Synthesis of heterocyclic N-acetoxyarylamines and their reactivity with DNA.
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.
Lutgerink
J T
JT
Division of Chemical Carcinogenesis, The Netherlands Cancer Institute (Antoni van Leeuwenhoekhuis), Amsterdam.
Stavenuiter
J F
JF
Zomer
G
G
Hamzink
M
M
van Dijk
P
P
Westra
J G
JG
Kriek
E
E
D000588:Amines / Q000138:chemical synthesis*; D002273:Carcinogens / Q000138:chemical synthesis*; D004247:DNA; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship
D000588:Amines; D002273:Carcinogens; D007202:Indicators and Reagents; D011725:Pyridines; D004247:DNA