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 by 1H 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 microM. 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.
Han
D H
DH
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
Pearson
P G
PG
Baillie
T A
TA
Dayal
R
R
Tsang
L H
LH
Gescher
A
A
D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D004952:Esters / Q000138:chemical synthesis / Q000633:toxicity; D005559:Formamides / Q000138:chemical synthesis / Q000633:toxicity*; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008223:Lymphoma / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D014407:Tumor Cells, Cultured
D002219:Carbamates; D004952:Esters; D005559:Formamides; C002950:methylformamide