Synthesis and structure determination of the adducts formed by electrochemical oxidation of 1,2,3,4-tetrahydro-7,12- dimethylbenz[a]anthracene in the presence of deoxyribonucleosides or adenine

Patrick P J Mulder, Liang Chen, B. Chandra Sekhar, Mathai George, Michael L. Gross, Eleanor G Rogan, Ercole Cavalieri

Research output: Contribution to journalArticle

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Abstract

Study of DNA adducts formed with aromatic hydrocarbons is part of the strategy to elucidate the mechanisms of tumor initiation by these compounds. 1,2,3,4-Tetrahydro-7,12-dimethylbenz-[a]anthracene (THDMBA) is of special interest because it allows discrimination between the pathways of bioactivation by one-electron oxidation and monooxygenation. To study and identify adducts formed biologically, synthetic adducts are needed as reference standards. THDMBA was electrochemically oxidized in the presence of deoxyadenosine (dA), adenine (Ade), deoxyguanosine (dG), or deoxycytidine (dC). In the presence of dA, four adducts were isolated: 7-methyl-1,2,3,4- tetrahydrobenz[a]anthracene-12-CH2-N7Ade (7-MTHBA-12-CH2-N7Ade, 3.6%), 12- MTHBA-7-CH2-N7Ade (4.2%), 7-MTHBA-12-CH2-N6dA (5.8%), and 12-exo- methylene-7-MTHBA-7-N6dA (22.8%); a dehydrogenated product, 7, 12-di-exo- methylene-THBA (44.2%), was also obtained. In the presence of Ade, nine adducts were synthesized: 7-MTHBA-12-CH2-N7Ade (1.1%), 12-MTHBA-7-CH2- N7Ade (2.4%), 7-MTHBA-12-CH2-N1Ade (10.2%), 12-MTHBA-7-CH2-N1Ade (13.2%), 7-MTHBA-12-CH2-N3Ade (1.7%), 12-MTHBA-7-CH2-N3Ade (1.7%), 7-exo-methylene- 12-MTHBA-12-N3Ade (11.2%), 12-exo-methylene-7-MTHBA-7-N3Ade (27.9%), and 12- exo-methylene-7-MTHBA-7-N6Ade (12.1%), as well as the dehydrogenated product 7, 12-di-exo-methylene-THBA (16.7%). In the presence of dG, three adducts were produced: 7-MTHBA-12-CH2-N7Gua (24.2%), 12-MTHBA-7-CH2-N7Gua (12.2%), and 7-MTHBA-12-CH2-N2dG (3.7%), as well as the dehydrogenated product 7,12- di-exo-methylene-THBA (38.9%). Anodic oxidation in the presence of dC yielded a large amount of 7,12-di-exo-methylene-THBA (80.4%), but no adducts. The structure of the adducts was elucidated by using UV, NMR, and MS. The N-7 positions in dG, dA, and Ade, the 2-NH2 in dG, and the N-1 position in Ade form exclusively methyl-linked adducts. In contrast, the 6-NH2 group of dA and Ade and the N-3 of Ade prefer to attack the meso-anthracenic positions rather than the methyl groups. The order of reactivity of dG and dA in the formation of methyl-linked THDMBA adducts agrees well with that previously found for 7,12-dimethylbenz[a]anthracene [RamaKrishna et al. (1992) J. Am. Chem. Soc. 114, 1863-1874].

Original languageEnglish (US)
Pages (from-to)1264-1277
Number of pages14
JournalChemical Research in Toxicology
Volume9
Issue number8
DOIs
StatePublished - Dec 14 1996

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Deoxyadenosines
Deoxyribonucleosides
Electrochemical oxidation
Adenine
Deoxyguanosine
Deoxycytidine
Aromatic Hydrocarbons
DNA Adducts
Anodic oxidation
1,2,3,4-tetrahydro-7,12-dimethylbenz(a)anthracene
Tumors
Nuclear magnetic resonance
2'-deoxyadenosine
Electrons
Oxidation
tetrahydrobenzo-4,6-dimethylangelicin
anthracene

ASJC Scopus subject areas

  • Toxicology

Cite this

Synthesis and structure determination of the adducts formed by electrochemical oxidation of 1,2,3,4-tetrahydro-7,12- dimethylbenz[a]anthracene in the presence of deoxyribonucleosides or adenine. / Mulder, Patrick P J; Chen, Liang; Sekhar, B. Chandra; George, Mathai; Gross, Michael L.; Rogan, Eleanor G; Cavalieri, Ercole.

In: Chemical Research in Toxicology, Vol. 9, No. 8, 14.12.1996, p. 1264-1277.

