Reactions of N-acetylcysteine adducts of aromatic (di)isocyanates with functional groups of organic molecules

摘要

Glutathione thiocarbamate conjugates of isocyanates play a key role in transport and finalreactions of isocyanates in the human body by transcarbamoylation. N-acetylcysteine is thesimplest model for thiocarbamate reactions. Therefore, transcarbamoylation of Nacetylcysteineadducts 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 aqueousphosphate buffer solution and in dimethylacetamide (DMAc). Expected reaction productshave been synthesised as reference compounds for HPLC-analysis. Concentrations of adductsand of reaction products were monitored by HPLC. Reaction rates and activation energieswere determined for pTI in both media, reactions of MDI(AcCys)2 were run at one temperatureonly. Formation of insoluble reaction products and side reactions due to hydrolysis preventedin depth kinetic analysis of the reactions. Two regimes of reaction rate were observedin aqueous buffer, clear second order kinetics resulted in DMAc. In aqueous buffer (pH 7.4) areactivity thiolysis > aminolysis > hydrolysis was found, while in DMAc aminolysis wasfaster than thiolysis. This can be explained by formation of thiolate at pH 7.4, which is notpossible in anhydrous DMAc. Reactions of (MDI(AcCys)2) are by a factor of 2 to 4 fasterthan 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 physiologicalconditions hydrolysis should compete with thiolysis under homogeneous conditions whileureas and carbamates should be much more stable against hydrolysis. No free isocyanategroups could be detected in any of the reactions. In conclusion the isocyanate moiety in thiocarbamatesis readily transferred to sulfhydryl- and amino groups but not to aliphatic hydroxygroups. Under physiological conditions hydrolysis competes with these transcarbamoylationreactions. Formation of free isocyanate groups in analytical quantities was shown to be highlyunlikely.