Synthesis of heterocyclic N-acetoxyarylamines and their reactivity with DNA

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Abstract
2-Acetoxyamino-5-phenylpyridine and 2-acetoxyamino-3-methyl-5-phenylpyridine, being proposed ultimate carcino gens of the heterocyclic aromatic amines 2-amino-5-phenyl-pyridine (APP) and 2-amino-3-methyl-5-phenylpyrldlne (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-hydroxyamlno-3-methyl-5-phenyl-pyridine, 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 O-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.

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