Mechanisms of reaction between ultimate chemical carcinogens and nucleic acid

Hathway, D. E.; Kolar, G.F.

doi:10.1039/cs9800900241

Cited by 41 publications

(18 citation statements)

References 1 publication

(1 reference statement)

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“…These are reactions of soft nucleophiles with soft electrophiles that proceed through an SN2 mechanism (29). From this perspective, polarization of the highest occupied orbitals at nucleotide target sites is expected to strongly influence transition state energies.…”

Section: Resultsmentioning

confidence: 99%

UV photoelectron and ab initio quantum mechanical characterization of valence electrons in Na(+)-water-2'-deoxyguanosine 5'-phosphate clusters: electronic influences on DNA alkylation by methylating and ethylating carcinogens.

Kim

Lebreton

1994

Proc. Natl. Acad. Sci. U.S.A.

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UV photoelectron data for 1,9-dImethylguanine, 3-hydroxytetrahydrofuran, and water, and results from ab initio self-consistent field (SCF) and post-SCF molecular orbital calculations were employed to describe valence electrons in clusters of 2'-deoxyguanosine 5'-phosphate (5'-dGMP-) with four water molecules and a phosphate-bound sodium ion. Two clusters (A and B) were ex . In A, Na+ is coordinated to 5'-dGMP-. In B, Na+ and 5'-dGMP-are separated by water. In 5'-dGMP-clusters, the nucleotide valence ionization potentials (IPs) are different from those previously reported for isolated 5'-dGMP-. The smIllest IP in isolated 5'-dGMP-(4.6 eV) arises from the phosphate group; thesmallestIPs inA (8.2 eV) andB (7.9 eV) arise from the base. In the clusters, the IPs associated with the seven upper occupied base orbitals differ from corresponding IPs in 1,9-dimethylguanine by less than 0.4 eV. In A and B, the smaller ]IP of the base, compared with the phosphate group, is consistent with reactivity data indicating that DNA and RNA are subject to electrophilic SN2 attack by carcinogens such as N-methyl-Nnitrosourea, dimethyl and diethyl sulfate, and methyl and ethyl methanesulfonate, in which more than 75% of nucleotide alkylation occurs at the bases. While isolated nucleotides (1, 2, 4) have been investigated, nucleotides in the presence of water and counterions, which interact with DNA in physiological environments, have not. One goal of this investigation is to examine electrons in 2'-deoxyguanosine 5'-phosphate (5'-dGMP-) with 4 water molecules and a Na+ counterion. DNA binding occurs dynamically on a picosecond time scale (5, 6); nevertheless, information about solvent-counterion influences on nucleotide electronic structure can be obtained by examining statistically significant clusters. Fig. 1 shows two clusters (A and B) in which Na+ and 3 of the 4 water molecules bind to the phosphate group of 5'-dGMP-.X-ray (7,8), IR (9), and NMR (10) data indicate that phosphate in DNA is a principal hydration and Na+ binding site. In crystals of guanylyl (3'-5')cytidine nonahydrate, Na+ ions are octahedrally coordinated to the negative 0 atoms of phosphate and to H20 (11). Different theoretical approaches (5,(12)(13)(14)(15) indicate that Na+ binds in the grooves of DNA and along the backbone; however, recent molecular dynamics calculations point to the importance of Na+ binding at

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Section: Resultsmentioning

confidence: 99%

UV photoelectron and ab initio quantum mechanical characterization of valence electrons in Na(+)-water-2'-deoxyguanosine 5'-phosphate clusters: electronic influences on DNA alkylation by methylating and ethylating carcinogens.

Kim

Lebreton

1994

Proc. Natl. Acad. Sci. U.S.A.

