Thietanium ion formation from the food mutagen 2-chloro-4-(methylthio)butanoic acid.
2-Chloro-4-(methylthio)butanoic acid (1) is a direct-acting mutagen and suspected gastric carcinogen isolated from fish preserved with salt and nitrite. The reactive intermediates formed from acid 1 that may be associated with its mutagenicity have not been identified. A candidate reactive intermediate is proposed in this work. 1-Methyl-2-thietaniumcarboxylic acid may result from internal displacement of chloride by neighboring-group participation of sulfide sulfur in the solvolysis of acid 1. Evidence for the formation of 1-methyl-2-thietaniumcarboxylic acid was derived from experiments in which 4-chlorophenol and aniline were included to react with electrophilic intermediates formed from acid 1. Incubation of acid 1 in the absence of the aniline or 4-chlorophenol resulted in the formation of 2,4-bis(methylthio)butanoic acid. Incubation of acid 1 with 4-chlorophenol or aniline gave adducts that were identified by 1H NMR spectroscopy and GC/MS as 2-(4-chlorophenoxy)-4-(methylthio)butanoic acid and 4-(4-chlorophenoxy)-2-(methylthio)butanoic acid or 2-anilino-4-(methylthio)butanoic acid and 4-anilino-2-(methylthio)butanoic acid, respectively. The structures of these adducts indicate the intermediate formation of 1-methyl-2-thietaniumcarboxylic acid as a reactive intermediate derived from acid 1 that may be associated with its observed mutagenicity.
Department of Pharmacology and Physiology, University of Rochester, 601 Elmwood Avenue, Box 711, Rochester, New York 14642, USA.
L J
LJ
Jolivette
A S
AS
Kende
M W
MW
Anders
D000814:Aniline Compounds / Q000032:analysis; D002087:Butyrates / Q000737:chemistry*; D002264:Carboxylic Acids / Q000737:chemistry*; D002733:Chlorophenols / Q000032:analysis; D002851:Chromatography, High Pressure Liquid; D005506:Food Contamination / Q000032:analysis*; D008401:Gas Chromatography-Mass Spectrometry; D006571:Heterocyclic Compounds / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009153:Mutagens / Q000737:chemistry*; D012996:Solutions; D013438:Sulfhydryl Compounds
C114290:1-methyl-2-thietaniumcarboxylic acid; C093068:2-chloro-4-methylthiobutanoic acid; D000814:Aniline Compounds; D002087:Butyrates; D002264:Carboxylic Acids; D002733:Chlorophenols; D006571:Heterocyclic Compounds; D009153:Mutagens; D012996:Solutions; D013438:Sulfhydryl Compounds; C029107:4-chlorophenol