Synthesis of heterocyclic N-acetoxyarylamines and their reactivity with DNA

• Published in: Carcinogenesis (New York) Vol. 10; no. 10; p. 1957
• Main Authors: Lutgerink, J T, Stavenuiter, J F, Zomer, G, Hamzink, M, van Dijk, P, Westra, J G, Kriek, E
• Format: Journal Article
• Language: English
• Published: England 01.10.1989
• Subjects: Amines - chemical synthesis; Carcinogens - chemical synthesis; DNA; Indicators and Reagents; Magnetic Resonance Spectroscopy; Molecular Structure; Pyridines - chemical synthesis; Structure-Activity Relationship
• ISSN: 0143-3334
• DOI: 10.1093/carcin/10.10.1957

2-Acetoxyamino-5-phenylpyridine and 2-acetoxyamino-3-methyl-5-phenylpyridine, being proposed ultimate carcinogens of the heterocyclic aromatic amines 2-amino-5-phenylpyridine (APP) and 2-amino-3-methyl-5-phenylpyridine (AMPP), respectively, were synthesized, crystallized and characterized. Using the 32P-postlabelling technique, we show that the total amount of adducts found in DNA after reaction with these N-acetoxyarylamines is at least 30- and 450-fold higher than in DNA reacted with equimolar amounts of the proposed proximate carcinogens 2-hydroxyamino-5-phenylpyridine and 2-hydroxyamino-3-methyl-5-phenylpyridine, respectively. These results support a postulated activation mechanism, in which N-acetoxyarylamines are the ultimate reactive species responsible for DNA modification by carcinogenic aromatic amines in vivo. The possibility to obtain the reactive 0-acetyl derivatives of APP and AMPP in crystalline form makes them unique model compounds for studies on the interaction of ultimate carcinogens of aromatic amines with DNA.