Mechanism of 1,<i>N</i><sup>2</sup>-Etheno-2′-deoxyguanosine Formation from Epoxyaldehydes

2,3-Epoxy-4-hydroxynonanal (EHN) is a potential product of lipid peroxidation that gives rise to genotoxic etheno adducts. We have synthesized all four stereoisomers of EHN and individually reacted them with 2'-deoxyguanosine. In addition to 1,N2-etheno-2'-deoxyguanosine, 12 stereoisomeric products were isolated and characterized by 1H NMR and circular dichroism spectroscopy. The stereochemical assignments were consistent with selective NOE spectra, vicinal coupling constants, and molecular mechanics calculations. Reversed-phase HPLC conditions were developed that could separate most of the adduct mixture.

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“…It should be noted that the stereochemistry of the allylic hydroxyl group of the C7-sidechain (C10) of 11–14 can slowly scramble over time. 31 …”

Section: Resultsmentioning

confidence: 99%

Synthesis of the four stereoisomers of 2,3-epoxy-4-hydroxynonanal and their reactivity with deoxyguanosine

et al. 2011

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“…59 Further support for the configurational assignments was obtained from comparison of the CD spectra of 1a and b with those of tetracyclic 1, N 2 -ethano-type dGuo adducts of 2,3-epoxy-4-hydroxynonanal which are excellent models for the Gua W -A-C rings in 1 . 60 …”

Section: Resultsmentioning

confidence: 99%

“…The formation of 8 is analogous to the reactions of dGuo with butene-1,4-dial, 64 4-oxo-2-nonenal, 65 and with 2,3-epoxyaldehydes. 60,66 …”

Section: Discussionmentioning

confidence: 99%

Deoxyguanosine Forms a Bis-Adduct with E,E-Muconaldehyde, an Oxidative Metabolite of Benzene: Implications for the Carcinogenicity of Benzene

Harris¹,

Stec²,

Christov³

et al. 2011

Chem. Res. Toxicol.

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Benzene is employed in large quantities in the chemical industry and is a ubiquitous contaminant in the environment. There is strong epidemiological evidence that benzene exposure induces hematopoietic malignancies, especially acute myeloid leukemia, in humans but the chemical mechanisms remain obscure. E,E-Muconaldehyde is one of the products of metabolic oxidation of benzene. This paper explores the proposition that E,E-muconaldehyde is capable of forming Gua-Gua cross-links. If formed in DNA, the replication and repair of such cross-links might introduce structural defects that could be the origin of the carcinogenicity. We have investigated the reaction of E,E-muconaldehyde with dGuo and found the reaction yields two pairs of interconverting diastereomers of a novel heptacyclic bis-adduct having a spiro ring system linking the two Gua residues. The structures of the four diastereomers have been established by NMR spectroscopy and their absolute configurations by comparison of CD spectra with those of model compounds having known configurations. The final two steps in formation of the bis-nucleoside (5-ring → 6-ring → 7-ring) have significant reversibility, which is the basis for the observed epimerization. The 6-ring precursor was trapped from the equilibrating mixture by reduction with NaBH4. The anti relationship of the two Gua residues in the heptacyclic bis-adduct precludes it from being formed in B DNA but the 6-ring precursor could readily be accommodated as an interchain or intrachain cross-link. It should be possible to form similar cross-links of dCyt, dAdo, the ε-amino group of lysine, and N-termini of peptides with the dGuo-muconaldehyde monoadduct.

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“…2−9 These lesions also arise from endogenous exposures to lipid peroxidation products,(10) particularly 4,5-epoxy-2( E )-decanal 11,12 and 4-hydroperoxynonenal. (13) Related etheno adducts from 4-oxo-2( E )-nonenal, 14,15 4-oxohexenal,(16) and 9,12-dioxo-10( E )-dodecanoic acid(17) have also been characterized.…”

Section: Introductionmentioning

confidence: 99%

1,N²-Etheno-2′-deoxyguanosine Adopts the syn Conformation about the Glycosyl Bond When Mismatched with Deoxyadenosine

Shanmugam

Kozekov

Guengerich

et al. 2011

Chem. Res. Toxicol.

