Ab initio modeling of the interaction between guanine?cytosine base pair and mustard alkylating agents

Broch, Henri; Hamza, Adel; Vasilescu, D.

doi:10.1002/(sici)1097-461x(1996)60:8<1745::aid-qua3>3.0.co;2-y

Cited by 18 publications

(11 citation statements)

References 25 publications

(17 reference statements)

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“…The magnitudes of the minima decrease in the order N7 < O 6 < N3. This ordering is the same as that found in earlier ab initio SCF investigations of the electrostatic potential of isolated guanine 32 and of guanine in the guanine−cytosine base pair 33a…”

Section: Resultssupporting

confidence: 85%

“…Stacking interactions that reduce guanine π ionization potentials are greatest in sequences containing G runs . Results from measurements of sequence-specific DNA methylation by MNU and the related alkylating agent, nitrogen mustard, indicate that reaction at N7 and O 6 is more favorable for guanines in G runs than for isolated guanines. 33b,, These observations are consistent with the results in Table and Figure and with the view that guanine π polarizabilities, which are related to π ionization potentials, strongly influence sequence-specific DNA alkylation.…”

Section: Discussionsupporting

confidence: 79%

“…The Relationship between Guanine π Ionization Energies and Sequence-Specific Reactivity with Carcinogenic Alkylating Agents. Early investigations of electronic influences on the selectivity of small electrophilic alkylating agents at different sites on DNA focused on the molecular electrostatic potential (MEP). ,33b The finding that, around DNA bases, the MEP is most negative in the region of the N7 atom of guanine 32,33a is consistent with the selectivity of several small cationic alkylating agents for the N7 position of guanine. ,,,33b, However, the difficulty associated with an electrostatic model of DNA site selectivity is that for reactions of small uncharged methylating and ethylating agents with S N 2 character, reaction at N7 of guanine is also most favored. In reactions of methyl and ethyl methanesulfonate (MeMs and EtMs) and dimethyl and diethyl sulfate (Me 2 SO 4 and Et 2 SO 4 ) yields at N7 of guanine are more than 4 times larger than at other base sites. , The electrostatic model of selectivity also fails to account for the low reactivity at the negatively charged O atoms of the phosphate groups.…”

Section: Discussionmentioning

confidence: 99%

“…One description of electronic factors that strongly influence the observed reaction patterns of methylating and ethylating reagents, and of other alkylating agents, has focused on the electrostatic potentials associated with nucleotides and nucleotide components. − A different description places greater emphasis on base polarizabilities as reflected in base π ionization potentials. ,, In the first description, activation barriers for electrophilic attack of DNA by methyl chloroethylaziridinium ions and similar alkylating agents are determined primarily by the nucleotide electrostatic potential. In this description, base reaction sites with large negative potentials give rise to transition states with low activation barriers. , In the second description, , nucleotide base polarizability is more important than the electrostatic potential in determining selectivity. Here S N 2 activation barrier heights for reactions with DNA decrease as base π polarizability increases, and π polarizabilities increase as π ionization energies decrease.…”

Section: Introductionmentioning

confidence: 99%

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Aqueous Ionization and Electron-Donating Properties of Dinucleotides: Sequence-Specific Electronic Effects on DNA Alkylation

