Synthesis and characterization of site-specific and stereoisomeric fjord dibenzo[a,l]pyrene diol epoxide - N6-adenine adducts: Unusual thermal stabilization of modified DNA duplexes

Qian Ruan, Alexander Kolbanovskiy, Ping Zhuang, Junxin Chen, Jacek Krzeminski, Shantu Amin, Nicholas Geacintov

Research output: Contribution to journalArticle

Abstract

The fjord polycyclic aromatic hydrocarbon compound dibenzo[a,l]pyrene (DB[a,l]P) is significantly more tumorigenic than the bay region benzo[a]pyrene in animal model systems. The molecular origins of the unusually strong genotoxic properties of DB[a,l]P and its fjord region diol epoxide metabolites are of great interest and are believed to be related to the structural characteristics of the DNA adducts formed. Site-specifically modified oligonucleotides were prepared by reacting the single adenine residue in 5′-d(CTCTCACTTCC) (I) with the racemic fjord diol epoxide r11,t12-dihydrodiol-t13,14-epoxide-11,12,13,14-tetrahydrodibenzo-[a,l]pyrene (anti-DB[a,l]PDE) in aqueous solutions. Four different oligonucleotides I with the single adenosine residues involving a covalent bond between the C14 position of DB[a,l]PDE and N6-dA are identified and purified. The CD spectra of the mononucleotide adducts are similar to those of Li et al. [Li et al. (1999) Chem. Res. Toxicol. 12, 758] who characterized DB[a,l]-PDE-N6-dA adducts by a combination of CD and NMR methods. The stereochemical properties of each of the four DB[a,l]PDE-modified oligonucleotides were assigned on the basis of a combination of empirical CD rules and other approaches and differ from those of Li et al. The thermal melting points, Tm, of the unmodified duplex of I with its complementary strand (IC), Tm = 43.8 ± 0.5 °C, were compared with the same duplexes containing stereoisomeric anti-DB[a,l]PDE-N6-dA lesions. The Tm of duplexes I·IC containing lesions with R absolute configurations at C14 of the DB[a,l]PDE residues are greater by 6-8 °C, while those with S configuration are lower by 6-10 °C. Similar effects are observed with adducts in the same sequence context derived from the fjord PAH anti-diol epoxides of benzo[g]chrysene, while duplexes containing lesions derived from benzo[c]phenanthrene diol epoxides with 1R and 1S configurations exhibit unchanged Tm values. In contrast, the Tm values of duplexes with lesions derived from the bay region benzo[a]pyrene diol epoxides (B[a]PDE) in the same sequence are lower by 12° (10R adducts) and by 19° (10S adducts). The greater thermal stabilities of duplexes with fjord PAH-N6-dA lesions relative to those with bay region B[a]PDE-N6-dA adducts, are correlated with lower susceptibilities of excision by human nucleotide excision repair enzymes [Buterin et al. (2000) Cancer Res. 60, 1849]. The implications of these relationships are discussed in terms of present knowledge of the conformations of fjord and bay region PAH diol epoxide-N6-dA lesions in double stranded DNA.

Original languageEnglish (US)
Pages (from-to)249-261
Number of pages13
JournalChemical Research in Toxicology
Volume15
Issue number2
DOIs
StatePublished - 2002

Fingerprint

Estuaries
Epoxy Compounds
Adenine
Stabilization
Hot Temperature
DNA
Benzo(a)pyrene
Polycyclic aromatic hydrocarbons
Oligonucleotides
Polycyclic Aromatic Hydrocarbon Bay-Region
Covalent bonds
DNA Adducts
dibenzo(a,l)pyrene diol epoxide
Polycyclic Aromatic Hydrocarbons
Metabolites
DNA Repair
Adenosine
Freezing
Melting point
Conformations

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Synthesis and characterization of site-specific and stereoisomeric fjord dibenzo[a,l]pyrene diol epoxide - N6-adenine adducts : Unusual thermal stabilization of modified DNA duplexes. / Ruan, Qian; Kolbanovskiy, Alexander; Zhuang, Ping; Chen, Junxin; Krzeminski, Jacek; Amin, Shantu; Geacintov, Nicholas.

In: Chemical Research in Toxicology, Vol. 15, No. 2, 2002, p. 249-261.

