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Nucleic Acids Research, 2001, Vol. 29, No. 9 1951-1959
© 2001 Oxford University Press

Synthesis and spectroscopic characterization of site-specific 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine oligodeoxyribonucleotide adducts

Karen Brown, Elizabeth A. Guenther, Karen H. Dingley, Monique Cosman, Chris A. Harvey1, Sharon J. Shields1 and Kenneth W. Turteltaub*

Biology and Biotechnology Research Program and 1Chemistry and Materials Science, Lawrence Livermore National Laboratory, Livermore, CA 94551, USA

The aim of the present study is to determine the chemical structure and conformation of DNA adducts formed by incubation of the bioactive form of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), N-acetoxy-PhIP, with a single-stranded 11mer oligodeoxyribonucleotide. Using conditions optimized to give the C8-dG-PhIP adduct as the major product, sufficient material was synthesized for NMR solution structure determination. The NMR data indicate that in duplex DNA this adduct exists in equilibrium between two different conformational states. In the main conformer, the covalently bound PhIP molecule intercalates in the helix, whilst in the minor conformation the PhIP ligand is probably solvent exposed. In addition to the C8-dG-PhIP adduct, at least eight polar adducts are found after reaction of N-acetoxy-PhIP with the oligonucleotide. Three of these were purified for further characterization and shown to exhibit lowest energy UV absorption bands in the range 342–347 nm, confirming the presence of PhIP or PhIP derivative. Accurate mass determination of two of the polar adducts by negative ion MALDI-TOF MS revealed ions consistent with a spirobisguanidino-PhIP derivative and a ring-opened adduct. The third adduct, which has the same mass as the C8-dG-PhIP oligonucleotide adduct, may contain PhIP bound to the N2 position of guanine.

* To whom correspondence should be addressed. Tel: +1 925 423 8152; Fax: +1 925 422 2282; Email: turteltaub2{at}llnl.gov


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Home page
 Proc. Natl. Acad. Sci. USAHome page
K. Brown, B. E. Hingerty, E. A. Guenther, V. V. Krishnan, S. Broyde, K. W. Turteltaub, and M. Cosman
Solution structure of the 2-amino-1- methyl-6-phenylimidazo[4,5-b]pyridine C8-deoxyguanosine adduct in duplex DNA
PNAS, June 28, 2001; (2001) 151251898.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
K. Brown, B. E. Hingerty, E. A. Guenther, V. V. Krishnan, S. Broyde, K. W. Turteltaub, and M. Cosman
Solution structure of the 2-amino-1- methyl-6-phenylimidazo[4,5-b]pyridine C8-deoxyguanosine adduct in duplex DNA
PNAS, July 17, 2001; 98(15): 8507 - 8512.
[Abstract] [Full Text] [PDF]


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