<sup>13</sup>C NMR studies of methylnucleosides

Chang, Ching‐Jer; Ashworth, Dennis J.; Chern, Lih‐Ju; Gomes, Jose DaSilva; Lee, Chi-Gen; Mou, Pih W.; Narayan, Ramáni

doi:10.1002/mrc.1270221102

Cited by 24 publications

(23 citation statements)

References 21 publications

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“…However, unlike singly substituted N 6 -dA derivatives, which exhibit one- proton signal at ~ 8 ppm corresponding to the exocyclic amino group, spectra of compounds 2a-base , 2b-base , and 2c-base lacked the N 6 -H proton signal, consistent with bis -alkylation of the N 6 position of adenine. 13 C chemical shifts of the aromatic part of the molecule were similar to those reported for other N 6 -alkyladenines (45,51). NMR spectra of compounds 2a-base and 2b-base were identical, consistent with their enantiomeric relationship.…”

Section: Resultssupporting

confidence: 82%

Exocyclic Deoxyadenosine Adducts of 1,2,3,4-Diepoxybutane: Synthesis, Structural Elucidation, and Mechanistic Studies

Seneviratne

Antsypovich

Goggin

et al. 2009

Chem. Res. Toxicol.

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Abstract1,2,3,4-Diepoxybutane (DEB)1 is considered the ultimate carcinogenic metabolite of 1,3-butadiene, an important industrial chemical and environmental pollutant present in urban air. Although it preferentially modifies guanine within DNA, DEB induces a large number of A → T transversions, suggesting that it forms strongly mispairing lesions at adenine nucleobases. We now report the discovery of three potentially mispairing exocyclic adenine lesions of DEB:. The structures and stereochemistry of the novel DEB-dA adducts were determined by a combination of UV and NMR spectroscopy, tandem mass spectrometry, and independent synthesis. We found that synthetic N 6 -(2-hydroxy-3,4-epoxybut-1-yl)-2′-deoxyadenosine (compound 1) representing the product of N 6 -adenine alkylation by DEB spontaneously cyclizes to form 3 under aqueous conditions or 2 under anhydrous conditions in the presence of organic base. Compound 3 can be interconverted with 4 by a reversible unimolecular pericyclic reaction favoring 4 as a more thermodynamically stable product. Both 3 and 4 are present in double stranded DNA treated with DEB in vitro and in liver DNA of laboratory mice exposed to 1,3-butadiene by inhalation. We propose that in DNA under physiological conditions, DEB alkylates the N-1 position of adenine in DNA to form N1- (2-hydroxy-3,4-epoxybut-1-yl)adenine adducts, which undergo an S N 2-type intramolecular nucleophilic substitution and rearrangement to give 3 (minor) and 4 (major). Formation of exocyclic DEB-adenine lesions following exposure to 1,3-butadiene provides a possible mechanism of mutagenesis at the A:T base pairs.

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Section: Resultssupporting

confidence: 82%

Exocyclic Deoxyadenosine Adducts of 1,2,3,4-Diepoxybutane: Synthesis, Structural Elucidation, and Mechanistic Studies

Seneviratne

Antsypovich

Goggin

et al. 2009

Chem. Res. Toxicol.

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“…In order to relate further the ultraviolet spectral and p determinations to specific changes in the structure of 8-OH-dG, the positions affected at each pK& were determined by recording 13C NMR spectra at various pH's (Figure 4). The largest effects are due to N1-C6 and N7-C8 ionizations, in accordance with the tautomeric changes that accompany these modifications (26,27). Thus, the C6 resonance exhibited a significant downfield chemical shift of 6.28 ppm from pH 7.4 to 9.3 consistent with the pK&1 (8.6), which confirms the locale of the first ionization.…”

Section: Methodssupporting

confidence: 69%

Structural and conformational analyses of 8-hydroxy-2'-deoxyguanosine

Culp¹,

Cho²,

Kadlubar³

et al. 1989

Chem. Res. Toxicol.

161

124

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Oxidative DNA damage has been shown to involve formation of 8-hydroxy-2'-deoxyguanosine, which may serve as a mispairing lesion during cellular DNA replication. In order to assess the mutagenic potential of this DNA adduct, we examined the possible occurrence of several tautomeric forms and of different base conformations about the deoxyribose. Several spectroscopic and electronic absorption techniques were employed and showed structural changes occurring over a broad pH range. Two pKa's near pH 8 and 12 were observed by pH-solvent partitioning experiments, ultraviolet absorption spectral analyses, and 13C NMR spectroscopic methods. The presence of two pKa's suggested the formation of a dianion, with the second being formed in strong alkali. A comparison of ultraviolet absorption band features of 8-hydroxy-2'-deoxyguanosine with that of different C6,C8-diketo or enol derivatives supported a C8-keto assignment and also provided evidence that this DNA adduct contains a C6-keto group at physiological pH. 13C NMR data showed marked chemical shifts at C6 in solutions of pH 7.4-9.3, indicating the location of the first ionization. Increasing basicity produced further shifts at C5 and C8, indicating the C8 position for the second ionization. Multiple infrared bands were observed in the carbonyl region of the neutral compound, but only a single carbonyl band at 1692 cm-1 remained at pH 9.1, implying a keto group at C8. Determination of the chemical shifts and the nuclear Overhauser enhancements of the N1 and N7 resonances in the proton-decoupled 15N NMR spectrum indicated that both nitrogens were indeed protonated at neutral pH.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…Accumulation of I3C nmr data has shown that C2' of a nucleoside always exhibits a lower chemical shift than C3', contrary to the recent announcement by Chang et al (6) who assigned "C chemical shifts of methylated nucleosides based on wrong assignments of C2' and C3' of adenosine.…”

mentioning

confidence: 82%

Discussion on ¹³C nuclear magnetic resonance spectra of nucleoside derivatives. Reflection of structural alterations on ¹³C chemical shifts

Uzawa¹,

Anzai²

1985

Can. J. Chem.

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¹³C NMR studies of methylnucleosides

Cited by 24 publications

References 21 publications

Exocyclic Deoxyadenosine Adducts of 1,2,3,4-Diepoxybutane: Synthesis, Structural Elucidation, and Mechanistic Studies

Exocyclic Deoxyadenosine Adducts of 1,2,3,4-Diepoxybutane: Synthesis, Structural Elucidation, and Mechanistic Studies

Structural and conformational analyses of 8-hydroxy-2'-deoxyguanosine

Discussion on ¹³C nuclear magnetic resonance spectra of nucleoside derivatives. Reflection of structural alterations on ¹³C chemical shifts

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13C NMR studies of methylnucleosides

Cited by 24 publications

References 21 publications

Exocyclic Deoxyadenosine Adducts of 1,2,3,4-Diepoxybutane: Synthesis, Structural Elucidation, and Mechanistic Studies

Exocyclic Deoxyadenosine Adducts of 1,2,3,4-Diepoxybutane: Synthesis, Structural Elucidation, and Mechanistic Studies

Structural and conformational analyses of 8-hydroxy-2'-deoxyguanosine

Discussion on 13C nuclear magnetic resonance spectra of nucleoside derivatives. Reflection of structural alterations on 13C chemical shifts

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¹³C NMR studies of methylnucleosides

Discussion on ¹³C nuclear magnetic resonance spectra of nucleoside derivatives. Reflection of structural alterations on ¹³C chemical shifts