CHEMICAL SYNTHESIS AND CYTOTOXIC PROPERTIES OF N-ALKYLCARBAMIC ACID THIOESTERS, METABOLITES OF HEPATOTOXIC FORMAMIDES

The S-linked cysteine and glutathione conjugates of N-methylformamide and N-ethylformamide, together with a series of methyl ester derivatives thereof, have been synthesized and characterized by1H NMR,13C NMR, FAB-MS, and FAB tandem mass spectrometry. In vitro cytotoxicity assays showed that all of the title conjugates were toxic to isolated mouse hepatocytes when incubated at concentrations in excess of 1 mM and that they served as potent growth inhibitors of murine TLX5 lymphoma cells when present at levels of 10–100 µM. Both of these effects were reversed by the addition to incubation media of glutathione (10 mM). The possibility is raised that N-alkylcarbamic acid thioester conjugates, which are formed during the metabolism of N-alkylformamides in mammalian systems, may act as important mediators of the antineoplastic and/or hepatotoxic activity of the parent formamides, possibly through their ability to liberate methyl isocyanate at cell membranes. © 1990, American Chemical Society. All rights reserved.