Research output: Contribution to journalArticle

@article{d75f2a920dfd4c408c29ed0a48e1fae8,
title = "Synthesis and structure determination of the adducts formed by electrochemical oxidation of 1,2,3,4-tetrahydro-7,12- dimethylbenz[a]anthracene in the presence of deoxyribonucleosides or adenine",
abstract = "Study of DNA adducts formed with aromatic hydrocarbons is part of the strategy to elucidate the mechanisms of tumor initiation by these compounds. 1,2,3,4-Tetrahydro-7,12-dimethylbenz-[a]anthracene (THDMBA) is of special interest because it allows discrimination between the pathways of bioactivation by one-electron oxidation and monooxygenation. To study and identify adducts formed biologically, synthetic adducts are needed as reference standards. THDMBA was electrochemically oxidized in the presence of deoxyadenosine (dA), adenine (Ade), deoxyguanosine (dG), or deoxycytidine (dC). In the presence of dA, four adducts were isolated: 7-methyl-1,2,3,4- tetrahydrobenz[a]anthracene-12-CH2-N7Ade (7-MTHBA-12-CH2-N7Ade, 3.6{\%}), 12- MTHBA-7-CH2-N7Ade (4.2{\%}), 7-MTHBA-12-CH2-N6dA (5.8{\%}), and 12-exo- methylene-7-MTHBA-7-N6dA (22.8{\%}); a dehydrogenated product, 7, 12-di-exo- methylene-THBA (44.2{\%}), was also obtained. In the presence of Ade, nine adducts were synthesized: 7-MTHBA-12-CH2-N7Ade (1.1{\%}), 12-MTHBA-7-CH2- N7Ade (2.4{\%}), 7-MTHBA-12-CH2-N1Ade (10.2{\%}), 12-MTHBA-7-CH2-N1Ade (13.2{\%}), 7-MTHBA-12-CH2-N3Ade (1.7{\%}), 12-MTHBA-7-CH2-N3Ade (1.7{\%}), 7-exo-methylene- 12-MTHBA-12-N3Ade (11.2{\%}), 12-exo-methylene-7-MTHBA-7-N3Ade (27.9{\%}), and 12- exo-methylene-7-MTHBA-7-N6Ade (12.1{\%}), as well as the dehydrogenated product 7, 12-di-exo-methylene-THBA (16.7{\%}). In the presence of dG, three adducts were produced: 7-MTHBA-12-CH2-N7Gua (24.2{\%}), 12-MTHBA-7-CH2-N7Gua (12.2{\%}), and 7-MTHBA-12-CH2-N2dG (3.7{\%}), as well as the dehydrogenated product 7,12- di-exo-methylene-THBA (38.9{\%}). Anodic oxidation in the presence of dC yielded a large amount of 7,12-di-exo-methylene-THBA (80.4{\%}), but no adducts. The structure of the adducts was elucidated by using UV, NMR, and MS. The N-7 positions in dG, dA, and Ade, the 2-NH2 in dG, and the N-1 position in Ade form exclusively methyl-linked adducts. In contrast, the 6-NH2 group of dA and Ade and the N-3 of Ade prefer to attack the meso-anthracenic positions rather than the methyl groups. The order of reactivity of dG and dA in the formation of methyl-linked THDMBA adducts agrees well with that previously found for 7,12-dimethylbenz[a]anthracene [RamaKrishna et al. (1992) J. Am. Chem. Soc. 114, 1863-1874].",
author = "Mulder, {Patrick P J} and Liang Chen and Sekhar, {B. Chandra} and Mathai George and Gross, {Michael L.} and Rogan, {Eleanor G} and Ercole Cavalieri",
year = "1996",
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TY - JOUR

T1 - Synthesis and structure determination of the adducts formed by electrochemical oxidation of 1,2,3,4-tetrahydro-7,12- dimethylbenz[a]anthracene in the presence of deoxyribonucleosides or adenine

AU - Mulder, Patrick P J

AU - Chen, Liang

AU - Sekhar, B. Chandra

AU - George, Mathai

AU - Gross, Michael L.