Research output: Contribution to journalArticle

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abstract = "The fjord polycyclic aromatic hydrocarbon compound dibenzo[a,l]pyrene (DB[a,l]P) is significantly more tumorigenic than the bay region benzo[a]pyrene in animal model systems. The molecular origins of the unusually strong genotoxic properties of DB[a,l]P and its fjord region diol epoxide metabolites are of great interest and are believed to be related to the structural characteristics of the DNA adducts formed. Site-specifically modified oligonucleotides were prepared by reacting the single adenine residue in 5′-d(CTCTCACTTCC) (I) with the racemic fjord diol epoxide r11,t12-dihydrodiol-t13,14-epoxide-11,12,13,14-tetrahydrodibenzo-[a,l]pyrene (anti-DB[a,l]PDE) in aqueous solutions. Four different oligonucleotides I with the single adenosine residues involving a covalent bond between the C14 position of DB[a,l]PDE and N6-dA are identified and purified. The CD spectra of the mononucleotide adducts are similar to those of Li et al. [Li et al. (1999) Chem. Res. Toxicol. 12, 758] who characterized DB[a,l]-PDE-N6-dA adducts by a combination of CD and NMR methods. The stereochemical properties of each of the four DB[a,l]PDE-modified oligonucleotides were assigned on the basis of a combination of empirical CD rules and other approaches and differ from those of Li et al. The thermal melting points, Tm, of the unmodified duplex of I with its complementary strand (IC), Tm = 43.8 ± 0.5 °C, were compared with the same duplexes containing stereoisomeric anti-DB[a,l]PDE-N6-dA lesions. The Tm of duplexes I·IC containing lesions with R absolute configurations at C14 of the DB[a,l]PDE residues are greater by 6-8 °C, while those with S configuration are lower by 6-10 °C. Similar effects are observed with adducts in the same sequence context derived from the fjord PAH anti-diol epoxides of benzo[g]chrysene, while duplexes containing lesions derived from benzo[c]phenanthrene diol epoxides with 1R and 1S configurations exhibit unchanged Tm values. In contrast, the Tm values of duplexes with lesions derived from the bay region benzo[a]pyrene diol epoxides (B[a]PDE) in the same sequence are lower by 12° (10R adducts) and by 19° (10S adducts). The greater thermal stabilities of duplexes with fjord PAH-N6-dA lesions relative to those with bay region B[a]PDE-N6-dA adducts, are correlated with lower susceptibilities of excision by human nucleotide excision repair enzymes [Buterin et al. (2000) Cancer Res. 60, 1849]. The implications of these relationships are discussed in terms of present knowledge of the conformations of fjord and bay region PAH diol epoxide-N6-dA lesions in double stranded DNA.",
author = "Qian Ruan and Alexander Kolbanovskiy and Ping Zhuang and Junxin Chen and Jacek Krzeminski and Shantu Amin and Nicholas Geacintov",
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T1 - Synthesis and characterization of site-specific and stereoisomeric fjord dibenzo[a,l]pyrene diol epoxide - N6-adenine adducts

