M. Overton, M. Threadgill, J. Chipman
Dec 1, 1986
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0
Influential Citations
2
Citations
Quality indicators
Journal
Biochemical pharmacology
Abstract
The electrophilic properties of 4-chloro-N-(hydroxymethyl)benzamide as a model compound of carbinolamides formed during the metabolic oxidation of N-methylamides were investigated. 4-Chloro-N-(hydroxymethyl)benzamide did not react with nucleophiles such as cyanide or glutathione under physiological conditions. In contrast, N-(acetoxymethyl)-4-chlorobenzamide yielded the cyanomethylamide with KCN and S-(4-chlorobenzamidomethyl)glutathione with glutathione. Under nonaqueous conditions, N-(acetoxymethyl)-4-chlorobenzamide reacted avidly with ethanethiol, with methanol and with diethylamine in the presence of base, whereas 4-chloro-N-(hydroxymethyl)benzamide did not afford products under these conditions. These results show clearly that N-(acetoxymethyl)-4-chlorobenzamide is the precursor of reactive electrophilic methyleneimines. 4-Chloro-N-(hydroxymethyl)benzamide was not biotransformed to such electrophilic species when incubated with mouse hepatic microsomes or a microsomal supernatant with acetyl-CoA or a PAPS generating system. Neither 4-chloro-N-(hydroxymethyl)benzamide nor its acetate ester were mutagenic in the short term bacterial assay using Salmonella typhimurium. Nevertheless, esters of carbinolamides, such as N-(acetoxymethyl)-4-chlorobenzamide, might possess toxic or carcinogenic properties.