AU - Rogan, Eleanor G

AU - Cavalieri, Ercole

PY - 1996/12/14

Y1 - 1996/12/14

N2 - Study of DNA adducts formed with aromatic hydrocarbons is part of the strategy to elucidate the mechanisms of tumor initiation by these compounds. 1,2,3,4-Tetrahydro-7,12-dimethylbenz-[a]anthracene (THDMBA) is of special interest because it allows discrimination between the pathways of bioactivation by one-electron oxidation and monooxygenation. To study and identify adducts formed biologically, synthetic adducts are needed as reference standards. THDMBA was electrochemically oxidized in the presence of deoxyadenosine (dA), adenine (Ade), deoxyguanosine (dG), or deoxycytidine (dC). In the presence of dA, four adducts were isolated: 7-methyl-1,2,3,4- tetrahydrobenz[a]anthracene-12-CH2-N7Ade (7-MTHBA-12-CH2-N7Ade, 3.6%), 12- MTHBA-7-CH2-N7Ade (4.2%), 7-MTHBA-12-CH2-N6dA (5.8%), and 12-exo- methylene-7-MTHBA-7-N6dA (22.8%); a dehydrogenated product, 7, 12-di-exo- methylene-THBA (44.2%), was also obtained. In the presence of Ade, nine adducts were synthesized: 7-MTHBA-12-CH2-N7Ade (1.1%), 12-MTHBA-7-CH2- N7Ade (2.4%), 7-MTHBA-12-CH2-N1Ade (10.2%), 12-MTHBA-7-CH2-N1Ade (13.2%), 7-MTHBA-12-CH2-N3Ade (1.7%), 12-MTHBA-7-CH2-N3Ade (1.7%), 7-exo-methylene- 12-MTHBA-12-N3Ade (11.2%), 12-exo-methylene-7-MTHBA-7-N3Ade (27.9%), and 12- exo-methylene-7-MTHBA-7-N6Ade (12.1%), as well as the dehydrogenated product 7, 12-di-exo-methylene-THBA (16.7%). In the presence of dG, three adducts were produced: 7-MTHBA-12-CH2-N7Gua (24.2%), 12-MTHBA-7-CH2-N7Gua (12.2%), and 7-MTHBA-12-CH2-N2dG (3.7%), as well as the dehydrogenated product 7,12- di-exo-methylene-THBA (38.9%). Anodic oxidation in the presence of dC yielded a large amount of 7,12-di-exo-methylene-THBA (80.4%), but no adducts. The structure of the adducts was elucidated by using UV, NMR, and MS. The N-7 positions in dG, dA, and Ade, the 2-NH2 in dG, and the N-1 position in Ade form exclusively methyl-linked adducts. In contrast, the 6-NH2 group of dA and Ade and the N-3 of Ade prefer to attack the meso-anthracenic positions rather than the methyl groups. The order of reactivity of dG and dA in the formation of methyl-linked THDMBA adducts agrees well with that previously found for 7,12-dimethylbenz[a]anthracene [RamaKrishna et al. (1992) J. Am. Chem. Soc. 114, 1863-1874].

AB - Study of DNA adducts formed with aromatic hydrocarbons is part of the strategy to elucidate the mechanisms of tumor initiation by these compounds. 1,2,3,4-Tetrahydro-7,12-dimethylbenz-[a]anthracene (THDMBA) is of special interest because it allows discrimination between the pathways of bioactivation by one-electron oxidation and monooxygenation. To study and identify adducts formed biologically, synthetic adducts are needed as reference standards. THDMBA was electrochemically oxidized in the presence of deoxyadenosine (dA), adenine (Ade), deoxyguanosine (dG), or deoxycytidine (dC). In the presence of dA, four adducts were isolated: 7-methyl-1,2,3,4- tetrahydrobenz[a]anthracene-12-CH2-N7Ade (7-MTHBA-12-CH2-N7Ade, 3.6%), 12- MTHBA-7-CH2-N7Ade (4.2%), 7-MTHBA-12-CH2-N6dA (5.8%), and 12-exo- methylene-7-MTHBA-7-N6dA (22.8%); a dehydrogenated product, 7, 12-di-exo- methylene-THBA (44.2%), was also obtained. In the presence of Ade, nine adducts were synthesized: 7-MTHBA-12-CH2-N7Ade (1.1%), 12-MTHBA-7-CH2- N7Ade (2.4%), 7-MTHBA-12-CH2-N1Ade (10.2%), 12-MTHBA-7-CH2-N1Ade (13.2%), 7-MTHBA-12-CH2-N3Ade (1.7%), 12-MTHBA-7-CH2-N3Ade (1.7%), 7-exo-methylene- 12-MTHBA-12-N3Ade (11.2%), 12-exo-methylene-7-MTHBA-7-N3Ade (27.9%), and 12- exo-methylene-7-MTHBA-7-N6Ade (12.1%), as well as the dehydrogenated product 7, 12-di-exo-methylene-THBA (16.7%). In the presence of dG, three adducts were produced: 7-MTHBA-12-CH2-N7Gua (24.2%), 12-MTHBA-7-CH2-N7Gua (12.2%), and 7-MTHBA-12-CH2-N2dG (3.7%), as well as the dehydrogenated product 7,12- di-exo-methylene-THBA (38.9%). Anodic oxidation in the presence of dC yielded a large amount of 7,12-di-exo-methylene-THBA (80.4%), but no adducts. The structure of the adducts was elucidated by using UV, NMR, and MS. The N-7 positions in dG, dA, and Ade, the 2-NH2 in dG, and the N-1 position in Ade form exclusively methyl-linked adducts. In contrast, the 6-NH2 group of dA and Ade and the N-3 of Ade prefer to attack the meso-anthracenic positions rather than the methyl groups. The order of reactivity of dG and dA in the formation of methyl-linked THDMBA adducts agrees well with that previously found for 7,12-dimethylbenz[a]anthracene [RamaKrishna et al. (1992) J. Am. Chem. Soc. 114, 1863-1874].

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