Mono‐ and Di‐Alkylation Processes of DNA Bases by Nitrogen Mustard Mechlorethamine

The reactivity of nitrogen mustard mechlorethamine (mec) with purine bases towards formation of mono‐ (G‐mec and A‐mec) and dialkylated (AA‐mec, GG‐mec and AG‐mec) adducts has been studied using density functional theory (DFT). To gain a complete overview of DNA‐alkylation processes, direct chloride...

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Bibliographic Details
Published in:Chemphyschem 2017-12, Vol.18 (23), p.3390-3401
Main Authors: Larranaga, Olatz, deCozar, Abel, Cossio, Fernando P
Format: Article
Language:English
Subjects:
Adducts
Alkylation
Computational chemistry
Computer simulation
Continuum modeling
density functional calculations
Density functional theory
Deoxyribonucleic acid
DNA
DNA damage
kinetics
Mathematical models
microsolvation
Mustard
Runge-Kutta method
Solvation
Water chemistry
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Summary:The reactivity of nitrogen mustard mechlorethamine (mec) with purine bases towards formation of mono‐ (G‐mec and A‐mec) and dialkylated (AA‐mec, GG‐mec and AG‐mec) adducts has been studied using density functional theory (DFT). To gain a complete overview of DNA‐alkylation processes, direct chloride substitution and formation through activated aziridinium species were considered as possible reaction paths for adduct formation. Our results confirm that DNA alkylation by mec occurs via aziridine intermediates instead of direct substitution. Consideration of explicit water molecules in conjunction with polarizable continuum model (PCM) was shown as an adequate computational method for a proper representation of the system. Moreover, Runge–Kutta numerical kinetic simulations including the possible bisadducts have been performed. These simulations predicted a product ratio of 83:17 of GG‐mec and AG‐mec diadducts, respectively. Alkylation: The reactivity of nitrogen mustard mechlorethamine towards adenine and guanine nucleobases is analyzed by means of DFT calculations. To gain a complete overview of the DNA alkylation processes, both direct second‐order nucleophilic substitution reactions (SN2) and SN2 processes involving strained activated aziridinium species are explored.
ISSN:1439-4235
1439-7641
DOI:10.1002/cphc.201700937