Structure-Mutagenicity Relationships of N-Oxidized Derivatives of Aniline, o-Toluidine, 2ʹ-Methyl-4-aminobiphenyl, and 3, 2ʹ-Dimethyl-4aminobiphenyl

Stephen S. Hecht, Karam El-Bayoumy, Lorraine Tulley, Edmond LaVoie

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Abstract

A series of N-oxidized derivatives of aniline (1a), 2ʹ-methyl-4-aminobiphenyl (5a), and the carcinogens o-toluidine (1b) and 3, 2ʹ-dimethyl-4-aminobiphenyl (5b) were prepared and tested for mutagenic activity toward S. typhimurium. The compounds tested were the hydroxylamines 2a, b and 6a, b; C-nitroso compounds 3a, b and 7a, b; and the hydroxamic acids 4a, b and 8a, b derived from the amines la, b and 5a, b, as well as the parent amines and N-[2-(hydroxymethyl)phenyl]hydroxylamine (2d), N-(2-methylphenyl)hydroxylamine-methyl-d3(2c), and 3, 2ʹ-dimethyl-4-aminobiphenyl-3-methyl-d3(5c). Compounds 2a, b and 2d-4b were obtained commercially and purified or were prepared according to previously described procedures, while 2c was synthesized by nitration of toluene-d3, separation of the isomers, and reduction. Compounds 5a, b and 6a-8b were prepared by standard procedures from 2ʹ-methyl-4-nitrobiphenyl (9) and 3, 2ʹ-dimethyl-4-nitrobiphenyl (10); 5c was prepared by treatment of 10 with NaOCD3in CD3OD to give 3, 2ʹ-dimethyl-4-nitrobiphenyl-3-methyl-d3(11), followed by reduction. Aniline (1a) and o-toluidine (1b) were inactive in strains TA 100, TA 1535, and TA 1538, both with or without activation by rat liver homogenate. The hydroxylamine 2b and C-nitroso compound 3b were mutagenic toward TA 100 and TA 1535 with activation but not toward TA 1538. Hydroxylamine 2d was less active than 2b toward TA 100. Hydroxylamine 2a and C-nitroso compound 3a were not mutagenic toward TA 100, TA 1535, or TA 1538 with activation. When assayed without activation, 2a, b and 3a, b were either toxic or nonmutagenic. The hydroxamic acid 4b was mutagenic toward TA 1535 without activation; 4a and 4b did not show activity in TA 100 or TA 1535 with activation. The aminobiphenyls 5a, b were highly mutagenic toward TA 1538 and TA 100 with activation but not toward TA 1535. Neither 5a nor 5b was active in the absence of rat liver homogenate. Hydroxylamines 6a, b, C-nitroso compounds 7a, b, and hydroxamic acids 8a, b were mutagenic toward strains TA 1538 and TA 100 with activation; 6b and 7b were highly mutagenic toward TA 1538 without activation. The biphenylamine derivatives were more mutagenic than the single ring compounds; the former were frameshift mutagens, while the latter were base-pair mutagens. Among the compounds showing mutagenic activity, the derivatives having a methyl group ortho to the amine functionality were generally more mutagenic, which parallels their carcinogenic activities. Substitution of deuterium for hydrogen in the o-methyl groups of 2b and 5b resulted in no significant loss of mutagenicity.

Original languageEnglish (US)
Pages (from-to)981-987
Number of pages7
JournalJournal of Medicinal Chemistry
Volume22
Issue number8
DOIs
StatePublished - Feb 1 1979

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2-toluidine
Hydroxylamine
Nitroso Compounds
Hydroxamic Acids
Hydroxylamines
Amines
Mutagens
Aminobiphenyl Compounds
Deuterium
Poisons
Liver
Toluene
Base Pairing
Carcinogens
Hydrogen
2',3-dimethyl-4-aminobiphenyl
aniline

