DNA Interchain Cross-Links Formed by Acrolein and Crotonaldehyde (original) (raw)

ArticleDecember 4, 2002

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Journal of the American Chemical Society

Cite this: J. Am. Chem. Soc. 2003, 125, 1

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Published December 4, 2002

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Copyright © 2003 American Chemical Society

Abstract

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Acrolein and higher α,β-unsaturated aldehydes are bifunctional genotoxins. The deoxyguanosine adduct of acrolein, 3-(2-deoxy-β-d-_erythro_-pentofuranosyl)-5,6,7,8-tetrahydro-8-hydroxypyrimido[1,2-a_]purin-10(3_H)-one (8-hydroxy-1,_N_2-propanodeoxyguanosine, 2a), is a major DNA adduct formed by acrolein. The potential for oligodeoxynucleotide duplexes containing 2a to form interchain cross-links was evaluated by HPLC, CZE, MALDI-TOF, and melting phenomena. Interchain cross-links represent one of the most serious types of damage in DNA since they are absolute blocks to replication. In oligodeoxynucleotides containing the sequence 5‘-dC-2a, cross-linking occurred in a slow, reversible manner to the extent of ∼50%. Enzymatic digestion to form 3-(2-deoxy-β-d-_erythro_-pentofuranosyl)_-_5,6,7,8-tetrahydro-8-(N_2-2‘-deoxyguanosinyl)pyrimido[1,2-a_]purin-10(3_H)one (5a) and reduction with NaCNBH3 followed by enzymatic digestion to give 1,3-bis(2‘-deoxyguanosin-N_2-yl)propane (6a) established that cross-linking had occurred with the exocyclic amino group of deoxyguanosine. It is concluded that the cross-link is a mixture of imine and carbinolamine structures. With oligodeoxynucleotide duplexes containing the sequence 5‘-2a-dC, cross-links were not detected by the techniques enumerated above. In addition, 15N−1H HSQC and HSQC-filtered NOESY spectra carried out with a duplex having 15N-labeling of the target amino group established unambiguously that a carbinolamine cross-link was not formed. The potential for interchain cross-link formation by the analogous crotonaldehyde adduct (2b) was evaluated in a 5‘-dC-2b sequence. Cross-link formation was strongly dependent on the configuration of the methyl group at C6 of 2b. The 6_R diastereomer of 2b formed a cross-link to the extent of 38%, whereas the 6_S diastereomer cross-linked only 5%.

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1H NMR spectra of compounds 5b (6_R_ and 6_S_ diastereomers) and 6b (1_R_ and 1_S_ diastereomers) and 7a and 7b (1_R_ and 1_S_ distereomers) (PDF). This material is available free of charge via the Internet at http://pubs.acs.org.

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Published December 4, 2002

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