Synthesis of (±) [5‐³H] N′‐nitrosoanatabine, a tobacco‐specific nitrosamine

Abstract

SummaryTobacco-specific N′-nitrosamines (TSNA) are a unique class of systemic organ-specific carcinogens. The TSNA are formed by N-nitrosation of nicotine and of the minor tobacco alkaloids after harvesting of tobacco and during smoking. The N-nitrosation of anatabine leads to N'-nitrosoanatabine (NAT; 1-nitroso-1,2,3,4-tetrahydro-2,3'-bipyridyl) which requires in-depth assays in laboratory animals other than the rat. Furthermore, delineation of its tissue distribution and metabolism is needed for structure:activity comparisons with other TSNA and for the assessment of potential human risk from this TSNA. We have, therefore, synthesized (+) [5-3 H]NAT. 5-Bromo-3-pyridine-carboxaldehyde was condensed with ethyl carbamate prior to Diels-Alder reaction with 1,4-butadiene to give the racemic anatabine ring system. Hydrolysis followed by reduction with LiAlT 4 and nitrosation, led to (+) [5-3 H]NAT (60% yield, specific activity 266 mCi/mmol, radiochemical purity of >99%).

Tritium-labelled alkaloids: Synthesis and applications

“…Publications using [ 3 H]nicotine for receptor binding studies number well over 800. Because they arise in tobacco smoke and are suspected carcinogens, nicotine‐related nitrosamines have also been labelled with tritium, typically by aromatic tritium debromination methods . The toxic pyridine alkaloid ricinine, biosynthetically produced from nicotinic acid by the castor plant Ricinus communis , has been tritiated by means of a Wilzbach tritium gas exposure …”

“…Because they arise in tobacco smoke and are suspected carcinogens, nicotine-related nitrosamines have also been labelled with tritium, typically by aromatic tritium debromination methods. 84,85 The toxic pyridine alkaloid ricinine, biosynthetically produced from nicotinic acid by the castor plant Ricinus communis, has been tritiated 86 by means of a Wilzbach tritium gas exposure. 87 Besides nicotine-related natural products, two other intriguing pyridine alkaloids clearly deserve mention.…”