TY - JOUR
T1 - 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
AU - Prodhomme, Emmanuel J.F.
AU - Ensch, Corinne
AU - Bouche, Fabienne B.
AU - Kaminski, Thomas
AU - Deroo, Sabrina
AU - Seek, Pierre
AU - Kirsch, Gilbert
AU - Muller, Claude P.
PY - 2007
Y1 - 2007
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=36849006606&partnerID=8YFLogxK
U2 - 10.1021/bc070046i
DO - 10.1021/bc070046i
M3 - Article
C2 - 17939731
AN - SCOPUS:36849006606
SN - 1043-1802
VL - 18
SP - 2045
EP - 2053
JO - Bioconjugate Chemistry
JF - Bioconjugate Chemistry
IS - 6
ER -