Solvolysis of Model Compounds for α-Hydroxylation of N’-Nitrosonornlcotine and 4-(Methylnitrosamino)-1-(3-pyrldyl)-1-butanone: Evidence for a Cyclic Oxonium Ion Intermediate in the Alkylation of Nucleophiles

Thomas E. Spratt, Lisa A. Peterson, William L. Confer, Stephen S. Hecht

Research output: Contribution to journalArticle

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Abstract

N-Nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), two potent tobacco-specific carcinogens, have been previously found to pyridyloxobutylate DNA. The adducts were found to be unstable and have not been fully characterized. In order to gain an understanding of the chemistry of the pyridyloxobutylating species, five model pyridyloxobutylating agents have been solvolyzed and the products identified. 4- [(Acetoxymethyl)- nitrosamino]-1-(3-pyridyl)-1-butanone (3), 4-(carbethoxynitrosamino)-1-(3-pyridyl)-1-butanone (4), 4-oxo-4-(3-pyridyl)-1-butyl p-toluenesulfonate (16), 2-chloro-2-(3-pyridyl)-2,3,4,5-tetrahydrofuran (17), and 4-[(acetoxymethyl) nitrosamino]-1-(3-pyridyl)-1-butanol (20) were solvolyzed in buffer and in buffer containing 20% MeOH. The solvolyses of 16 and 17 in H2O produced only 4-hydroxy-1-(3-pyridyl)-1-butanone (7). In the presence of 20% MeOH, 7 and 2-methoxy-2-(3-pyridyl)-2,3,4,5-tetrahydrofuran (12) were produced from 16 and 17 in a 4:1 ratio. The solvolysis of 3 and 4 in the presence of esterase gave similar products. 4-Methoxy-1-(3-pyridyl)-1-butanone (8) was not detected as a product. In the absence of MeOH, compound 7, 3-pyridyl cyclopropyl ketone (10), and 1-(3-pyridyl)-but-2-en-1-one (18) were observed. In the presence of MeOH, 12 was also formed and the ratio of 7 to 12 was again about 4:1. The esterase-catalyzed hydrolysis of 20 yielded 1-(3-pyridyl)-1,4-butanediol (22), 1-(3-pyridyl)-1,3-butanediol (27), 1-(3-pyridyl)-but-3-en-1-ol (25), 1-(3-pyridyl)but-2-en-l-ol (26), and 2-(3-pyridyl)-2,3,4,5-tetrahydrofuran (24). 4-Methoxy-1-(3-pyridyl)-1-butanol (23) was observed in low yields when the solvolysis of 20 was performed in the presence of MeOH. Hydrolyses of compounds 3 and 20 in deuterated buffer showed that deuterium incorporation was proportional to the buffer concentration. The results indicate that the 4-oxo-4-(3-pyridyl)-1-butanediazonium ion (2), which is formed by metabolism of NNN and NNK, can cyclize to form an electrophilic cyclic oxonium ion (13) which can react with cellular nucleophiles.

Original languageEnglish (US)
Pages (from-to)350-356
Number of pages7
JournalChemical research in toxicology
Volume3
Issue number4
DOIs
StatePublished - Jan 1 1990

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