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

@article{11a3e4ee3974415ba0ef835397e6c835,
title = "Structure-Mutagenicity Relationships of N-Oxidized Derivatives of Aniline, o-Toluidine, 2ʹ-Methyl-4-aminobiphenyl, and 3, 2ʹ-Dimethyl-4aminobiphenyl",
abstract = "A series of N-oxidized derivatives of aniline (1a), 2ʹ-methyl-4-aminobiphenyl (5a), and the carcinogens o-toluidine (1b) and 3, 2ʹ-dimethyl-4-aminobiphenyl (5b) were prepared and tested for mutagenic activity toward S. typhimurium. The compounds tested were the hydroxylamines 2a, b and 6a, b; C-nitroso compounds 3a, b and 7a, b; and the hydroxamic acids 4a, b and 8a, b derived from the amines la, b and 5a, b, as well as the parent amines and N-[2-(hydroxymethyl)phenyl]hydroxylamine (2d), N-(2-methylphenyl)hydroxylamine-methyl-d3(2c), and 3, 2ʹ-dimethyl-4-aminobiphenyl-3-methyl-d3(5c). Compounds 2a, b and 2d-4b were obtained commercially and purified or were prepared according to previously described procedures, while 2c was synthesized by nitration of toluene-d3, separation of the isomers, and reduction. Compounds 5a, b and 6a-8b were prepared by standard procedures from 2ʹ-methyl-4-nitrobiphenyl (9) and 3, 2ʹ-dimethyl-4-nitrobiphenyl (10); 5c was prepared by treatment of 10 with NaOCD3in CD3OD to give 3, 2ʹ-dimethyl-4-nitrobiphenyl-3-methyl-d3(11), followed by reduction. Aniline (1a) and o-toluidine (1b) were inactive in strains TA 100, TA 1535, and TA 1538, both with or without activation by rat liver homogenate. The hydroxylamine 2b and C-nitroso compound 3b were mutagenic toward TA 100 and TA 1535 with activation but not toward TA 1538. Hydroxylamine 2d was less active than 2b toward TA 100. Hydroxylamine 2a and C-nitroso compound 3a were not mutagenic toward TA 100, TA 1535, or TA 1538 with activation. When assayed without activation, 2a, b and 3a, b were either toxic or nonmutagenic. The hydroxamic acid 4b was mutagenic toward TA 1535 without activation; 4a and 4b did not show activity in TA 100 or TA 1535 with activation. The aminobiphenyls 5a, b were highly mutagenic toward TA 1538 and TA 100 with activation but not toward TA 1535. Neither 5a nor 5b was active in the absence of rat liver homogenate. Hydroxylamines 6a, b, C-nitroso compounds 7a, b, and hydroxamic acids 8a, b were mutagenic toward strains TA 1538 and TA 100 with activation; 6b and 7b were highly mutagenic toward TA 1538 without activation. The biphenylamine derivatives were more mutagenic than the single ring compounds; the former were frameshift mutagens, while the latter were base-pair mutagens. Among the compounds showing mutagenic activity, the derivatives having a methyl group ortho to the amine functionality were generally more mutagenic, which parallels their carcinogenic activities. Substitution of deuterium for hydrogen in the o-methyl groups of 2b and 5b resulted in no significant loss of mutagenicity.",
author = "Hecht, {Stephen S.} and Karam El-Bayoumy and Lorraine Tulley and Edmond LaVoie",
year = "1979",
month = "2",
day = "1",
doi = "10.1021/jm00194a019",
language = "English (US)",
volume = "22",
pages = "981--987",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "8",

}

Structure-Mutagenicity Relationships of N-Oxidized Derivatives of Aniline, o-Toluidine, 2ʹ-Methyl-4-aminobiphenyl, and 3, 2ʹ-Dimethyl-4aminobiphenyl. / Hecht, Stephen S.; El-Bayoumy, Karam; Tulley, Lorraine; LaVoie, Edmond.

In: Journal of Medicinal Chemistry, Vol. 22, No. 8, 01.02.1979, p. 981-987.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Structure-Mutagenicity Relationships of N-Oxidized Derivatives of Aniline, o-Toluidine, 2ʹ-Methyl-4-aminobiphenyl, and 3, 2ʹ-Dimethyl-4aminobiphenyl

AU - Hecht, Stephen S.

