An Improved Synthesis of (±)-<i>N</i>′-Nitrosonornicotine 5′-Acetate

Marriner, Gwendolyn A.; Kerwin, Sean M.

doi:10.1021/jo9000417

Cited by 4 publications

(6 citation statements)

References 17 publications

(18 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5′-Acetoxy- N ′-nitrosonornicotine (5′-acetoxyNNN) was synthesized as reported previously. , N 6 -PHB-dAdo was synthesized as described before . The isotopically labeled internal standards [pyridine- d 4 ] N 6 -POB-dAdo and [ 15 N 5 ] N 6 -PHB-dAdo were available from our previous study …”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Identification of an N′-Nitrosonornicotine-Specific Deoxyadenosine Adduct in Rat Liver and Lung DNA

Hecht

2021

Chem. Res. Toxicol.

View full text Add to dashboard Cite

The tobacco-specific nitrosamines N′-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are considered to be two of the most important carcinogens in unburned tobacco and its smoke. They readily cause tumors in laboratory animals and are classified as “carcinogenic to humans” by the International Agency for Research on Cancer. DNA adduct formation by these two carcinogens is believed to play a critical role in tobacco carcinogenesis. Among all the DNA adducts formed by NNN and NNK, 2′-deoxyadenosine (dAdo)-derived adducts have not been fully characterized. In the study reported here, we characterized the formation of N 6-[4-(3-pyridyl)-4-oxo-1-butyl]-2′-deoxyadenosine (N 6-POB-dAdo) and its reduced form N 6-PHB-dAdo formed by NNN 2′-hydroxylation in rat liver and lung DNA. More importantly, we characterized a new dAdo adduct N 6-[4-hydroxy-1-(pyridine-3-yl)butyl]-2′-deoxyadenosine (N 6-HPB-dAdo) formed after NaBH3CN or NaBH4 reduction both in vitro in calf thymus DNA reacted with 5′-acetoxy-N′-nitrosonornicotine and in vivo in rat liver and lung upon treatment with NNN. This adduct was specifically formed by NNN 5′-hydroxylation. Chemical standards of N 6-HPB-dAdo and the corresponding isotopically labeled internal standard [pyridine-d 4]N 6-HPB-dAdo were synthesized using a four-step method. Both NMR and high-resolution mass spectrometry data agreed well with the proposed structure of N 6-HPB-dAdo. The new adduct coeluted with the synthesized internal standard under various LC conditions. Its product ion patterns of MS2 and MS3 transitions were also consistent with the proposed fragmentation patterns. Chromatographic resolution of the two diastereomers of N 6-HPB-dAdo was successfully achieved. Quantitation suggested a dose-dependent response of the levels of this new adduct in the liver and lung of rats treated with NNN. However, its level was lower than that of 2-[2-(3-pyridyl)-N-pyrrolidinyl]-2′-deoxyinosine, a previously reported dGuo adduct that is also formed from NNN 5′-hydroxylation. The identification of N 6-HPB-dAdo in this study leads to new insights pertinent to the mechanism of carcinogenesis by NNN and to the development of biomarkers of NNN metabolic activation.

show abstract

Section: Methodsmentioning

confidence: 99%

“…5′-AcetoxyNNN was synthesized using the method described before. , The reaction details and 1 H NMR data can be found in the Supporting Information (Scheme S1 and Figure S1). NMR data were consistent with the reported values.…”

Section: Methodsmentioning

confidence: 99%

Identification of an N′-Nitrosonornicotine-Specific Deoxyadenosine Adduct in Rat Liver and Lung DNA

Hecht

2021

Chem. Res. Toxicol.

View full text Add to dashboard Cite

show abstract

“…28 The previous method employed (±)- tert -butylsulfinamide, but here we utilized enantiopure ( S )-(−)- or ( R )-(+)- tert -butylsulfinamide. The synthetic procedure is detailed in the Supporting Information (Scheme S1 and Table S1).…”

Section: Methodsmentioning

confidence: 99%

“…This synthetic procedure was adapted from a previously published synthesis of racemic 5′-acetoxyNNN. 28 The previous method employed (±)-tert-butylsulfinamide, but here, we utilized enantiopure (S)-(−)-or (R)-(+)-tert-butylsulfinamide. The synthetic procedure is detailed in the Supporting Information (Scheme S1 and Table S1).…”

Section: ■ Experimental Proceduresmentioning

confidence: 99%

DNA Adduct Formation from Metabolic 5′-Hydroxylation of the Tobacco-Specific Carcinogen N′-Nitrosonornicotine in Human Enzyme Systems and in Rats

Zarth

Upadhyaya

Yang

et al. 2016

Chem. Res. Toxicol.

