Structure-mutagenicity relationships within a series of para-alkoxynitrosobenzenes

Gupta, Raveena; Dey, Deepa; Juneja, T.R.

doi:10.1016/0378-4274(85)90020-7

Cited by 7 publications

(2 citation statements)

References 13 publications

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“…Caution: Nitrosoarenes bearing π-donating substituents have tested positive in the Ames mutagenicity assay with Salmonella typhimurium without activation ( − ).…”

Section: Methodsmentioning

confidence: 99%

Additional Pathways of S-Conjugate Formation during Interaction of 4-Nitrosophenetole with Glutathione

Gallemann

Greif

Eyer

et al. 1998

Chem. Res. Toxicol.

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The rapid reactions of nitrosoarenes with cellular SH groups have proved to be main metabolic conversions during detoxication. Interactions of the phenacetin metabolite 4-nitrosophenetole with glutathione have been investigated in detail during the last years, revealing a complex pattern of products depending on the stoichiometry of the reactants and reaction conditions. Eight metabolites have been identified hitherto, and the present work extends this medley by six additional products. Three metastable sulfenamides, 4-ethoxy-2,N-bis(glutathion-S-yl)-aniline, N4-(glutathion-S-yl)-4-amino-4'-ethoxydiphenylamine, and N-(glutathion-S-yl)-4-aminophenol, as well as the N-sulfenylquinonimine N-(glutathion-S-yl)-1,4-benzoquinonimine were characterized by chemical reactivity, chromatographic behavior, UV/vis absorption, 1H NMR, and FAB-MS data. The structure of the sulfenamide 2,N4-bis(glutathion-S-yl)-4-amino-4'-ethoxydiphenylamine could not be proved unequivocally, but is strongly suggested due to the chemical reactivity, chromatographic behavior, and UV/vis absorption of the compound. Finally, traces of 4-aminophenol were detected. A reaction scheme is presented explaining the formation of all identified metabolites via a central sulfenamide cation. Molecular orbital calculations for this sulfenamide cation have been performed, corroborating the proposed reaction mechanisms on the basis of Klopman's generalized perturbation theory.

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“…Caution: Nitrosoarenes bearing π-donating substituents have tested positive in the Ames mutagenicity assay with Salmonella typhimurium without activation ( − ).…”

Section: Methodsmentioning

confidence: 99%

Additional Pathways of S-Conjugate Formation during Interaction of 4-Nitrosophenetole with Glutathione

Gallemann

Greif

Eyer

et al. 1998

Chem. Res. Toxicol.

View full text Add to dashboard Cite

show abstract

“…Caution: Nitrosoarenes bearing π-donating substituents have tested positive in the Ames mutagenicity assay with S. typhimurium without activation ( − ) .…”

Section: Methodsmentioning

confidence: 99%

Formation of 4,4-Dialkoxycyclohexa-2,5-dienone N-(Thiol-S-yl)imine during Reaction of 4-Alkoxynitrosobenzenes with Thiols in Alcoholic Solvents

Gallemann

Greif

Eyer

et al. 1998

Chem. Res. Toxicol.

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During the interaction of nitrosoarenes with glutathione in aqueous media, intermediate generation of a highly resonance-stabilized sulfenamide cation has been repeatedly suggested. Most intermediates and end products could be explained by reactions of this sulfenamide cation with different nucleophiles such as excess thiol, solvent water, and metabolically produced arylamine. The present paper presents evidence for adduct formation of the sulfenamide cation with solvent alcohol at neutral pH. Sulfenamide cations generated from 4-nitrosophenetole and 4-nitrosoanisole, respectively, are strongly suggested to form the metastable ketals 4-ethoxy-4-methoxycyclohexa-2,5-dienone N-(glutathion-S-yl)imine and 4,4-dimethoxycyclohexa-2,5-dienone N-(glutathion-S-yl)imine, respectively, during reaction with solvent methanol. Reaction of the two sulfenamide cations in ethanol yielded 4,4-diethoxycyclohexa-2, 5-dienone N-(glutathion-S-yl)imine and 4-ethoxy-4-methoxycyclohexa-2, 5-dienone N-(glutathion-S-yl)imine, respectively. Although the metastability of the ketals did not allow isolation of pure solid material, chromatographic and chemical behavior as well as tandem MS fragmentation substantiate a ketal structure of these intermediates. To confirm the proposed structure, new compounds, 2, 6-dimethyl-4-nitrosophenetole, 2,6-dimethyl-4-nitrophenetole, 2, 6-dimethyl-4-phenetidine, and N-(glutathion-S-yl)-N-hydroxy-4-aminoacetophenone, were synthesized and included in supportive experiments. In summary, the detection of ketals corroborates once more the occurrence of a sulfenamide cation which obviously not only reacts with soft nucleophiles such as GSH but, to a limited extent, also reacts with hard nucleophiles. The toxicological significance of this result is discussed.

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(Q)SAR Models for Genotoxicity Assessment

Kulkarni

Zhu

2009

Ecotoxicology Modeling

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Structure-mutagenicity relationships within a series of para-alkoxynitrosobenzenes

Cited by 7 publications

References 13 publications

Additional Pathways of S-Conjugate Formation during Interaction of 4-Nitrosophenetole with Glutathione

Additional Pathways of S-Conjugate Formation during Interaction of 4-Nitrosophenetole with Glutathione

Formation of 4,4-Dialkoxycyclohexa-2,5-dienone N-(Thiol-S-yl)imine during Reaction of 4-Alkoxynitrosobenzenes with Thiols in Alcoholic Solvents

(Q)SAR Models for Genotoxicity Assessment

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