T2 - Unusual thermal stabilization of modified DNA duplexes

AU - Ruan, Qian

AU - Kolbanovskiy, Alexander

AU - Zhuang, Ping

AU - Chen, Junxin

AU - Krzeminski, Jacek

AU - Amin, Shantu

AU - Geacintov, Nicholas

PY - 2002

Y1 - 2002

N2 - The fjord polycyclic aromatic hydrocarbon compound dibenzo[a,l]pyrene (DB[a,l]P) is significantly more tumorigenic than the bay region benzo[a]pyrene in animal model systems. The molecular origins of the unusually strong genotoxic properties of DB[a,l]P and its fjord region diol epoxide metabolites are of great interest and are believed to be related to the structural characteristics of the DNA adducts formed. Site-specifically modified oligonucleotides were prepared by reacting the single adenine residue in 5′-d(CTCTCACTTCC) (I) with the racemic fjord diol epoxide r11,t12-dihydrodiol-t13,14-epoxide-11,12,13,14-tetrahydrodibenzo-[a,l]pyrene (anti-DB[a,l]PDE) in aqueous solutions. Four different oligonucleotides I with the single adenosine residues involving a covalent bond between the C14 position of DB[a,l]PDE and N6-dA are identified and purified. The CD spectra of the mononucleotide adducts are similar to those of Li et al. [Li et al. (1999) Chem. Res. Toxicol. 12, 758] who characterized DB[a,l]-PDE-N6-dA adducts by a combination of CD and NMR methods. The stereochemical properties of each of the four DB[a,l]PDE-modified oligonucleotides were assigned on the basis of a combination of empirical CD rules and other approaches and differ from those of Li et al. The thermal melting points, Tm, of the unmodified duplex of I with its complementary strand (IC), Tm = 43.8 ± 0.5 °C, were compared with the same duplexes containing stereoisomeric anti-DB[a,l]PDE-N6-dA lesions. The Tm of duplexes I·IC containing lesions with R absolute configurations at C14 of the DB[a,l]PDE residues are greater by 6-8 °C, while those with S configuration are lower by 6-10 °C. Similar effects are observed with adducts in the same sequence context derived from the fjord PAH anti-diol epoxides of benzo[g]chrysene, while duplexes containing lesions derived from benzo[c]phenanthrene diol epoxides with 1R and 1S configurations exhibit unchanged Tm values. In contrast, the Tm values of duplexes with lesions derived from the bay region benzo[a]pyrene diol epoxides (B[a]PDE) in the same sequence are lower by 12° (10R adducts) and by 19° (10S adducts). The greater thermal stabilities of duplexes with fjord PAH-N6-dA lesions relative to those with bay region B[a]PDE-N6-dA adducts, are correlated with lower susceptibilities of excision by human nucleotide excision repair enzymes [Buterin et al. (2000) Cancer Res. 60, 1849]. The implications of these relationships are discussed in terms of present knowledge of the conformations of fjord and bay region PAH diol epoxide-N6-dA lesions in double stranded DNA.

AB - The fjord polycyclic aromatic hydrocarbon compound dibenzo[a,l]pyrene (DB[a,l]P) is significantly more tumorigenic than the bay region benzo[a]pyrene in animal model systems. The molecular origins of the unusually strong genotoxic properties of DB[a,l]P and its fjord region diol epoxide metabolites are of great interest and are believed to be related to the structural characteristics of the DNA adducts formed. Site-specifically modified oligonucleotides were prepared by reacting the single adenine residue in 5′-d(CTCTCACTTCC) (I) with the racemic fjord diol epoxide r11,t12-dihydrodiol-t13,14-epoxide-11,12,13,14-tetrahydrodibenzo-[a,l]pyrene (anti-DB[a,l]PDE) in aqueous solutions. Four different oligonucleotides I with the single adenosine residues involving a covalent bond between the C14 position of DB[a,l]PDE and N6-dA are identified and purified. The CD spectra of the mononucleotide adducts are similar to those of Li et al. [Li et al. (1999) Chem. Res. Toxicol. 12, 758] who characterized DB[a,l]-PDE-N6-dA adducts by a combination of CD and NMR methods. The stereochemical properties of each of the four DB[a,l]PDE-modified oligonucleotides were assigned on the basis of a combination of empirical CD rules and other approaches and differ from those of Li et al. The thermal melting points, Tm, of the unmodified duplex of I with its complementary strand (IC), Tm = 43.8 ± 0.5 °C, were compared with the same duplexes containing stereoisomeric anti-DB[a,l]PDE-N6-dA lesions. The Tm of duplexes I·IC containing lesions with R absolute configurations at C14 of the DB[a,l]PDE residues are greater by 6-8 °C, while those with S configuration are lower by 6-10 °C. Similar effects are observed with adducts in the same sequence context derived from the fjord PAH anti-diol epoxides of benzo[g]chrysene, while duplexes containing lesions derived from benzo[c]phenanthrene diol epoxides with 1R and 1S configurations exhibit unchanged Tm values. In contrast, the Tm values of duplexes with lesions derived from the bay region benzo[a]pyrene diol epoxides (B[a]PDE) in the same sequence are lower by 12° (10R adducts) and by 19° (10S adducts). The greater thermal stabilities of duplexes with fjord PAH-N6-dA lesions relative to those with bay region B[a]PDE-N6-dA adducts, are correlated with lower susceptibilities of excision by human nucleotide excision repair enzymes [Buterin et al. (2000) Cancer Res. 60, 1849]. The implications of these relationships are discussed in terms of present knowledge of the conformations of fjord and bay region PAH diol epoxide-N6-dA lesions in double stranded DNA.

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