Theoretical study of gas-phase methylation and ethylation by diazonium ions and rationalization of some aspects of DNA reactivity

Ford, George P.; Scribner, John D.

doi:10.1021/ja00341a009

Cited by 53 publications

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“…2,5,9,10 However, for many alkylating agents, reaction at guanine O 6 represents less than 10% of the total alkylation in DNA and RNA. [4][5][6][7][8] The methane diazonium ion, CH 3 N 2 þ , is the reactive intermediate formed from MeNU, 3,[11][12][13][14][15] N-methyl-N 0 -nitro-N-nitrosoguanidine (MNNG), 16 methylnitrosocarbamates, 17 trimethyltriazenes, 18 and nitrosamines. 17 This intermediate undergoes sequence specific reactions with guanine N7 and guanine O 6 in DNA.…”

Section: Introductionmentioning

confidence: 99%

“…12 This led to the conclusion that O atom reactions in nucleotide bases are more strongly governed by electrostatic interactions than N atom reactions, where there is a larger orbital component 11,12 More recent descriptions of gas-phase nucleotide base reactions with CH 3 N 2 þ , employing more rigorous ab initio methods, provide a different picture. 40 Results from MP2 and density functional calculations with the 6-31 þ G* basis set show that the forming bonds in transition states of O atom reactions are shorter than forming bonds in transition-states of N atom reactions.…”

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confidence: 99%

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Model transition states for methane diazonium ion methylation of guanine runs in oligomeric DNA

Ekanayake

Lebreton

2007

J Comput Chem

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The DNA reaction pattern of the methane diazonium ion, which is the reactive intermediate formed from several carcinogenic methylating agents, was examined at N7 and O(6) sites in guanine runs occurring in oligonucleotides and model oligonucleotides. Density functional B3LYP/6-31G*, and SCF 3-21G and STO-3G energies of model transition states were calculated in the gas phase and in the CPCM reaction field. For nucleotides containing two, three, and four stacked guanines with counterions in the gas phase, O(6) reactivity is greater than N7 reactivity. In the reaction field, N7 reactivity is 9.0 to 9.8 times greater than O(6) reactivity. For a double-stranded oligonucleotide containing two stacked guanines with counterions in the reaction field, the N7 and O(6) reactivities of the 3'-guanine are 3.9 times greater than the corresponding sites in the 5'-guanine. For double-stranded oligonucleotides with three or four stacked guanines and counterions, the reactivities of the interior guanines are higher than corresponding reactivities of guanines at the ends. These reaction patterns agree with most of the available experimental data. Activation energy decomposition analysis for gas-phase reactions in a double-stranded dinucleotide containing two stacked guanines with counterions indicates that selectivity at O(6) is almost entirely due to electrostatic forces. Selectivity at N7 also has a large electrostatic interaction. However, the orbital interaction also contributes significantly to the gas-phase selectivity, accounting for 32% of the total interaction energy difference between the 3'- and 5'-guanine reactions. In aqueous solution, the relative orbital contribution to N7 selectivity is likely to be larger.

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

Model transition states for methane diazonium ion methylation of guanine runs in oligomeric DNA

Ekanayake

Lebreton

2007

J Comput Chem

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“…These approaches need to be supplemented by studies of the actual alkylation step. The most fruitful approach may be to follow the lead of Ford and Scribner [40] and to determine the transition structures for alkylation by both methylating and ethylating agents. The experimental study of ethylations has certainly contributed a great deal to our understanding of tumor initiation; theoretical studies of ethylations may prove to be equally rewarding.…”

Section: Discussionmentioning

confidence: 99%

“…However, Ford and Scribner did observe rearrangement at O6 [ 171; interestingly, they attributed the rearrangement to a loose transition structure rather than to carbonium ions. They have subsequently carried out a semiempirical study of the alkylation of various model nucleophiles by both CH,N; and C2HJN: [40]. They found that the transition structures for ethylation are indeed looser than those for methylation.…”

Section: Cationic Alkylating Agentsmentioning

confidence: 99%

A theoretical study of N‐nitrosamine metabolites: Possible alkylating species in carcinogenesis by N,N'‐dimethyl nitrosamine

Thomson

Reynolds

1986

Int J of Quantum Chemistry

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“…The reaction mechanisms and intermediate structures have been the topics of several detailed studies [38][39][40][41][43][44][45], although there are still some points that deserve explanation. We have focused our attention on the terminating steps of the biodegradation mechanisms of N-nitrosocompounds common for both series NA and NU (Fig.…”

Section: Metabolic Activation Mechanismsmentioning

confidence: 99%

QSAR and Mechanistic studies on the genotoxic compounds including environmental effects

Miertuš

Frecer

Májeková

1989

Int J of Quantum Chemistry

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The effects of a proximate condensed environment as the solvent and cellular structured patterns (biopolymers, membranes, etc.) play an important role in determination of the courses of molecular processes in biology. We present here the background of methods developed for such an environmental effects estimation combining the continuum and discrete models. Their applications within theoretical studies into the mechanisms of carcinogenic action of akylating N-nitrosocompounds are shown. The results given cover four different areas, namely the quantitative structure-activity relationship, mechanistic studies into their metabolic activation reactions, interactions of the ultimate carcinogens with DNA, and finally their genetic consequences.

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Theoretical study of gas-phase methylation and ethylation by diazonium ions and rationalization of some aspects of DNA reactivity

Cited by 53 publications

References 0 publications

Model transition states for methane diazonium ion methylation of guanine runs in oligomeric DNA

Model transition states for methane diazonium ion methylation of guanine runs in oligomeric DNA

A theoretical study of N‐nitrosamine metabolites: Possible alkylating species in carcinogenesis by N,N'‐dimethyl nitrosamine

QSAR and Mechanistic studies on the genotoxic compounds including environmental effects

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