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The oligodeoxynucleotide 5′-CGCATXGAATCC-3′·5′-GGATTCAATGCG-3′ containing 1,N2-etheno-2′-deoxyguanosine (1,N2-εdG) opposite deoxyadenosine (named the 1,N2-εdG·dA duplex) models the mismatched adenine product associated with error-prone bypass of 1,N2-εdG by the Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4) and by Escherichia coli polymerases pol I exo– and pol II exo–. At pH 5.2, the Tm of this duplex was increased by 3 °C as compared to the duplex in which the 1,N2-εdG lesion is opposite dC, and it was increased by 2 °C compared to the duplex in which guanine is opposite dA (the dG·dA duplex). A strong NOE between the 1,N2-εdG imidazole proton and the anomeric proton of the attached deoxyribose, accompanied by strong NOEs to the minor groove A20 H2 proton and the mismatched A19 H2 proton from the complementary strand, establish that 1,N2-εdG rotated about the glycosyl bond from the anti to the syn conformation. The etheno moiety was placed into the major groove. This resulted in NOEs between the etheno protons and T5 CH3. A strong NOE between A20 H2 and A19 H2 protons established that A19, opposite to 1,N2-εdG, adopted the anti conformation and was directed toward the helix. The downfield shifts of the A19 amino protons suggested protonation of dA. Thus, the protonated 1,N2-εdG·dA base pair was stabilized by hydrogen bonds between 1,N2-εdG N1 and A19 N1H+ and between 1,N2-εdG O9 and A19N6H. The broad imino proton resonances for the 5′- and 3′-flanking bases suggested that both neighboring base pairs were perturbed. The increased stability of the 1,N2-εdG·dA base pair, compared to that of the 1,N2-εdG·dC base pair, correlated with the mismatch adenine product observed during the bypass of 1,N2-εdG by the Dpo4 polymerase, suggesting that stabilization of this mismatch may be significant with regard to the biological processing of 1,N2-εdG.

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Mechanism of 1,N²-Etheno-2′-deoxyguanosine Formation from Epoxyaldehydes

Cited by 27 publications

References 42 publications

Synthesis of the four stereoisomers of 2,3-epoxy-4-hydroxynonanal and their reactivity with deoxyguanosine

Synthesis of the four stereoisomers of 2,3-epoxy-4-hydroxynonanal and their reactivity with deoxyguanosine

Deoxyguanosine Forms a Bis-Adduct with E,E-Muconaldehyde, an Oxidative Metabolite of Benzene: Implications for the Carcinogenicity of Benzene

1,N²-Etheno-2′-deoxyguanosine Adopts the syn Conformation about the Glycosyl Bond When Mismatched with Deoxyadenosine

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Mechanism of 1,N2-Etheno-2′-deoxyguanosine Formation from Epoxyaldehydes

Cited by 27 publications

References 42 publications

Synthesis of the four stereoisomers of 2,3-epoxy-4-hydroxynonanal and their reactivity with deoxyguanosine

Synthesis of the four stereoisomers of 2,3-epoxy-4-hydroxynonanal and their reactivity with deoxyguanosine

Deoxyguanosine Forms a Bis-Adduct with E,E-Muconaldehyde, an Oxidative Metabolite of Benzene: Implications for the Carcinogenicity of Benzene

1,N2-Etheno-2′-deoxyguanosine Adopts the syn Conformation about the Glycosyl Bond When Mismatched with Deoxyadenosine

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Mechanism of 1,N²-Etheno-2′-deoxyguanosine Formation from Epoxyaldehydes

1,N²-Etheno-2′-deoxyguanosine Adopts the syn Conformation about the Glycosyl Bond When Mismatched with Deoxyadenosine