Synthesis and Structure Determination of the Adducts of the Potent Carcinogen 7,12-Dimethylbenz[a]anthracene and Deoxyribonucleosides Formed by Electrochemical Oxidation: Models for Metabolic Activation by One-Electron Oxidation

N. V S Ramakrishna, Ercole Cavalieri, Eleanor G Rogan, G. Dolnikowski, Ronald Cerny, M. L. Gross, H. Jeong, R. Jankowiak, G. J. Small

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Abstract

Anodic oxidation of 7,12-dimethylbenz[a]anthracene (7,12-DMBA) in the presence of dG yields four adducts and one oxygenated derivative of 7,12-DMBA: 7-methylbenz[a]anthracene (MBA)-12-CH2-C8dG (13%), 7-MBA-12-CH2-N7Gua (55%), 12-MBA-7-CH2-N7Gua (12%), 7-MBA-12-CH2-C8Gua (10%), and 7,12-(CH2OH)2-BA (10%). The first three are primary products of the electrochemical reaction, whereas the last two are secondary products. Binding occurs predominantly at the 12-CH3 group of 7,12-DMBA and specifically to the N-7 and C-8 of Gua. On the other hand, anodic oxidation of 7.12-DMBA in the presence of dA gives only two detectable adducts: 7-MBA-12-CH2-N7Ade (45%) and 12-MBA-7-CH2-N3Ade (55%). Binding at the 12-CH3 group is specific for the N-7 of Ade, whereas the 7-CH3 group of 7,12-DMBA is specific for the N-3 of Ade. Structures of the adducts were elucidated by NMR and fast atom bombardment tandem mass spectrometry (FAB MS/MS). The adducts were also investigated by fluorescence line narrowing spectroscopy (FLNS). Both the FAB MS/MS and FLNS techniques can be used to distinguish between the adducts formed at the 7-CH3 and 12-CH3 groups of 7.12-DMBA (i.e., between 7-MBA-12-CH2-N7Gua and 12-MBA-7-CH2-N7Gua and between 7-MBA-12-CH2-N7Gua and 7-MBA-12-CH2-C8Gua). FLNS can distinguish 12-MBA-7-CH2-N3Ade from 7-MBA-12-CH2-N7Ade. On the other hand, the distinction between 7-MBA-12-CH2-C8Gua and 7-MBA-12-CH02-C8dG is straightforward by FAB MS but very difficult by FLNS. The electrochemical synthesis not only provides a demonstration of the specific reactivity of nucleosides and 7,12-DMBA under oxidizing conditions but is also a source of the necessary reference materials for studying the 7,12-DMBA-DNA adducts formed in biological systems. Furthermore, the analytical methodology is now appropriate for supporting in vivo studies of 7.12-DMBA-DNA adducts. A mechanism is proposed, although there are not sufficient data to prove it.

Original languageEnglish (US)
Pages (from-to)1863-1874
Number of pages12
JournalJournal of the American Chemical Society
Volume114
Issue number5
DOIs
StatePublished - Feb 1 1992

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Deoxyribonucleosides
Carcinogens
Anthracene
Electrochemical oxidation
Fluorescence
Chemical activation
Spectroscopy
Electrons
Spectrum Analysis
Oxidation
9,10-Dimethyl-1,2-benzanthracene
Anodic oxidation
Fast Atom Bombardment Mass Spectrometry
Biological systems
Nucleosides
Mass spectrometry
Tandem Mass Spectrometry
Demonstrations
Nuclear magnetic resonance
Derivatives

