Avoidance of the Ames test liability for aryl–amines via computation

McCarren, Patrick; Bebernitz, Gregory R.; Gedeck, Peter; Glowienke, Susanne; Grondine, Melissa; Kirman, Louise; Klickstein, Jacob; Schuster, Herbert F.; Whitehead, Lewis

doi:10.1016/j.bmc.2011.03.066

Cited by 29 publications

(44 citation statements)

References 60 publications

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“…This hydroxylation would be similar to N-hydroxyl aryl amino functionalities, some of which have been dmd.aspetjournals.org reported to be positive in Ames testing (McCarren et al, 2011). Some N-aryl hydroxylamine have also been shown to be liable for toxicities associated to their bioactivation to generate the electrophilic intermediates that could react with cellular thiols to form sulfinamide adducts (Harrison and Jollow, 1986;Liu et al, 2008;Siraki, 2013).…”

Section: Discussionmentioning

confidence: 95%

Identification of 2-Aminothiazolobenzazepine Metabolites in Human, Rat, Dog, and Monkey Microsomes by Ion-Molecule Reactions in Linear Quadrupole Ion Trap Mass Spectrometry

et al. 2014

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2-Aminothiazolobenzazepine (2-ATBA), 7-[(1-methyl-1H-pyrazol-4-yl)methyl]-6,7,8,9-tetrahydro-5H-[1,3]thiazolo[4,5-h][3]benzazepin-2-amine, is a D2 partial agonist that has demonstrated antipsychotic effects in a rodent in vivo efficacy model. The metabolite profile showed that 2-ATBA is mainly metabolized by oxidation. However, identification of the oxidation site(s) in the 2-aminothiazole group presents a challenge for the traditional metabolite identification methods such as liquid chromatography/mass spectrometry and NMR due to the lack of unique tandem mass spectrometry fragmentation patterns for ions with the 2-aminothiazole group oxidized at different sites and the lack of stability for purification or reference standard synthesis. We describe the characterization of the oxidized heteroatoms of the 2-aminothiazole group via gas-phase ion-molecule reactions (GPIMR) in a modified linear quadrupole ion trap mass spectrometer. The GPIMR reagents used were dimethyl disulfide, tert-butyl peroxide, and tri(dimethylamino)borane. Each reagent was introduced into the ion trap through the helium line and was allowed to react with the protonated metabolites. The ionic ion-molecule reaction products and their fragmentation profiles were compared with the profiles of the ionic ion-molecule reaction products of protonated reference compounds that had specific heteroatom functionalities. The oxidized 2-aminothiazole metabolite of 2-ATBA showed a similar GPIMR profile to that of the reference compounds with a tertiary N-oxide functionality and distinct from the profiles of the reference compounds with N-aryl hydroxylamine, nitroso, or pyridine N-oxide functionalities. This study demonstrates the feasibility of fingerprinting the chemical nature of oxidized nitrogen functional groups via GPIMR profiling for metabolite structure elucidation.

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Section: Discussionmentioning

confidence: 95%

Identification of 2-Aminothiazolobenzazepine Metabolites in Human, Rat, Dog, and Monkey Microsomes by Ion-Molecule Reactions in Linear Quadrupole Ion Trap Mass Spectrometry

et al. 2014

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“…Loew et al [1985] also found that the ease of formation of phenols (a detoxifying pathway) is negatively correlated with the carcinogenic activity. In the recent years, the stability of the nitrenium ion has been a major focus of several studies that have confirmed its correlation with toxicity [Borosky, 2007[Borosky, , 2008Bentzien et al, 2010;McCarren et al, 2011]. The study by McCarren et al [2011] has Environmental and Molecular Mutagenesis.…”

Section: Discussionmentioning

confidence: 93%

“…In the recent years, the stability of the nitrenium ion has been a major focus of several studies that have confirmed its correlation with toxicity [Borosky, 2007[Borosky, , 2008Bentzien et al, 2010;McCarren et al, 2011]. The study by McCarren et al [2011] has Environmental and Molecular Mutagenesis. DOI 10.1002/em also attempted to transform the theoretical chemistry results into a rule suitable for predicting the mutagenicity of further aromatic amines; this rule has been compared to the performance of Eq.…”

Section: Discussionmentioning

confidence: 93%

“…Equation (1) was applied as implemented in Toxtree v. 1.60 [McCarren et al, 2011]. The evidence from this comparison of models should be taken with caution, because McCarren et al [2011] modeled the overall Ames outcome (irrespective of the strains used), whereas Eq. (1) QSAR models specifically TA100 data, but the comparison is still interesting.…”

Section: Discussionmentioning

confidence: 99%

“…The comparison is based on the application of the two models to aromatic amines (with molecular weight lower than 250) present in three different databases. Equation (1) was applied as implemented in Toxtree v. 1.60 [McCarren et al, 2011]. The evidence from this comparison of models should be taken with caution, because McCarren et al [2011] modeled the overall Ames outcome (irrespective of the strains used), whereas Eq.…”

Section: Discussionmentioning

confidence: 99%

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Flexible use of qsar models in predictive toxicology: A case study on aromatic amines

Benigni

Bossa

2011

Environ and Mol Mutagen

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Over the last years, predictive toxicology approaches based on Structure-Activity Relationships have emerged as fundamental tools in the regulatory assessments of chemicals, especially in those programs where regulatory constraints and assessment schemes limit the amount of data available from experimental test methods. Both the qualitative (e.g., Structural Alerts) and the quantitative (Quantitative Structure-Activity Relationships, QSAR) approach can play important roles. However, the two approaches are not familiar to the same extent to the regulators that most often use only the qualitative approach, so that the potentiality of the more sophisticated QSAR approach is neglected. In fact, QSAR is a very flexible tool that allows the user to modulate its response according to different goals and requirements. Here, we present a non-naïve approach to the use of a QSAR relative to a dichotomous biological activity (such as mutagen/nonmutagen), and we show how the user can maximize alternatively the reliability of the prediction of negative compounds (i.e., safe chemicals) or that of positive chemicals (i.e., chemicals that pose high hazard). Because of the environmental and industrial importance of the class of aromatic amines, we apply the approach to a previously published QSAR on the Salmonella typhimurium mutagenicity of these chemicals.

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Carbocations

McClelland

2014

Organic Reaction Mechanisms Series

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Avoidance of the Ames test liability for aryl–amines via computation

Cited by 29 publications

References 60 publications

Identification of 2-Aminothiazolobenzazepine Metabolites in Human, Rat, Dog, and Monkey Microsomes by Ion-Molecule Reactions in Linear Quadrupole Ion Trap Mass Spectrometry

Identification of 2-Aminothiazolobenzazepine Metabolites in Human, Rat, Dog, and Monkey Microsomes by Ion-Molecule Reactions in Linear Quadrupole Ion Trap Mass Spectrometry

Flexible use of qsar models in predictive toxicology: A case study on aromatic amines

Carbocations

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