Dioxododecenoic acid: A lipid hydroperoxide-derived bifunctional electrophile responsible for etheno DNA adduct formation

Seon Hwa Lee, Maria V.Silva Elipe, Jasbir S. Arora, Ian A. Blair

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)

Abstract

It has been proposed that 13(S)-hydroperoxy-9Z,11E-octadecadienoic acid [13(S)-HPODE]-mediated formation of 4-oxo-2(E)-nonenal and 4-hydroxy-2(E)- nonenal arises from a Hock rearrangement. This suggested that a 4-oxo-2(E)-nonenal-related molecule, 9,12-dioxo-10(E)-dodecenoic acid (DODE), could also result from the intermediate formation of 9-hydroperoxy-12-oxo-10(E)- dodecenoic acid. A recent report has described the formation of DODE-derived etheno adducts when 13(S)-HPODE was allowed to decompose in the presence of 2′-deoxynucleosides or DNA. However, the regioselectivity of lipid hydroperoxide-derived DODE addition to 2′-deoxyguanosine (dGuo) or other 2′-deoxynucleosides was not determined. The structure of carboxynonanone-etheno-dGuo formed from vitamin C-mediated 13(S)-HPODE decomposition has now been established by a combination of 1H and 13C NMR spectroscopy studies of its bis-methylated derivative. The site of dGuo methylation was first established as being at N-5 rather than at O-9 from NMR analysis of a methyl derivative of the model compound, heptanone-etheno-dGuo. 1H,13C 2D heteronuclear multiple bond correlations were then used to establish unequivocally that the bis-methyl derivative of carboxynonanone-ethenod-Guo was 3-(2′-deoxy-β-D- erythropentafuranosyl)imidazo-7-(9″-carboxymethylnona-2″-one) -9-oxo-5-N-methyl[1,2-α]purine rather than its 6-(9″- carboxymethylnona-2″-one)-9-oxo-5-N-methyl-[1,2-α]purine regioisomer. Therefore, etheno adduct formation occurred by initial nucleophilic attack of the exocyclic N2 amino group of dGuo at the C-12 aldehyde of DODE to form an unstable carbinolamine intermediate. This was followed by intramolecular Michael addition of the pyrimidine N1 of dGuo to C-11 of the resulting α,β-unsaturated ketone. Subsequent dehydration gave 3-(2′-deoxy-β-D-erythropentafuranosyl)imidazo-7-(9″- carboxynona-2″-one)-9-oxo-[1,2-α]purine (carboxynonanone-etheno- dGuo). An efficient synthesis of DODE was developed starting from readily available 1,8-octanediol using a furan homologation procedure. This synthetic method allowed multigram quantities of DODE to be readily prepared. Synthetic DODE when reacted with dGuo gave carboxynonanone-etheno-dGuo that was identical with that derived from vitamin C-mediated 13(S)-HPODE decomposition in the presence of dGuo.

Original languageEnglish
Pages (from-to)566-578
Number of pages13
JournalChemical Research in Toxicology
Volume18
Issue number3
DOIs
Publication statusPublished - 2005 Mar 1
Externally publishedYes

ASJC Scopus subject areas

  • Toxicology

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