1999

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He I, UV photoelectron data and results from self-consistent-field (SCF) and post-SCF molecular orbital calculations were used to evaluate multiple gas-phase ionization potentials (IPs) of the phosphorylated dinucleotide 5′ pGpAp both isolated and in a cluster with Na + and H 2 O. SCF calculations with a split-valence basis set indicate that the ground-state valence orbital structure of 5′ pGpAp is generally localized on the base, sugar, or phosphate groups and that orbitals in the dinucleotide are similar to orbitals in the model compounds and anion, 1,9-dimethylguanine, 9-methyladenine, 3-hydroxytetrahydrofuran, and H 2 PO 4 -. This correlation parallels that in mononucleotides (Fernando, H.; Papadantonakis, G. A.; Kim, N. S.; LeBreton, P. R. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 5550-5555; Kim, N. S.; LeBreton, P. R. J. Am. Chem. Soc. 1996, 118, 3694-3707) and permits the correction of SCF ionization potentials using experimental IPs for the model compounds and theoretical IPs from post-SCF calculations on H 2 PO 4 -. A comparison of IPs of 5′ pGpAp, 5′ pGpA, 2′-deoxyguanosine 5′-phosphate (5′-dGMP -), and 2′-deoxyadenosine 5′-phosphate (5′-dAMP -), both isolated and in gas-phase clusters with Na + and H 2 O, indicates that the electrostatic influence of Na + and the anionic phosphate groups is great. IPs decrease significantly as the number of phosphate groups increases. For 5′-dGMP -, 5′ pGpA, and 5′ pGpAp, the lowest adiabatic guanine ionization potentials are 5.2, 3.1, and 1.6 eV, respectively; the lowest phosphate vertical IPs are 5.1, 3.1, and 1.9 eV. Gas-phase IPs were combined with hydration energies obtained with a Langevin dipole relaxation model to evaluate the 22 lowest aqueous ionization energies in 5′ pGpAp as well as ionization energies in the other nucleotides with and without counterions. The electrostatic dependence of the gas-phase IPs on the number of phosphate groups is modulated in aqueous solution. For 5′-dGMP -, 5′ pGpA, and 5′ pGpAp, the aqueous guanine and phosphate ionization energies lie in the ranges 4.2-4.9 eV and 5.5-6.1 eV, respectively. Solvent relaxation similarly modulates Na + electrostatic effects. It also alters the relative energies of ionization events. In the gas phase, the first adiabatic base IP is equal to or larger than the lowest phosphate vertical IP. In water, the base ionization energies are 1.2-1.3 eV smaller than the phosphate ionization energies. Guanine gas-phase π ionization energies in five different B-DNA oligomer models, each containing six stacked base pairs, were compared with site-specific reactivity data for methylation at the guanine N7 and O 6 atoms by the carcinogen, N-methyl-N-nitrosourea (MNU). O 6 methylation is associated with MNU carcinogenesis; N7 methylation is the principal DNA reaction pathway. At both guanine atoms, reactivity increases as the lowest guanine π ionization potential decreases. This is consistent with a description of transition states in which activation barriers are lowered as nucleotide base π polarizability increas...

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Section: Resultssupporting

confidence: 85%

Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Aqueous Ionization and Electron-Donating Properties of Dinucleotides: Sequence-Specific Electronic Effects on DNA Alkylation

1999

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“…Ab initio SCF gas‐phase calculations with the 6‐31G basis set have identified transition states for reactions of nitrogen mustard with N7 of guanine in the free base and in the guanine‐cytosine base pair 38, 39…”

Section: Introductionmentioning

confidence: 99%

Activation barriers for DNA alkylation by carcinogenic methane diazonium ions

Ekanayake

Lebreton

2005

J Comput Chem

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Methylation reactions of the DNA bases with the methane diazonium ion, which is the reactive intermediate formed from several carcinogenic methylating agents, were examined. The SN2 transition states of the methylation reactions at N7, N3, and O6 of guanine; N7, N3, and N1 of adenine; N3 and O2 of cytosine; and O2 and O4 of thymine were calculated using the B3LYP density functional method. Solvation effects were examined using the conductor-like polarizable continuum method and the combined discrete/SCRF method. The transition states for reactions at guanine N3, adenine N7, and adenine N1 are influenced by steric interactions between the methane diazonium ion and exocyclic amino groups. Both in the gas phase and in aqueous solution, the methylation reactions at N atoms have transition states that are looser, and generally occur earlier along the reaction pathways than reactions at O atoms. The forming bonds in the transition states in water are 0.03 to 0.13 A shorter than those observed in the gas phase, and the activation energies are 13 to 35 kcal/mol higher. The combined discrete/SCRF solvation energy calculations using base-water complexes with three water molecules yield base solvation energies that are larger than those obtained from the CPCM continuum method, especially for cytosine. Reactivities calculated using barriers obtained with the discrete/SCRF method are consistent with the experimentally observed high reactivity at N7 of guanine.

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

2017

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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.

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Ab initio modeling of the interaction between guanine?cytosine base pair and mustard alkylating agents

Cited by 18 publications

References 25 publications

Aqueous Ionization and Electron-Donating Properties of Dinucleotides: Sequence-Specific Electronic Effects on DNA Alkylation

Aqueous Ionization and Electron-Donating Properties of Dinucleotides: Sequence-Specific Electronic Effects on DNA Alkylation

Activation barriers for DNA alkylation by carcinogenic methane diazonium ions

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

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