Journal Article

Site-specific adducts derived from the binding of <i>anti</i>-5-methylchrysene diol epoxide enantiomers to DNA: Synthesis and characteristics

Rong Xu, Sulatha Dwarakanath, Monique Cosman, Shantu Amin and Nicholas E. Geacintov

in Carcinogenesis

Volume 17, issue 9, pages 2035-2042
Published in print September 1996 | ISSN: 0143-3334
Published online September 1996 | e-ISSN: 1460-2180 | DOI:
Site-specific adducts derived from the binding of
                        anti-5-methylchrysene diol epoxide enantiomers to DNA:
                    Synthesis and characteristics

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The direct synthesis and characterization of site-specific adducts derived from the binding of ( + )-1R, 2S-dihydroxy-3S, 4R-epoxide-l,2,3,4-tetrahydro-5-methylchrysene and the ( − )-1S, 2R, 3R, 4S-enantiomer [( + )- and ( − )-5-MeCDE, respectively], to the N2-guanine residues in the oligonucleo-tide d(CCATCGCTACC) are described. The spectroscopic characteristics of the 5-MeCDE-modified oligonucleotides are discussed, and it is shown that their CD characteristics can be used to distinguish between the trans-addition products of the binding of the ( + )- and ( − )-enantiomers of 5-MeCDE (C4 position). The 11-mer duplexes with the normal complementary strands are destabilized by the site-specific, covalently bound 5-MeCDE residues: the melting points, Tm, are 5-10° lower than in the case of the unmodified duplex. Stereoselective exonuclease enzyme digestion patterns of the single-stranded ( + )- and ( − )-trans-5-MeCDE-modified oligonucleotides (Mao et al., 1993, Biochemistry, 32, 11785-11793) were used to probe the orientations of the covalently bound 5-MeCDE residues relative to the modified guanine and the 5'-3' strand polarity, the aromatic residues are positioned either on the 5'-side [( + )-5-MeCDE], or the 3-side [( − )-5-MeCDE adduct] of the modified guanine residues. The electrophoretic mobilities of the ( + )-5-MeCDE-modified 11-mer duplexes in native polyacrylamide gels are slower than those of unmodified and modified duplexes containing the stereoisomeric ( − )-5-MeCDE-N2-dG lesions. This indicates that the lesions derived from the tumorigenic ( + )-5-MeCDE induce greater degrees of bending or local flexibility than the non-tumor-igenic ( − )-5- MeCDE enantiomer. These differences in the orientational and structural characteristics are similar to those observed with analogous DNA adducts derived from the tumorigenic ( + )-7R, 8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[α]pyrene and the non-tumor-igenic 7S,8R,9R,10S-enantiomer, respectively. The adducts derived from BPDE and 5-MeCDE enantiomers thus display similar characteristics that depend primarily on the PAH diol epoxide enantiomer stereochemistry. This direct synthesis approach can be used to generate milligram quantities of site-specific 5-MeCDE-modified oligonucleotides that are suitable for NMR studies (Cosman et al., 1995, Biochemistry, 34, 6247-6260).

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Subjects: Clinical Cytogenetics and Molecular Genetics

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