Synthesis of 4‐ (methylnitrosamino)‐1‐ (3‐pyridyl)‐1‐butanone, 4‐ (carbethoxynitrosamino)‐1‐ (3‐pyridyl)‐1‐butanone, and N′ ‐nitrosonornicotine labelled with tritium in the pyridine ring

Abstract

The carcinogenic tobacco-specif ic nitrosamines 4-(methylnitrosemino) -1-(3-pyridyl) -1-butanone (NNK) and N'-nitrosonornicotine (NNN), as well as the model compound 4-(carbethoxynitrosamino) -1-(3-pyridyl) -1butanone, were synthesized with tritium at the 5-position of the pyridine ring. In each case, the tritium labelled compound was prepared by catalytic tritium replacement of the corresponding brominated precursor. This intermediate as well as the a-hydroxy compounds , 1 and 2 are unstable and have not been synthesized. However, 4-(carbethoxynitrosamino) -1-(3-pyridyl) -1-butanone, 1, is a stable precursor to A (2.3). In order to investigate the interactions of NNK, NNN, and 1 with DNA and protein, the tritium labelled compounds were required. Metabolic studies of "K and "N indicate that hydroxylation of the pyridine ring is not a major process ( 4 ) . Thus, to avoid exchange L n -0, tritium was specifically incorporated at the 5-position of the pyridine ring. DNA and globln adducts Scheme 1 RESULTS AND DISCUSSION The synthesis of [5-3H]NNK is illustrated in Scheme 2. The method is based on that used for unlabelled "K ( 5 , 6 ) . Ethyl 5bromonicotinate, 2, was reacted with N-methylpyrrolidinone, 5 , to give the intermediate condensation product 2. Tritiation of 1 by J. C. Wiley Jr. et al.

Stereospecific Deuterium Substitution Attenuates the Tumorigenicity and Metabolism of the Tobacco-Specific Nitrosamine 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)

“…[5-3 H]NNK (14 Ci mmol -1 , 98% radiochemical purity) was purchased from Moravek Biochemicals, Inc. (Brea, CA) and purified to >99% radiochemical purity by reverse phase HPLC. [5-3 H]-(4R)-[4-2 H1]NNK (9a, Scheme 3, 14.9 Ci mmol -1 , >99% radiochemical purity) and [5-3 H]-(4S)-[4-2 H1]NNK (9b, Scheme 3, 14.9 Ci mmol -1 , >99% radiochemical purity) were synthesized by Moravek Biochemicals, Inc. from the respective precursors containing bromine at the 5-position of the pyridine ring (8a,b, Scheme 3, vide infra) (32). Gua, O 6 -mG, 7-mG, NADP + , glucose-6-phosphate, glucose-6-phosphate dehydrogenase, coumarin, sodium bisulfite, EDTA, barium hydroxide, zinc sulfate, phenol, RNase A, RNase T1, proteinase K, L-glutamic acid decarboxylase (type V from Escherichia coli, EC 4.1.1.15), glutamic-oxaloacetic transaminase (type II-A from porcine heart, EC 2.6.1.1), pyridoxal 5-phosphate, and L-glutamic acid were purchased from Sigma Chemical Co. (St. Louis, MO).…”

Mitochondrial DNA Adducts in the Lung and Liver of F344 Rats Chronically Treated with 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone and (S)-4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol

“…Of these, polycyclic aromatic hydrocarbons (PAH), tobacco-specific N -nitrosamines (TSNA), and aromatic amines have been most thoroughly studied due to their widely acknowledged carcinogenicity to humans ,− . Since TSNA are formed from nicotine during tobacco processing, the unique attribute of these carcinogens is their specificity to tobacco products , . One of the most important representatives of this group is 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a remarkably effective systemic lung carcinogen in laboratory animals .…”

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

“…The reaction did not proceed in the presence of triethylamine, a surprising observation given published studies with similar compounds. 10 TLC purification of the reaction product followed by NMR analysis confirmed the production of the desired product, NNKOAc.…”