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

@article{3fe4b449706d43f4835f648ca66b68cd,
title = "Synthesis and Structure Determination of the Adducts of the Potent Carcinogen 7,12-Dimethylbenz[a]anthracene and Deoxyribonucleosides Formed by Electrochemical Oxidation: Models for Metabolic Activation by One-Electron Oxidation",
abstract = "Anodic oxidation of 7,12-dimethylbenz[a]anthracene (7,12-DMBA) in the presence of dG yields four adducts and one oxygenated derivative of 7,12-DMBA: 7-methylbenz[a]anthracene (MBA)-12-CH2-C8dG (13{\%}), 7-MBA-12-CH2-N7Gua (55{\%}), 12-MBA-7-CH2-N7Gua (12{\%}), 7-MBA-12-CH2-C8Gua (10{\%}), and 7,12-(CH2OH)2-BA (10{\%}). The first three are primary products of the electrochemical reaction, whereas the last two are secondary products. Binding occurs predominantly at the 12-CH3 group of 7,12-DMBA and specifically to the N-7 and C-8 of Gua. On the other hand, anodic oxidation of 7.12-DMBA in the presence of dA gives only two detectable adducts: 7-MBA-12-CH2-N7Ade (45{\%}) and 12-MBA-7-CH2-N3Ade (55{\%}). Binding at the 12-CH3 group is specific for the N-7 of Ade, whereas the 7-CH3 group of 7,12-DMBA is specific for the N-3 of Ade. Structures of the adducts were elucidated by NMR and fast atom bombardment tandem mass spectrometry (FAB MS/MS). The adducts were also investigated by fluorescence line narrowing spectroscopy (FLNS). Both the FAB MS/MS and FLNS techniques can be used to distinguish between the adducts formed at the 7-CH3 and 12-CH3 groups of 7.12-DMBA (i.e., between 7-MBA-12-CH2-N7Gua and 12-MBA-7-CH2-N7Gua and between 7-MBA-12-CH2-N7Gua and 7-MBA-12-CH2-C8Gua). FLNS can distinguish 12-MBA-7-CH2-N3Ade from 7-MBA-12-CH2-N7Ade. On the other hand, the distinction between 7-MBA-12-CH2-C8Gua and 7-MBA-12-CH02-C8dG is straightforward by FAB MS but very difficult by FLNS. The electrochemical synthesis not only provides a demonstration of the specific reactivity of nucleosides and 7,12-DMBA under oxidizing conditions but is also a source of the necessary reference materials for studying the 7,12-DMBA-DNA adducts formed in biological systems. Furthermore, the analytical methodology is now appropriate for supporting in vivo studies of 7.12-DMBA-DNA adducts. A mechanism is proposed, although there are not sufficient data to prove it.",
author = "Ramakrishna, {N. V S} and Ercole Cavalieri and Rogan, {Eleanor G} and G. Dolnikowski and Ronald Cerny and Gross, {M. L.} and H. Jeong and R. Jankowiak and Small, {G. J.}",
year = "1992",
month = "2",
day = "1",
doi = "10.1021/ja00031a047",
language = "English (US)",
volume = "114",
pages = "1863--1874",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "American Chemical Society",
number = "5",

}

TY - JOUR

T1 - Synthesis and Structure Determination of the Adducts of the Potent Carcinogen 7,12-Dimethylbenz[a]anthracene and Deoxyribonucleosides Formed by Electrochemical Oxidation

T2 - Models for Metabolic Activation by One-Electron Oxidation

AU - Ramakrishna, N. V S

AU - Cavalieri, Ercole

AU - Rogan, Eleanor G

AU - Dolnikowski, G.

AU - Cerny, Ronald

AU - Gross, M. L.

AU - Jeong, H.

AU - Jankowiak, R.

AU - Small, G. J.

