Mutagenicity of nitro- and amino-substituted carbazoles in Salmonella typhimurium.

André, Véronique; Boissart, C.; Lechevrel, M.; Gauduchon, Pascal; Talaer, J. Y. Le; Lancelot, Jean‐Charles; Letois, B.; Saturnino, C.; Rault, Syl­vain; Robba, M.

doi:10.1016/0165-1218(93)90120-3

Cited by 13 publications

(6 citation statements)

References 26 publications

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“…Carbazoles as a chemical class have been relatively well-studied for carcinogenicity and mutagenicity because they are commonly detected environmental pollutants resulting from coal burning and are a major component of cigarette smoke. Carbazole itself, although hepatocarcinogenic in rats and mice, is not genotoxic, but a variety of relatively simple substituted carbazoles display in vitro genotoxicity with apparently differing modes of action. 18a-d In particular, amino-substituted carbazoles have been shown to contribute to the mutagenicity of some tobacco components and behave as reactive frame shift mutagens acting mainly through the formation of esterified (acetylated) hydroxylamines in a similar way to other planar aromatic amines. 19a,b Alkyl substituents, including 9-methyl and 9-ethyl carbazole, have been shown to be mutagenic in salmonella with the 9-hydroxy metabolites as the probable proximate mutagens. 18c,d …”

Section: Resultsmentioning

confidence: 99%

Discovery and Optimization of a Series of Carbazole Ureas as NPY5 Antagonists for the Treatment of Obesity

et al. 2002

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The hypothesis that antagonists of the neuropeptide Y5 receptor would provide safe and effective appetite suppressants for the treatment of obesity has prompted vigorous research to identify suitable compounds. We discovered a series of acylated aminocarbazole derivatives (e.g., 3a) that are potent and selective Y5 antagonists, representing interesting starting points but suffering from poor bioavailability and concerns about potential toxicity as a consequence of the embedded aminocarbazole fragment. It proved relatively easy to improve the drug metabolism and pharmacokinetic (DMPK) properties by variation of the side chain (as in 4a) but difficult to eliminate the aminocarbazole fragment. For compounds in this series to have the potential to be drugs, we believed that both the compound itself and the component aniline must be free of mutagenic activity. Parallel structure-activity relationship studies looking at the effects of ring substitution have proved that it is possible by incorporation of a 4-methyl substituent to produce carbazole ureas with potent Y5 activity, comprised of carbazole anilines that in themselves are devoid of mutagenic activity in the Ames test. Compound 4o (also known as NPY5RA-972) is highly selective with respect to Y1, Y2, and Y4 receptors (and also to a diverse range of unrelated receptors and enzymes), with an excellent DMPK profile including central nervous system penetration. NPY5RA-972 (4o) is a highly potent Y5 antagonist in vivo but does not block neuropeptide Y-induced feeding nor does it reduce feeding in rats, suggesting that the Y5 receptor alone has no significant role in feeding in these models.

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Section: Resultsmentioning

confidence: 99%

Discovery and Optimization of a Series of Carbazole Ureas as NPY5 Antagonists for the Treatment of Obesity

et al. 2002

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“… a The following compounds all gave no response in the Ames assay (BEF = 0): naphthalene (); 1-methylanthracene (); acridine ( , ); 3-methylphenanthrene, 4-methylphenanthrene, 1,9-dimethylphenanthrene, 2,7-dimethylphenanthrene, 4,5-dimethylphenanthrene, 4,9-dimethylphenanthrene, 2-ethylphenanthrene, 3-ethylphenanthrene, 9-ethylphenanthrene, 9- n -propylphenanthrene, 9-isopropylphenanthrene, 2,4,5,7-tetramethylphenanthrene, and 3,4,5,6-tetramethylphenanthrene (); 9-phenanthrol (); fluorene (); 1-methylfluorene, 2-methylfluorene, 3-methylfluorene, and 4-methylfluorene ( , ); 2,3-dimethylfluorene, 9,9-dimethylfluorene, 2,7-dimethylfluorene, 2,7,9-trimethylfluorene, 9-hydroxymethylfluorene, benzo[ a ]fluorene 3 , benzo[ b ]fluorene 3 , and benzo[ c ]fluorene 3 (); carbazole (); dibenzothiophene ( , ); 1-methyldibenzothiophene, 2-methyldibenzothiophene, 3-methyldibenzothiophene, 4-methyldibenzothiophene, benzo[ b ]naphtho[1,2- d ]thiophene, 1-methylbenzo[ b ]naphtho[1,2- d ]thiophene, 2-methylbenzo[ b ]naphtho[1,2- d ]thiophene, 4-methylbenzo[ b ]naphtho[1,2- d ]thiophene, 5-methylbenzo[ b ]naphtho[1,2- d ]thiophene, 6-methylbenzo[ b ]naphtho[1,2- d ]thiophene, benzo[ b ]naphtho[2,1- d ]thiophene, 1-methylbenzo[ b ]naphtho[2,1- d ]thiophene, 2-methylbenzo[ b ]naphtho[2,1- d ]thiophene, 3-methylbenzo[ b ]naphtho[2,1- d ]thiophene, 4-methylbenzo[ b ]naphtho[2,1- d ]thiophene, benzo[ b ]naphtho[2,3- d ]thiophene, 1-methylbenzo[ b ]naphtho[2,3- d ]thiophene, 2-methylbenzo[ b ]naphtho[2,3- d ]thiophene, 3-methylbenzo[ b ]naphtho[2,3- d ]thiophene, 5-methylbenzo[ b ]naphtho[2,3- d ]thiophene, and 6-methylbenzo[ b ]naphtho[2,3- d ]thiophene (); 1-methylchrysene 3 , 2-methylchrysene 3 , 3-methylchrysene 3 , and 6-methylchrysene 3 (); naphthoquinone, anthraquinone, 2-methylanthraquinone, 1,6-dimethylpyrenequinone, and 1,8-dimethylpyrenequinone (); and phenanthrenequinone ( , ). b IARC, 1987.…”

