A-Acetylpenicillamine

Al-Kaabi et al. 1982 Ignarro and Gruetter 1980 Williams 1985). Application of the cell pemeable nitrosothiol, S-nitroso-A-acetylpenicillamine (SNAP E.l), resulted in a decrease in the invasive phenotype in DU-145, PC-3, and RWPEl-derived human prostate cancer cell lines in vitro (Chaiswing et al. 2008). At a pH between 6.0 and 8.0 at 37°C, in the presence of transition metal chelators, SNAP has a half-life of about 6 h (Singh et al. 1996). 

FIGURE 1. Rate constant for decomposition of 5-nitroso-A-acety I penicillamine in the presence of added JV-acetylpenicillamine (NAP)... 

In the absence of added nucleophiles, nitrosation occurs virtually irreversibly by an acid-catalysed pathway, presumably by attack by HjNO or NO". The third order rate constant from the rate equation equivalent to (46) has a value of 840 dm moF s- at 31°C (c/. 456 and 6960 dm mol- s for cysteine and thiourea respectively at 25°C) which suggests that for this neutral substrate the reaction rate is somewhat less than that expected for an encounter-controlled process. There is a major difference between the nitrosation of alcohols and that of thiols in that, whilst the former reactions are reversible (with equilibrium constants around 1), the reactions of thiols are virtually irreversible. It is possible to effect denitrosation of thionitrites but only at high acidity and in the presence of a nitrous acid trap to ensure reversibility (Al-Kaabi et al., 1982). Direct comparisons are not possible, but it is likely that nitrosation at sulphur is much more favoured than reaction at oxygen (by comparison of the reactions of N-acetylpenicillamine and t-butyl alcohol). This is in line with the greater nucleophilicity expected of the sulphur atom in the thiol. For the reverse reaction of denitrosation [(52) and (53)], the acid catalysis observed suggests the intermediacy of the protonated forms... 

The kinetics of reaction of a number of S-nitrosothiols (334) in water with mercmy(n) salts have been reported. Reaction is first order in both reactants and the products are nitrous acid and the corresponding thiol-Hg complex. The mechanism involves slow attack by water at the nitrogen atom in the complex. The same group has also studied the copper(ll)-catalysed decomposition of the 5-nitrosothiols derived Ifom penicillamine, cysteamine, thiomahc acid, TV acetylpenicillamine, and cysteine. ... 

Acetylpenicillamine is a weaker chelating agent than penicillamine, has no effect on collagen cross-links, and is not effective in rheumatoid arthritis. It has been used in the treatment of mercury poisoning (1). 

Methylmercury compounds undergo extensive enterohepatic recirculation therefore, introduction of a nonabsorbable mercury-binding substance into the intestinal tract should facilitate their removal from the body. A polythiol resin has been used for this purpose in humans and appears to be effective. The resin has certain advantages over penicillamine. It does not cause redistribution of mercury in the body with a subsequent increase in the concentration of mercury in blood, and it has fewer adverse effects than do sulfhydryl agents that are absorbed. Clinical experience with various treatments for methylmercury poisoning in Iraq indicates that penicillamine, N-acetylpenicillamine, and an oral nonabsorbable thiol resin all can reduce blood concentrations of mercury however, clinical improvement was not clearly related to reduction of the body burden of methylmercury. 

Nitrosothiols such as cysteine-NO, glutathione-NO, and S-nitroso-N-acetylpenicillamine (SNAP) are often used a nitric oxide donors. The biological effects of these compounds suggest that they do, in fact, release significant amounts of nitric oxide, but the mechanism of release is not at... 

FIGURE 2 Inhibition of shear stress-induced release of nitric oxide in isolated endothelial cells by S-nitroso-N-acetylpenicillamine (SNAP). Relaxant responses of the first arterial strip in a three-tissue cascade are illustrated. The flow rate through the column of endothelial cells was varied from 0.3 to 3 ml/min. Three sets of control responses were obtained at 15-min intervals before the addition of SNAP. After the third set of control responses, 1 /rmol/liter SNAP was perfused through the column for 15 min (positioned away from the target arterial strips), following which the column was perfused with plain Krebs bicarbonate solution for a further 15 min. The perfusate was then directed over the target strips, and responses to shear stress were obtained. Data represent the means se from at least four separate experiments. 

FIGURE 4 Inhibitory effect of S-nitroso-N-acetylpenicillamine (SNAP) on vasodilator responses to acetylcholine. Solid columns represent control responses to intraarterial (i.a.) bolus injections of acetylcholine in the doses indicated. Hatched columns represent identical injections of acetylcholine during concurrent intraarterial infusion of SNAP (100 jug/kg/min) and phenylephrine (the infusion rate of phenylephrine was adjusted to keep the baseline perfusion pressure constant). The open column represents the intraarterial bolus injection of 1 /Ag of acetylcholine 15 min after the SNAP-phenylephrine infusion was discontinued. All experiments were conducted in rabbits under conditions of constant blood flow. 0, No Responses , P < 0.05. Data represent absolute changes in hindquarters perfusion pressure (in mm Hg), expressed as means se of one determination from four to seven animals. 

We have compared the chemical (i.e., spontaneous ) NO-generating activities of a series of S-nitrosothiols versus their vasodilating properties and observed that these two characteristics were not correlated (Kowaluk and Fung, 1990). Chemical degradation of S-nitrosothiols to release NO was enhanced in the presence of N-acetylpenicillamine and inhibited by 100 U/ml superoxide dismutase. However, the relaxant effects of S-nitrosothiols were enhanced by superoxide dismutase and diminished by N-acetylpenicillamine. These results argue against the spontaneous liberation of NO as a predominant mechanism of S-nitrosothiol action, a conclusion that was subsequently supported by Mathews and Kerr (1993). 

Using the same procedure from mannose, mannosylamine was coupled with cyclic AT-acetylpenicillamine to afford after nitrosation a gly-coconjugate with potent cytotoxicity against DU 145 human prostate cancer cells and hela R cancer cells (Scheme 13). ... 

Janssens, M.Y., Verovski, VIN., Van den Beige, DJ., Monsaeit, C., and Storme, G.A. (1999). Radiosensitization of hypoxic tumour cells by S-nitroso-N-acetylpenicillamine implicates a bioreductive mechanism of nitric oxide generation. Br. J. Cancer 79,1085-1089. 

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