Synthesis of 4-[2-aminoethyl(nitrosamino)]-1-pyridin-3-yl-butan-1-one, a new NNK hapten for the induction of N-nitrosamine-specific antibodies

Emmanuel J.F. Prodhomme, Corinne Ensch, Fabienne B. Bouche, Thomas Kaminski, Sabrina Deroo, Pierre Seek, Gilbert Kirsch, Claude P. Muller*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

6 Citations (Scopus)

Abstract

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the most abundant and potent procarcinogens in tobacco smoke. In order to induce a strong and substained antibody response against NNK, we developed a functionalized derivative that closely mimicked its structural features, in particular, the pyridyloxobutyl moiety, the adjacent ketone, and the N-nitrosamino group. This hapten was conjugated via a C2 linker to the highly immunogenic diphteria toxoid licensed as a vaccine in humans to induce polyclonal and monoclonal antibodies. Two monoclonal antibodies were obtained with K d values of 45.8 nM (P9D5) and 37.6 nM (P7H3), respectively, for NNK-C2. Both the monoclonal (P9D5 and P7H3) and polyclonal antibodies reacted strongly with NNK (IC50 = 80 μM or 160 μM) and NNAL (IC50 = 29 μM or 93 μM;) and to a lesser extent with some of the metabolites of NNK. Interestingly, the mAbs did not react with the metabolites of the detoxification pathways such as NNK-N-Oxide and NNAL-N-Oxide (IC50 > 512 μM). Therefore, such antibodies detect NNK and NNAL and may have the potential to modulate their redistribution in vivo, perhaps reducing some detrimental effects of smoking.

Original languageEnglish
Pages (from-to)2045-2053
Number of pages9
JournalBioconjugate Chemistry
Volume18
Issue number6
DOIs
Publication statusPublished - 2007

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