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

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• 作者：Emmanuel J. F. Prodhomme ; Corinne Ensch ; Fabienne B. Bouche ; Thomas Kaminski ; Sabrina Deroo ; Pierre Seck ; Gilbert Kirsch ; Claude P. Muller
• 刊名：Bioconjugate Chemistry
• 出版年：2007
• 出版时间：November 2007
• 年：2007
• 卷：18
• 期：6
• 页码：2045 - 2053
• 全文大小：273K
• 年卷期：v.18,no.6(November 2007)
• ISSN：1520-4812

文摘

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.