Mechanisms of Decomposition of α-Hydroxydialkylnitrosamines in Aqueous Solution

Mesić, Milan; Peuralahti, Jari; Blans, Patrick; Fishbein, James C.

doi:10.1021/tx000084p

Cited by 9 publications

(1 citation statement)

References 35 publications

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“…Following α–C–H oxidation, the resulting α-hydroxynitrosamine ( II , Figure ) fragments to yield a diazoic acid ( IV , Figure ) and either a ketone or aldehyde, depending upon substitution at the site of oxidation. There have been several computational reports implicating this fragmentation step as rate-limiting in the sequence converting nitrosamines to reactive diazonium ions. ,, However, these reports appear to neglect the kinetic data acquired by Fishbein, which clearly indicate that this step is facile for aliphatic nitrosamines, and proceed by three mechanistic paths, the relative contributions of which depends upon pH. − While there may be specific nitrosamines for which this step impacts carcinogenic potency, we did not find a correlation between this step and available TD 50 data, consistent with a rapid step that neither limits the rate of formation nor leads to detoxifying products.…”

Section: Resultsmentioning

confidence: 48%

A Kinetic Model for Assessing Potential Nitrosamine Carcinogenicity

Yu,

McWilliams,

Dirat

et al. 2024

Chem. Res. Toxicol.

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Understanding the potential carcinogenic potency of nitrosamines is necessary to setting acceptable intake limits. Nitrosamines and the components that can form them are commonly present in food, water, cosmetics, and tobacco. The recent observation of nitrosamines in pharmaceuticals highlighted the need for effective methods to determine acceptable intake limits. Herein, we describe two computational models that utilize properties based upon quantum mechanical calculations in conjunction with mechanistic insights and established data to determine the carcinogenic potency of a variety of common nitrosamines. These models can be applied to experimentally untested nitrosamines to aid in the establishment of acceptable intake limits.

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Section: Resultsmentioning

confidence: 48%

A Kinetic Model for Assessing Potential Nitrosamine Carcinogenicity

Yu,

McWilliams,

Dirat

et al. 2024

Chem. Res. Toxicol.

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Mechanism and Kinetics of the Reaction of Nitrosamines with OH Radical: A Theoretical Study

Ponnusamy

Sandhiya

Senthilkumar

2017

Int. J. Chem. Kinet.

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The reaction of nitrosodimethylamine, nitrosoazetidine, nitrosopyrrolidine, and nitrosopiperidine with the hydroxyl radical has been studied using electronic structure calculations in gas and aqueous phases. The rate constant was calculated using variational transition state theory. The reactions are initiated by H‐atom abstraction from the αC─H group of nitrosamines and leads to the formation of alkyl radical intermediate. In the subsequent reactions, the initially formed alkyl radical intermediate reacts with O2 forming a peroxy radical. The reaction of peroxy radical with other atmospheric oxidants, such as HO2 and NO radicals, is studied. The structures of the reactive species were optimized by using the density functional theory methods, such as M06‐2X, MPW1K, and BHandHLYP, and hybrid methods G3B3. The single‐point energy calculations were also performed at CCSD(T)/6‐311+G(d,p)// M062X/6‐311+G(d,p) level. The calculated thermodynamical parameters show that the reactions corresponding to the formation of intermediates and products are highly exothermic. We have calculated the rate constant for the initial H‐atom abstraction and subsequent favorable secondary reactions using canonical variational transition state theory over the temperature range of 150–400 K. The calculated rate constant for initial H‐atom abstraction reaction is ∼3 × 10−12 cm3 molecule−1 s−1 and is in agreement with the previous experimental results. The calculated thermochemical data and rate constants show that the reaction profile and kinetics of the reactions are less dependent on the number of methyl groups present in the nitrosoamines. Furthermore, it has been found that the atmospheric lifetime of nitrosamines is around 5 days in the normal atmospheric OH concentration.

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Comparative theoretical investigation of the formation of DNA interstrand crosslinks induced by two kinds of N‐nitroso compounds: nitrosoureas and nitrosamines

Zhao

Zhong

2012

J of Physical Organic Chem

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Nitrosamines and nitrosoureas are two families of N‐nitroso compounds (NNCs) with a common nitroso group connected to the nitrogen atom; however, the two types of analogs often exhibit distinct bioactivities when they have similar substructures in the side chains. Nitrosamines are usually considered to be potent carcinogens to various organs and species, whereas nitrosoureas can inhibit cancer cell growth. This distinction between the two types of compounds complicates our understanding of the structure–bioactivity relationship of NNCs. In this work, the mechanisms for the formation of DNA interstrand crosslinks induced by nitrosoureas and nitrosamines, which are an important DNA damage related to the cytotoxicity of NNCs, were compared using the density functional theory method. 1,3‐Bis‐(2‐chloroethyl)‐1‐nitrosourea (BCNU) and the bifunctional metabolite of diethylnitrosamine, N‐nitrosoethyl‐(2‐hydroxyethyl)amine sulfonate (NEHEAS), were used as the computational models. Four pathways for the formation of G–C crosslinks induced by BCNU and NEHEAS were compared. The results show that the crosslinking mechanisms initiated by α‐alkylation are energetically feasible for both BCNU and NEHEAS, and the decompositions of BCNU and NEHEAS represent the rate‐limiting steps. However, for the crosslinking mechanisms initiated by β‐alkylation, BCNU and NEHEAS exhibit different preferences. The energy barrier for the decomposition of the BCNU‐induced β‐alkylation product is much higher than that of NEHEAS. Such an energy barrier may inhibit the mechanism of BCNU initiated by β‐alkylation. Consequently, it is postulated that BCNU and NEHEAS induce DNA interstrand crosslinks via different mechanisms, which may distinguish the bioactivity of the two types of NNCs. Copyright © 2012 John Wiley & Sons, Ltd.

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Mechanisms of Decomposition of α-Hydroxydialkylnitrosamines in Aqueous Solution

Cited by 9 publications

References 35 publications

A Kinetic Model for Assessing Potential Nitrosamine Carcinogenicity

A Kinetic Model for Assessing Potential Nitrosamine Carcinogenicity

Mechanism and Kinetics of the Reaction of Nitrosamines with OH Radical: A Theoretical Study

Comparative theoretical investigation of the formation of DNA interstrand crosslinks induced by two kinds of N‐nitroso compounds: nitrosoureas and nitrosamines

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