A study of chemical carcinogenesis. 14. Hydrolysis of model compounds for .alpha.-hydroxylation of the carcinogens N-nitrosopyrrolidine and N'-nitrosonornicotine

Hecht, Stephen S.; Chen, Chi hong B.

doi:10.1021/jo01323a043

Cited by 23 publications

(21 citation statements)

References 7 publications

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“…The deuterium incorporations in the products of the hydrolysis of the -acetoxy NNAL deriv- The keto alcohol 7 was the major hydrolysis product of the -acetoxy nitrosamine 3 and carbamate 4. This observation was previously reported for compound 4 (10,13).…”

Section: Resultssupporting

confidence: 90%

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Solvolysis of model compounds of .alpha.-hydroxylation of N'-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone: evidence for a cyclic oxonium ion intermediate in the alkylation of nucleophiles

Spratt

Peterson

Confer

et al. 1990

Chem. Res. Toxicol.

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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-1-ol (26), and 2-(3-pyridyl)-2,3,4,5-tetrahydrofuran (24).(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Resultssupporting

confidence: 90%

“…(B) Cyclopropyl 3-Pyridyl Ketone (10) (17). K2C03 (14.8 mg, 107 mmol) was added to 34.5 mg of 16 (108 mmol) dissolved in 5 mL of MeOH, and the suspension was stirred for 2 h at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Solvolysis of model compounds of .alpha.-hydroxylation of N'-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone: evidence for a cyclic oxonium ion intermediate in the alkylation of nucleophiles

Spratt

Peterson

Confer

et al. 1990

Chem. Res. Toxicol.

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“…The intermediates of these pathways are highly reactive diazohydroxides (structure 2) or methyldiazohydroxide, which alkylate both DNA and proteins (Carmella and Hecht 1987;Hecht et al 1988). Hecht et al (1979) have shown that these unstable intermediates can be generated efficiently by simple ester hydrolysis of 4-(carbethoxynitrosamino)-1-(3-pyridyl)-l-butanone (structure 1). Both enzymatic activation of NNK and hydrolysis of structure 1 yield the keto alcohol (structure 4), which implies the formation of the common intermediate, structure 2.…”

Section: Discussionmentioning

confidence: 99%

“…NNK and its metabolites were synthesized as previously described (Hecht et al 1977(Hecht et al , 1980. Synthesis of 4-(carbethoxynitrosamino)-l-(3-pyridyl)-l-butanone has been reported (Hecht et al 1979). Bovine albumin (Fraction V), 4-chloronaphthol, streptavidin peroxidase and tetramethyl benzidine were purchased from Sigma Chemical Co. (St Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

Immunoassays for proteins alkylated by nicotine-derived N-nitrosamines

1990

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Polyclonal antibodies recognizing the pyridyloxobutyl (POB) moiety of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were produced in rabbits immunized either with POB-bovine albumin or POB-Sepharose. The POB intermediates necessary to modify the protein were generated by alkaline (pH 9.0) treatment of the synthetic precursor 4-(carbethoxynitrosamino)-1-(3-pyridyl)-1-butanone. In a competitive enzyme linked immunoabsorbent assay (ELISA), 70 pmole NNK inhibited 50% of the binding of the anti-POB antibodies to POB-protein absorbed on microtiterplates. This 50% inhibition varied from 70 pmole to 200 nmole using a series of NNK analogues, depending on the integrity of the POB moiety. Immunological techniques initiated in this study detect NNK-protein conjugates or measure the quantity of POB groups liberated upon alkaline or acid treatment of NNK modified protein.

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“…Analogous experiments with N-nitrosopyrrolidine showed that its o-hydroxylation resulted in the formation of 2-hydroxytetrahydrofuran, a major metabolite (37,38).…”

Section: Effect Of Dose On Levels Of Urinary Metabolites Of Nnnmentioning

confidence: 99%

Tobacco specific nitrosamines: Carcinogenicity, metabolism, and possible role in human cancer

Hecht

Castonguay

Rivenson

et al. 1983

Journal of Environmental Science and Health. Part C: Environmen

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A study of chemical carcinogenesis. 14. Hydrolysis of model compounds for .alpha.-hydroxylation of the carcinogens N-nitrosopyrrolidine and N'-nitrosonornicotine

Cited by 23 publications

References 7 publications

Solvolysis of model compounds of .alpha.-hydroxylation of N'-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone: evidence for a cyclic oxonium ion intermediate in the alkylation of nucleophiles

Solvolysis of model compounds of .alpha.-hydroxylation of N'-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone: evidence for a cyclic oxonium ion intermediate in the alkylation of nucleophiles

Immunoassays for proteins alkylated by nicotine-derived N-nitrosamines

Tobacco specific nitrosamines: Carcinogenicity, metabolism, and possible role in human cancer

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