Reactions of N-acetylcysteine adducts of aromatic (di)isocyanates with functional groups of organic molecules
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Date
2008-02-21
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Abstract
Glutathione thiocarbamate conjugates of isocyanates play a key role in transport and final
reactions of isocyanates in the human body by transcarbamoylation. N-acetylcysteine is the
simplest model for thiocarbamate reactions. Therefore, transcarbamoylation of Nacetylcysteine
adducts of p-tolylisocyanate (pTI-AcCys) and 4,4’-diisocyanatodiphenyl-
methane (MDI(AcCys)2) with N-acetylcysteine methyl ester (thiolysis), morpholine (aminolysis),
methoxyethanol (alcoholysis), and water (hydrolysis) has been studied in aqueous
phosphate buffer solution and in dimethylacetamide (DMAc). Expected reaction products
have been synthesised as reference compounds for HPLC-analysis. Concentrations of adducts
and of reaction products were monitored by HPLC. Reaction rates and activation energies
were determined for pTI in both media, reactions of MDI(AcCys)2 were run at one temperature
only. Formation of insoluble reaction products and side reactions due to hydrolysis prevented
in depth kinetic analysis of the reactions. Two regimes of reaction rate were observed
in aqueous buffer, clear second order kinetics resulted in DMAc. In aqueous buffer (pH 7.4) a
reactivity thiolysis > aminolysis > hydrolysis was found, while in DMAc aminolysis was
faster than thiolysis. This can be explained by formation of thiolate at pH 7.4, which is not
possible in anhydrous DMAc. Reactions of (MDI(AcCys)2) are by a factor of 2 to 4 faster
than those of pTI-AcCys. p-Toluidine (pTA) was found in the aqueous system due to hydrolysis,
while no 4,4’-methylene dianiline (MDA) could be detected. Under physiological
conditions hydrolysis should compete with thiolysis under homogeneous conditions while
ureas and carbamates should be much more stable against hydrolysis. No free isocyanate
groups could be detected in any of the reactions. In conclusion the isocyanate moiety in thiocarbamates
is readily transferred to sulfhydryl- and amino groups but not to aliphatic hydroxy
groups. Under physiological conditions hydrolysis competes with these transcarbamoylation
reactions. Formation of free isocyanate groups in analytical quantities was shown to be highly
unlikely.
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Keywords
amines, Aromatic isocyanates, N-acetyl cysteine-S-adducts, transcarbamoylation reactions, ureas, urethanes