PY - 1992/2/1

Y1 - 1992/2/1

N2 - Anodic oxidation of 7,12-dimethylbenz[a]anthracene (7,12-DMBA) in the presence of dG yields four adducts and one oxygenated derivative of 7,12-DMBA: 7-methylbenz[a]anthracene (MBA)-12-CH2-C8dG (13%), 7-MBA-12-CH2-N7Gua (55%), 12-MBA-7-CH2-N7Gua (12%), 7-MBA-12-CH2-C8Gua (10%), and 7,12-(CH2OH)2-BA (10%). The first three are primary products of the electrochemical reaction, whereas the last two are secondary products. Binding occurs predominantly at the 12-CH3 group of 7,12-DMBA and specifically to the N-7 and C-8 of Gua. On the other hand, anodic oxidation of 7.12-DMBA in the presence of dA gives only two detectable adducts: 7-MBA-12-CH2-N7Ade (45%) and 12-MBA-7-CH2-N3Ade (55%). Binding at the 12-CH3 group is specific for the N-7 of Ade, whereas the 7-CH3 group of 7,12-DMBA is specific for the N-3 of Ade. Structures of the adducts were elucidated by NMR and fast atom bombardment tandem mass spectrometry (FAB MS/MS). The adducts were also investigated by fluorescence line narrowing spectroscopy (FLNS). Both the FAB MS/MS and FLNS techniques can be used to distinguish between the adducts formed at the 7-CH3 and 12-CH3 groups of 7.12-DMBA (i.e., between 7-MBA-12-CH2-N7Gua and 12-MBA-7-CH2-N7Gua and between 7-MBA-12-CH2-N7Gua and 7-MBA-12-CH2-C8Gua). FLNS can distinguish 12-MBA-7-CH2-N3Ade from 7-MBA-12-CH2-N7Ade. On the other hand, the distinction between 7-MBA-12-CH2-C8Gua and 7-MBA-12-CH02-C8dG is straightforward by FAB MS but very difficult by FLNS. The electrochemical synthesis not only provides a demonstration of the specific reactivity of nucleosides and 7,12-DMBA under oxidizing conditions but is also a source of the necessary reference materials for studying the 7,12-DMBA-DNA adducts formed in biological systems. Furthermore, the analytical methodology is now appropriate for supporting in vivo studies of 7.12-DMBA-DNA adducts. A mechanism is proposed, although there are not sufficient data to prove it.

AB - Anodic oxidation of 7,12-dimethylbenz[a]anthracene (7,12-DMBA) in the presence of dG yields four adducts and one oxygenated derivative of 7,12-DMBA: 7-methylbenz[a]anthracene (MBA)-12-CH2-C8dG (13%), 7-MBA-12-CH2-N7Gua (55%), 12-MBA-7-CH2-N7Gua (12%), 7-MBA-12-CH2-C8Gua (10%), and 7,12-(CH2OH)2-BA (10%). The first three are primary products of the electrochemical reaction, whereas the last two are secondary products. Binding occurs predominantly at the 12-CH3 group of 7,12-DMBA and specifically to the N-7 and C-8 of Gua. On the other hand, anodic oxidation of 7.12-DMBA in the presence of dA gives only two detectable adducts: 7-MBA-12-CH2-N7Ade (45%) and 12-MBA-7-CH2-N3Ade (55%). Binding at the 12-CH3 group is specific for the N-7 of Ade, whereas the 7-CH3 group of 7,12-DMBA is specific for the N-3 of Ade. Structures of the adducts were elucidated by NMR and fast atom bombardment tandem mass spectrometry (FAB MS/MS). The adducts were also investigated by fluorescence line narrowing spectroscopy (FLNS). Both the FAB MS/MS and FLNS techniques can be used to distinguish between the adducts formed at the 7-CH3 and 12-CH3 groups of 7.12-DMBA (i.e., between 7-MBA-12-CH2-N7Gua and 12-MBA-7-CH2-N7Gua and between 7-MBA-12-CH2-N7Gua and 7-MBA-12-CH2-C8Gua). FLNS can distinguish 12-MBA-7-CH2-N3Ade from 7-MBA-12-CH2-N7Ade. On the other hand, the distinction between 7-MBA-12-CH2-C8Gua and 7-MBA-12-CH02-C8dG is straightforward by FAB MS but very difficult by FLNS. The electrochemical synthesis not only provides a demonstration of the specific reactivity of nucleosides and 7,12-DMBA under oxidizing conditions but is also a source of the necessary reference materials for studying the 7,12-DMBA-DNA adducts formed in biological systems. Furthermore, the analytical methodology is now appropriate for supporting in vivo studies of 7.12-DMBA-DNA adducts. A mechanism is proposed, although there are not sufficient data to prove it.

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