An improved synthesis of radiolabeled 4‐(acetoxymethylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone

Peterson, Lisa A.; Spratt, Thomas E.; Shan, Weifeng; Wang, Lijuan; Subotkowski, Witold; Roth, Robert W.

doi:10.1002/jlcr.469

Cited by 8 publications

(6 citation statements)

References 9 publications

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“…Strata-X SPE cartridges were obtained from Phenomenex (Torrence, CA). 4-(Acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (NNKOAc), [5- 3 H]NNKOAc, and O 6 -[1,2,2- 2 H 3 -4-oxo-4-(3-pyridyl)butyl]-2‘-deoxyguanosine ([ 2 H 3 ] O 6 -pobG) were prepared as described previously ( − ). All other reagents were obtained from Sigma Aldrich Chemical Co. (Milwaukee, WI) or Fisher Scientific (Fairlawn, NJ).…”

Section: Methodsmentioning

confidence: 99%

O⁶-Pyridyloxobutylguanine Adducts Contribute to the Mutagenic Properties of Pyridyloxobutylating Agents

Mijal

Loktionova

et al. 2005

Chem. Res. Toxicol.

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The tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) are potent carcinogens in animal models and likely human carcinogens. Both NNK and NNN can be activated to a pyridyloxobutylating agent. This alkylating agent contributes to the carcinogenic effects of NNK and NNN via the formation of miscoding DNA adducts. One of these adducts, O6-[4-oxo-4-(3-pyridyl)butyl]guanine (O6-pobG) has been characterized as a mutagenic adduct which is a substrate for the repair protein O6-alkylguanine-DNA alkyltransferase (AGT). Repair of O6-alkylguanine adducts by AGT protects cells from the mutagenic and carcinogenic effects of alkylating agents and is likely to play a similar role in shielding cells from the adverse effects of pyridyloxobutylating agents. Therefore, we examined the mutagenicity of the model pyridyloxobutylating agent, 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (NNKOAc), in Salmonella typhimurium YG7108 expressing hAGT. Expression of hAGT protected cells from NNKOAc-induced mutagenicity. Interestingly, hAGT did not shield cells from the toxicity of this agent. To confirm that the repair of O6-pobG was increased in the bacteria expressing hAGT, we measured levels of this adduct in NNKOAc-treated cultures. The levels of O6-pobG were lower in DNA from bacteria expressing hAGT. This work establishes an important role for O6-pobG in mediating the mutagenic, and possibly carcinogenic, effects of pyridyloxobutylating compounds.

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Section: Methodsmentioning

confidence: 99%

O⁶-Pyridyloxobutylguanine Adducts Contribute to the Mutagenic Properties of Pyridyloxobutylating Agents

Mijal

Loktionova

et al. 2005

Chem. Res. Toxicol.

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“…[5-3 H]NNK (14 Ci/mmol) was obtained from Moravek Biochemicals Inc. (Brea, CA). [5-3 H]NNKOAc, HPB, O 6 -bG, and O 6 -pobG were synthesized by published methods (8,(17)(18)(19). [ 3 H-CH3]MNU (specific activity: 19 Ci/mmol) was purchased from Amersham Pharmacia Biotech (Piscataway, NJ).…”

Section: Methodsmentioning

confidence: 99%

The Pyridyloxobutyl DNA Adduct, O⁶-[4-Oxo-4-(3-pyridyl)butyl]guanine, Is Detected in Tissues from 4-(Methylnitrosamino)- 1-(3-pyridyl)-1-butanone-treated A/J Mice

Thomson

Kenney

Peterson

2002

Chem. Res. Toxicol.

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The tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is a potent pulmonary carcinogen. This unsymmetric nitrosamine can be metabolically activated to lung DNA methylating and pyridyloxobutylating intermediates. The methyl DNA adducts are well characterized. The pyridyloxobutyl adducts are unstable under DNA hydrolysis conditions and decompose to release 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB). One of the HPB-releasing adducts,O6-[4-oxo-4-(3-pyridyl)butyl]guanine (O6-pobG), has been detected in DNA reacted in vitro with the model pyridyloxobutylating agent, 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (NNKOAc). To determine whether this adduct was formed in vivo, A/J mice were treated with 10 mumol of [5-3H]NNK and sacrificed 24 h postinjection. The mutagenic O6-pobG was detected in liver but not lung DNA from these animals. Since 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is a major metabolite of NNK, it is also possible that these animals are activating NNAL to a pyridylhydroxybutylating agent. Therefore, we also measured the levels of O6-[4-hydroxy-4-(3-pyridyl)butyl]guanine (O6-phbG) in these DNA samples. While radioactivity did coelute with synthetic standard for this potential NNAL adduct in one lung DNA sample, significant levels of O6-phbG were not detected in any other lung or liver DNA samples. The pyridyloxobutyl adduct, O6-pobG, was also observed in lung and liver DNA from mice treated with 4.2 mumol of [5-3H]NNKOAc in the presence but not absence of 2.5 mumol of O6-benzylguanine, a known depletor of the repair protein O6-alkylguanine-DNA alkyltransferase (AGT). These data indicate that this adduct is formed in vivo but is repaired in part by AGT. Cell-free extracts from A/J mouse lung and liver were used to determine the relative rate of O6-alkylguanine repair. O6-mG and O6-pobG were removed from DNA to the same extent in a competitive assay, suggesting that low levels of O6-pobG in lungs of NNK-treated mice did not result from preferential repair of O6-pobG by AGT. It is more likely that initial levels of O6-pobG are much lower than initial levels of O6-mG in lung DNA from NNK-treated A/J mice. These data are consistent with previous studies, which indicate that DNA methylation is the critical pathway for NNK-induced lung carcinogenesis in A/J mice.