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“…In theoretical investigations of DNA reactions, much work has focused on the reactivity of methane (CH 3 N

_{2}^{+}

) and ethane (C 2 H 5 N

_{2}^{+}

) diazonium ions 6–11. These ions are the reactive intermediates formed from MeNU and EtNU 3, 12–14. Methane and ethane diazonium ions are also formed as intermediates from direct‐acting methylating and ethylating agents such as N‐alkyl‐N′‐nitro‐N‐nitrosoguanidines,15 alkylnitrosocarbamates,16 and trialkyltriazenes 17.…”

Section: Introductionmentioning

confidence: 99%

“…This approach has been used to examine reactions of nucleotide bases with methane and ethane diazonium ions 6–9. Methylation of DNA and RNA by methane diazonium ions occurs through a bimolecular S N 2 nucleophilic substitution mechanism 3, 7, 8, 12. The experimental selectivity observed at different sites indicates that activation barriers exist.…”

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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“…* If the carcinogenic pathways of these molecules do involve the adducts 111 and XV, and if they are S N 2 processes (for which there is some support [42,43]), then our results indicate that it is the oxygen-protonated epoxides that should be the starting points. Thus, the lesser probability of trans-dichlorooxirane undergoing oxygen protonation may be a factor in its low level of carcinogenic activity.…”

Section: E Possible Reaction Pathways To Dna Adductmentioning

confidence: 79%

Reactive properties of trans‐dichlorooxirane in relation to the contrasting carcinogenicities of vinyl chloride and trans‐dichloroethylen

Laurence

Proctor

Politzer

1984

Int J of Quantum Chemistry

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Our objective in this work is to gain insight into the contrasting carcinogenic activities of vinyl chloride (definitely carcinogenic) and trans-dichloroethylene (apparently inactive). The initial metabolic step for each molecule is believed to be epoxidation of the double bond, and there is evidence indicating that for vinyl chloride, this epoxide (chlorooxirane) is its ultimate (direct-acting) carcinogenic form. This article presents the findings of a computational study of the reactive properties of trans-dichlorooxirane (the epoxide of trans-dichloroethylene). An ab initio SCF-MO procedure was used to determine the energy requirements for stretching the C-0 and C-CI bonds (SN1 reactivity) and to study the epoxide's S N 2 interactions with ammonia, taken as a model nucleophile. The starting points were the oxygen-and chlorine-protonated forms of the epoxide. The structure of the system was reoptimized at each step along the various reaction pathways. The results of this work are compared to an analogous earlier study of the reactive properties of chlorooxirane. The chlorineprotonated C-CI bonds are found to have much lower energy barriers to stretching than do the oxygen-protonated C-0 bonds. In the S N 2 processes, intermediate complexes are formed with ammonia by both the oxygen-and the chlorine-protonated epoxides; the latter complexes are the more stable. Based on our results, we propose two mechanisms (one SN 1 and the other SN2) whereby trans-dichlorooxirane can interact with N7 of guanine to produce an adduct analogous to one formed by chlorooxirane, which has been found to be the primary in uivo DNA alkylation product of vinyl chloride and to which has been attributed the carcinogenicity of the latter. Overall, transdichlorooxirane is found to be chemically more reactive than chiorooxirane; this may help to account for the much lesser carcinogenic and mutagenic activities of trans-dichloroethylene, since the epoxide may be reacting with other cellular nucleophiles before it reaches the key site(s) at which the carcinogenic or mutagenic interaction would occur. We also offer some speculations concerning other possible factors related to the differing carcinogenicities of vinyl chloride and trans-dichloroethylene, such as ease of epoxide formation and the likelihood of oxygen protonation.

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Mechanisms of reaction between ultimate chemical carcinogens and nucleic acid

Cited by 41 publications

References 1 publication

UV photoelectron and ab initio quantum mechanical characterization of valence electrons in Na(+)-water-2'-deoxyguanosine 5'-phosphate clusters: electronic influences on DNA alkylation by methylating and ethylating carcinogens.

UV photoelectron and ab initio quantum mechanical characterization of valence electrons in Na(+)-water-2'-deoxyguanosine 5'-phosphate clusters: electronic influences on DNA alkylation by methylating and ethylating carcinogens.

Activation barriers for DNA alkylation by carcinogenic methane diazonium ions

Reactive properties of trans‐dichlorooxirane in relation to the contrasting carcinogenicities of vinyl chloride and trans‐dichloroethylen

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