View full text Add to dashboard Cite

N ′-Nitrosonornicotine (NNN) is carcinogenic in multiple animal models and has been evaluated as a human carcinogen. NNN can be metabolized by cytochrome P450s through two activation pathways: 2′-hydroxylation and 5′-hydroxylation. While most previous studies have focused on 2′-hydroxylation in target tissues of rats, available evidence suggests that 5′-hydroxylation is a major activation pathway in human enzyme systems, in non-human primates, and in target tissues of some other rodent carcinogenicity models. In the study reported here, we investigated DNA damage resulting from NNN 5′-hydroxylation by quantifying the adduct 2-(2-(3-pyridyl)-N-pyrrolidinyl)-2′-deoxyinosine (py-py-dI). In rats treated with NNN in the drinking water (7–500 ppm), py-py-dI was the major DNA adduct resulting from 5′-hydroxylation of NNN in vivo. Levels of py-py-dI in lung and nasal cavity were highest, consistent with the tissue distribution of CYP2A3. In rats treated with (S)-NNN or (R)-NNN, the ratios of formation of (R)-py-py-dI to (S)-py-py-dI were not the expected mirror image, suggesting that there may be a carrier for one of the unstable intermediates formed upon 5′-hydroxylation of NNN. Rat hepatocytes treated with (S)- or (R)-NNN or (2′S)- or (2′R)-5′-acetoxyNNN exhibited a pattern of adduct formation similar to live rats. In vitro studies with human liver S9 fraction or human hepatocytes incubated with NNN (2–500 μM) demonstrated that py-py-dI formation was greater than formation of pyridyloxobutyl-DNA adducts resulting from 2′-hydroxylation of NNN. (S)-NNN formed more total py-py-dI adducts than (R)-NNN in human liver enzyme systems, which is consistent with the critical role of CYP2A6 in the 5′-hydroxylation of NNN in human liver. The results of this study demonstrate that the major DNA adduct resulting from NNN metabolism by human enzymes is py-py-dI and provide potentially important new insights on the metabolic activation of NNN in rodents and humans.

show abstract

“…The stereochemical outcome of Grignard addition is consistent with an open transition state rather than a chelated one, presumably due to disruption of chelation control by the coordinating ability of the pendant acetal. This method of pyrroline synthesis was utilized by Marriner and Kerwin in a concise synthesis of racemic N ′-nitrosonornicotine 5′-acetate ( 183 ) (Scheme ) . Instead of in situ reduction of pyrroline 182 to the corresponding pyrrolidine, nitrosoacylation provided the desired adduct 183 in 37% yield over two steps.…”

Section: Synthesis Of α-Branched Aminesmentioning

confidence: 99%

Synthesis and Applications of tert-Butanesulfinamide

2010

View full text Add to dashboard Cite

An Improved Synthesis of (±)-N′-Nitrosonornicotine 5′-Acetate

Abstract: A concise and efficient route to (+/-)-N'-nitrosonornicotine 5'-acetate (NNN-5'-OAc), a stable precursor of the active metabolite 5'-hydroxy(+/-)-N'-nitrosonornicotine NNN-5'-OH is reported. The synthesis utilizes sulfinimine chemistry to give (+/-)-NNN-5'-OAc in 26% yield over 4 steps.

Cited by 4 publications

References 17 publications

Identification of an N′-Nitrosonornicotine-Specific Deoxyadenosine Adduct in Rat Liver and Lung DNA

Identification of an N′-Nitrosonornicotine-Specific Deoxyadenosine Adduct in Rat Liver and Lung DNA

DNA Adduct Formation from Metabolic 5′-Hydroxylation of the Tobacco-Specific Carcinogen N′-Nitrosonornicotine in Human Enzyme Systems and in Rats

Synthesis and Applications of tert-Butanesulfinamide

Contact Info

Product

Resources

About