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“…8 mmol) in CH 3 CN (30 ml) was heated to reflux and treated with a solution of iodomethyl 2-(2-(2-(2-methoxyethoxy)-ethoxy)-ethoxy)-ethyl carbonate 7 (1.1 g, 2.7 mmol) in CH 3 CN (5 ml). After reflux for 20 min, the mixture was cooled to room temperature and evaporated in vacuo.…”

Section: Generalmentioning

confidence: 99%

“…A similar tritio-debromination of a substituted 3-bromopyridine has recently been reported. 7 Further, we wanted to introduce tritium in EB 1627 in the last synthetic step using the same method, but the outcome of this reaction would seem less predictable due to the labile polyethercarboxymethyl group (the prodrug moiety) attached to the obtained when THF was used as solvent. Thus, compound 1c was dissolved in THF and treated with tritium-gas, diisopropylethylamine and 5% Pd/C for 24 h. TLC purification afforded 1d (1.08 GBq) with a radiochemical purity of 99.3% and a specific activity of 1960 GBq/mmol (average: 1.8 tritium per molecule).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of tritium labelled CHS 828 and its prodrug EB 1627

Schou¹,

Hunneche²,

Binderup³

et al. 2005

J Label Compd Radiopharm

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SummaryThe potent antitumoral cyanoguanidine CHS 828 and its prodrug EB 1627 have successfully been labelled with tritium. The pyridyl-3,5-dibromo derivative of CHS 828 was debrominated with tritium-gas using Pd/C catalyst to give [pyridyl-3,5-3 H 2 ]-CHS 828 with a radiochemical purity of 99.3% and a specific activity of 1960 GBq/ mmol. Similarly, the pyridyl-3-bromo derivative of the prodrug EB 1627 was debrominated with tritium-gas to give [pyridyl-3-3 H]-EB 1627 with a radiochemical purity of 98.1% and a specific activity of 894 GBq/mmol.

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An improved synthesis of radiolabeled 4‐(acetoxymethylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone

Cited by 8 publications

References 9 publications

O⁶-Pyridyloxobutylguanine Adducts Contribute to the Mutagenic Properties of Pyridyloxobutylating Agents

O⁶-Pyridyloxobutylguanine Adducts Contribute to the Mutagenic Properties of Pyridyloxobutylating Agents

The Pyridyloxobutyl DNA Adduct, O⁶-[4-Oxo-4-(3-pyridyl)butyl]guanine, Is Detected in Tissues from 4-(Methylnitrosamino)- 1-(3-pyridyl)-1-butanone-treated A/J Mice

Synthesis of tritium labelled CHS 828 and its prodrug EB 1627

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An improved synthesis of radiolabeled 4‐(acetoxymethylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone

Cited by 8 publications

References 9 publications

O6-Pyridyloxobutylguanine Adducts Contribute to the Mutagenic Properties of Pyridyloxobutylating Agents

O6-Pyridyloxobutylguanine Adducts Contribute to the Mutagenic Properties of Pyridyloxobutylating Agents

The Pyridyloxobutyl DNA Adduct, O6-[4-Oxo-4-(3-pyridyl)butyl]guanine, Is Detected in Tissues from 4-(Methylnitrosamino)- 1-(3-pyridyl)-1-butanone-treated A/J Mice

Synthesis of tritium labelled CHS 828 and its prodrug EB 1627

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O⁶-Pyridyloxobutylguanine Adducts Contribute to the Mutagenic Properties of Pyridyloxobutylating Agents

O⁶-Pyridyloxobutylguanine Adducts Contribute to the Mutagenic Properties of Pyridyloxobutylating Agents

The Pyridyloxobutyl DNA Adduct, O⁶-[4-Oxo-4-(3-pyridyl)butyl]guanine, Is Detected in Tissues from 4-(Methylnitrosamino)- 1-(3-pyridyl)-1-butanone-treated A/J Mice