AU - El-Bayoumy, Karam

AU - Tulley, Lorraine

AU - LaVoie, Edmond

PY - 1979/2/1

Y1 - 1979/2/1

N2 - A series of N-oxidized derivatives of aniline (1a), 2ʹ-methyl-4-aminobiphenyl (5a), and the carcinogens o-toluidine (1b) and 3, 2ʹ-dimethyl-4-aminobiphenyl (5b) were prepared and tested for mutagenic activity toward S. typhimurium. The compounds tested were the hydroxylamines 2a, b and 6a, b; C-nitroso compounds 3a, b and 7a, b; and the hydroxamic acids 4a, b and 8a, b derived from the amines la, b and 5a, b, as well as the parent amines and N-[2-(hydroxymethyl)phenyl]hydroxylamine (2d), N-(2-methylphenyl)hydroxylamine-methyl-d3(2c), and 3, 2ʹ-dimethyl-4-aminobiphenyl-3-methyl-d3(5c). Compounds 2a, b and 2d-4b were obtained commercially and purified or were prepared according to previously described procedures, while 2c was synthesized by nitration of toluene-d3, separation of the isomers, and reduction. Compounds 5a, b and 6a-8b were prepared by standard procedures from 2ʹ-methyl-4-nitrobiphenyl (9) and 3, 2ʹ-dimethyl-4-nitrobiphenyl (10); 5c was prepared by treatment of 10 with NaOCD3in CD3OD to give 3, 2ʹ-dimethyl-4-nitrobiphenyl-3-methyl-d3(11), followed by reduction. Aniline (1a) and o-toluidine (1b) were inactive in strains TA 100, TA 1535, and TA 1538, both with or without activation by rat liver homogenate. The hydroxylamine 2b and C-nitroso compound 3b were mutagenic toward TA 100 and TA 1535 with activation but not toward TA 1538. Hydroxylamine 2d was less active than 2b toward TA 100. Hydroxylamine 2a and C-nitroso compound 3a were not mutagenic toward TA 100, TA 1535, or TA 1538 with activation. When assayed without activation, 2a, b and 3a, b were either toxic or nonmutagenic. The hydroxamic acid 4b was mutagenic toward TA 1535 without activation; 4a and 4b did not show activity in TA 100 or TA 1535 with activation. The aminobiphenyls 5a, b were highly mutagenic toward TA 1538 and TA 100 with activation but not toward TA 1535. Neither 5a nor 5b was active in the absence of rat liver homogenate. Hydroxylamines 6a, b, C-nitroso compounds 7a, b, and hydroxamic acids 8a, b were mutagenic toward strains TA 1538 and TA 100 with activation; 6b and 7b were highly mutagenic toward TA 1538 without activation. The biphenylamine derivatives were more mutagenic than the single ring compounds; the former were frameshift mutagens, while the latter were base-pair mutagens. Among the compounds showing mutagenic activity, the derivatives having a methyl group ortho to the amine functionality were generally more mutagenic, which parallels their carcinogenic activities. Substitution of deuterium for hydrogen in the o-methyl groups of 2b and 5b resulted in no significant loss of mutagenicity.

AB - A series of N-oxidized derivatives of aniline (1a), 2ʹ-methyl-4-aminobiphenyl (5a), and the carcinogens o-toluidine (1b) and 3, 2ʹ-dimethyl-4-aminobiphenyl (5b) were prepared and tested for mutagenic activity toward S. typhimurium. The compounds tested were the hydroxylamines 2a, b and 6a, b; C-nitroso compounds 3a, b and 7a, b; and the hydroxamic acids 4a, b and 8a, b derived from the amines la, b and 5a, b, as well as the parent amines and N-[2-(hydroxymethyl)phenyl]hydroxylamine (2d), N-(2-methylphenyl)hydroxylamine-methyl-d3(2c), and 3, 2ʹ-dimethyl-4-aminobiphenyl-3-methyl-d3(5c). Compounds 2a, b and 2d-4b were obtained commercially and purified or were prepared according to previously described procedures, while 2c was synthesized by nitration of toluene-d3, separation of the isomers, and reduction. Compounds 5a, b and 6a-8b were prepared by standard procedures from 2ʹ-methyl-4-nitrobiphenyl (9) and 3, 2ʹ-dimethyl-4-nitrobiphenyl (10); 5c was prepared by treatment of 10 with NaOCD3in CD3OD to give 3, 2ʹ-dimethyl-4-nitrobiphenyl-3-methyl-d3(11), followed by reduction. Aniline (1a) and o-toluidine (1b) were inactive in strains TA 100, TA 1535, and TA 1538, both with or without activation by rat liver homogenate. The hydroxylamine 2b and C-nitroso compound 3b were mutagenic toward TA 100 and TA 1535 with activation but not toward TA 1538. Hydroxylamine 2d was less active than 2b toward TA 100. Hydroxylamine 2a and C-nitroso compound 3a were not mutagenic toward TA 100, TA 1535, or TA 1538 with activation. When assayed without activation, 2a, b and 3a, b were either toxic or nonmutagenic. The hydroxamic acid 4b was mutagenic toward TA 1535 without activation; 4a and 4b did not show activity in TA 100 or TA 1535 with activation. The aminobiphenyls 5a, b were highly mutagenic toward TA 1538 and TA 100 with activation but not toward TA 1535. Neither 5a nor 5b was active in the absence of rat liver homogenate. Hydroxylamines 6a, b, C-nitroso compounds 7a, b, and hydroxamic acids 8a, b were mutagenic toward strains TA 1538 and TA 100 with activation; 6b and 7b were highly mutagenic toward TA 1538 without activation. The biphenylamine derivatives were more mutagenic than the single ring compounds; the former were frameshift mutagens, while the latter were base-pair mutagens. Among the compounds showing mutagenic activity, the derivatives having a methyl group ortho to the amine functionality were generally more mutagenic, which parallels their carcinogenic activities. Substitution of deuterium for hydrogen in the o-methyl groups of 2b and 5b resulted in no significant loss of mutagenicity.

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