Section: Resultsmentioning

confidence: 99%

“…We have searched the literature in order to determine tentative BEFs for PACs in aqueous media (Table 4) using Ames assay data obtained in the presence of metabolic activation. These were available as rpp/µg of PAC (4,(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). Because data were usually insufficient to draw dose-response curves, we report in Table 4 the largest reported ratio rpp/µg of PAC to give the highest (most conservative) BEF.…”

Section: Resultsmentioning

confidence: 99%

Comparison of the Ames Salmonella Assay and Mutatox Genotoxicity Assay for Assessing the Mutagenicity of Polycyclic Aromatic Compounds in Porewater from Athabasca Oil Sands Mature Fine Tailings

Madill

Brownlee

Josephy

et al. 1999

Environ. Sci. Technol.

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The oil sands in the Athabasca region of northeastern Alberta, Canada, represent a significant hydrocarbon resource that is currently exploited by mining, followed by separation of bitumen from sand using hot water flotation. This process generates large quantities of bitumen-contaminated tailings. Current research involves an assessment of whether the tailings ponds can ultimately be converted to biologically productive lakes, with one unresolved issue being the toxicity of the polycyclic aromatic compounds (PACs) that might be released from the tailings. In this paper, we have identified several polycyclic aromatic hydrocarbons in the porewater from oil sands mature fine tailings and have compared the responses of 17 PACs in the Ames and Mutatox genotoxicity assays. The Mutatox assay was unsuitable as a surrogate for the Ames test in this application; poor (50%) concordance between the two assays occurred because the mechanism of light emission in the Mutatox assay is uncertain, leading to positive responses that could not be unambiguously associated with genotoxicity. Benzo[a]pyrene equivalency factors (BEFs) in the Ames assay were determined for a large number of PACs, from this work and from literature data, to express the genotoxic potencies of environmental mixtures in terms of benzo[a]pyrene equivalent concentrations (BEQs). In the case of porewater samples obtained from the mature fine tailings, even extracts concentrated 10,000-fold were below the detection limit of 1 μg/L BEQ, consistent with the value of 0.14 μg/L calculated using BEFs of PACs identified in the porewater.

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“…However, based on further studies of more recent reports ( , ), nitrated DBC and hydroxylated DBC have also been found in airborne particulates . Only carbazole, a three ring analog of DBC, has been studied with respect to the synthesis and mutagenicities of a series of its nitrated and hydroxylated nitro derivatives ( − ).…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Characterization, and Mutagenicity of Nitrated 7H-Dibenzo[c,g]carbazole and Its Phenolic Derivatives

Xue

LaDow

Warshawsky

1997

Chem. Res. Toxicol.

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The nitrated N-heterocyclic aromatic hydrocarbons (NAHs) are found in a variety of environmental sources; many of them have been determined to be mutagenic in short-term assays and/or carcinogenic in animal tests. In this laboratory, we synthesized and characterized nitrated 7H-dibenzo[c,g]carbazole (DBC) and the nitrophenolic metabolites of DBC as potential mutagenic and carcinogenic xenobiotics. The nitro group was formed exclusively at the 5 and/or the symmetric 9 position of DBC, 2-hydroxy-DBC, 3-hydroxy-DBC, and 4-hydroxy-DBC. Ames plate incorporation mutagenicity assays were conducted using Salmonella typhimurium strains TA98 and TA100, with or without rat liver homogenates (S9). Mutagenicities of the nitrated DBCs were higher than the parent DBC in strain TA98, 5,9-Dinitro-DBC had stronger mutagenic responses than 5-nitro-DBC in all assays, particularly in strain TA98 with S9. 5,9-Dinitro-DBC had a higher reduction potential relative to 5-nitro-DBC (-1.09 V and -1.37 V, respectively). Hydroxyl derivatives of 5-nitro-DBC at the 2, 3, 4, 10, or 12 position, synthesized through nitration of the corresponding hydroxy-DBC, possessed greater mutagenicity than the parent 5-nitro-DBC, especially in strain TA100 with or without S9. Our data suggest that nitrated DBC undergoes both nitroreduction and ring oxidation as the primary pathways for the metabolic activation leading to mutagenesis. The relative mutagenicities of the nitrohydroxy-DBC isomers are generally consistent with the resonance stabilization of the positive charge at the arylnitrenium ion, formed from the nitro functional group, as the proposed active electrophile responsible for genotoxic effects.

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Mutagenicity of nitro- and amino-substituted carbazoles in Salmonella typhimurium.

Cited by 13 publications

References 26 publications

Discovery and Optimization of a Series of Carbazole Ureas as NPY5 Antagonists for the Treatment of Obesity

Discovery and Optimization of a Series of Carbazole Ureas as NPY5 Antagonists for the Treatment of Obesity

Comparison of the Ames Salmonella Assay and Mutatox Genotoxicity Assay for Assessing the Mutagenicity of Polycyclic Aromatic Compounds in Porewater from Athabasca Oil Sands Mature Fine Tailings

Synthesis, Characterization, and Mutagenicity of Nitrated 7H-Dibenzo[c,g]carbazole and Its Phenolic Derivatives

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