Theoretical investigation of mono- and bi-function alkylating agents transformed from nitrosodimethylamine derivatives

Lü, Chun Lin; Liu, Yong Dong; Zhong, Ru Gang

doi:10.1016/j.theochem.2008.09.029

Cited by 6 publications

(1 citation statement)

References 29 publications

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“…There have been several computational reports implicating this fragmentation step as rate-limiting in the sequence converting nitrosamines to reactive diazonium ions. 17,37,38 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. 39−42 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: ■ Results and Discussionmentioning

confidence: 99%

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: ■ Results and Discussionmentioning

confidence: 99%

A Kinetic Model for Assessing Potential Nitrosamine Carcinogenicity

Yu,

McWilliams,

Dirat

et al. 2024

Chem. Res. Toxicol.

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Multi‐level quantum monte Carlo wave functions for complex reactions: The decomposition of α‐hydroxy‐dimethylnitrosamine

2013

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We present here several novel features of our recently proposed Jastrow linear generalized valence bond (J-LGVB) wave functions, which allow a consistently accurate description of complex potential energy surfaces (PES) of medium-large systems within quantum Monte Carlo (QMC). In particular, we develop a multilevel scheme to treat different regions of the molecule at different levels of the theory. As prototypical study case, we investigate the decomposition of α-hydroxy-dimethylnitrosamine, a carcinogenic metabolite of dimethylnitrosamine (NDMA), through a two-step mechanism of isomerization followed by a retro-ene reaction. We compute a reliable reaction path with the quadratic configuration interaction method and employ QMC for the calculation of the electronic energies. We show that the use of multideterminantal wave functions is very important to correctly describe the critical points of this PES within QMC, and that our multilevel J-LGVB approach is an effective tool to significantly reduce the cost of QMC calculations without loss of accuracy. As regards the complex PES of α-hydroxy-dimethylnitrosamine, the accurate energies computed with our approach allows us to confirm the validity of the two-step reaction mechanism of decomposition originally proposed within density functional theory, but with some important differences in the barrier heights of the individual steps.

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