremely well with the value of 73 mol-I dm3 found for the same binding constant obtained from the hydrolysis experiments.…”

Reactivity of phenolic nucleophiles towards nitroso compounds

“…The question arises whether 0-nitrosation followed by internal rearrangement is not also the mechanism of the Cnitrosation of phenols by strong electrophiles in acid media, which has hitherto been assumed to involve direct attack on the C atom. 1, 3 The mechanism involving rearrangement would parallel the known behaviour of aromatic secondary amines, whose initial N-nitrosation is followed by Fischer-Hepp rearrangement to the 4-nitroso compound, but for phenols this possibility would be difficult to substantiate experimentally. 2 7 The polyphenols studied in this work reacted exclusively with the MNTS nitroso group.…”

Nitric Oxide-Releasing Molecules for Cancer Therapy and Chemoprevention

“…20.4: Class I includes dialkyl, alkyl aryl, and diaryl derivatives, and Class II includes the N-nitrosamines, N-nitrosoureas, N-nitrosocarbamates, N-nitrosoguanidines, and N-acyl-N-nitroso compounds. Class II nitrosamines act as trans-nitrosating agents toward thiol nucleophiles, readily yielding nitrosothiols (Oh and Williams 1989). N-nitrosamines are potential NO • /NO + donors via cleavage of the N−NO bond, N-aryl-N-nitrosamines being viewed as more prone to release of NO.…”