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An unusual DNA adduct derived from the powerfully mutagenic environmental contaminant 3-nitrobenzanthrone
T Enya1, M Kawanishi, H Suzuki
1Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan. Community Environmental Science,
Abstract:
The covalent binding of an N-hydroxy metabolite of the powerfully mutagenic 3-nitrobenzanthrone (NBA) to 2'-deoxyguanosine (dG) and calf thymus DNA has been investigated in vitro. The major adduct obtained from the reaction of the N-acetoxy-N-acetyl derivative (N-Aco-N-Ac-ABA) of 3-aminobenzanthrone (ABA) and dG was identified as N-acetyl-3-amino-2-(2'-deoxyguanosin-8-yl)benzanthrone (dG-N-Ac-ABA) by 1H NMR and mass spectroscopies as well as by the reaction of N-Aco-N-Ac-ABA with the double-stranded calf thymus DNA. The coupling with the dG moiety occurred exclusively at C-2 of benzanthrone (BA), suggesting a significant contribution of a resonance-stabilized arenium ion intermediate derived from BA to the production of this new type of adduct. The preferred conformation of the adduct has been shown to be syn by 1H and 13C NMR.
Insights
Researchers investigated the binding of a mutagenic 3-nitrobenzanthrone (NBA) metabolite to DNA. They identified a new DNA adduct, N-acetyl-3-amino-2-(2'-deoxyguanosin-8-yl)benzanthrone (dG-N-Ac-ABA), formed via covalent binding.
Area of Science:
- Chemical carcinogenesis
- DNA adducts
- Organic chemistry
Background:
- 3-Nitrobenzanthrone (NBA) is a potent mutagen.
- Metabolites of NBA can covalently bind to DNA, forming adducts.
- Understanding these interactions is crucial for assessing mutagenic risk.
Purpose of the Study:
- To investigate the in vitro covalent binding of an N-hydroxy metabolite of 3-nitrobenzanthrone (NBA) to 2'-deoxyguanosine (dG) and calf thymus DNA.
- To characterize the structure and formation mechanism of the resulting DNA adducts.
Main Methods:
- In vitro reaction of N-acetoxy-N-acetyl derivative (N-Aco-N-Ac-ABA) of 3-aminobenzanthrone (ABA) with 2'-deoxyguanosine (dG).
- Reaction with double-stranded calf thymus DNA.
- Structural elucidation using 1H NMR and mass spectrometry.
Main Results:
- The major adduct formed was identified as N-acetyl-3-amino-2-(2 -deoxyguanosin-8-yl)benzanthrone (dG-N-Ac-ABA).
- Covalent coupling occurred exclusively at the C-2 position of benzanthrone (BA).
- The preferred conformation of the dG-N-Ac-ABA adduct was determined to be syn.
Conclusions:
- The study identified a novel DNA adduct formed from an NBA metabolite.
- The exclusive C-2 coupling suggests a resonance-stabilized arenium ion intermediate in adduct formation.
- The syn conformation of the adduct provides insights into its potential biological effects.