ORGANIC
LETTERS
2008
Vol. 10, No. 9
1839-1842
Oxidation of a Biomarker for Phenol
Carcinogen Exposure: Expanding the
Redox Chemistry of 2′-Deoxyguanosine
Jennifer L. Weishar, Christopher K. McLaughlin, Michael Baker,
Wojciech Gabryelski,* and Richard A. Manderville*
Departments of Chemistry and Toxicology, UniVersity of Guelph,
Guelph, Ontario, Canada N1G 2W1
rmanderV@uoguelph.ca
Received March 1, 2008
ABSTRACT
A biomarker for phenolic carcinogen exposure, 8-(4′′-hydroxyphenyl)-2′-deoxyguanosine, has been found to undergo oxidative coupling in the
presence of Na2IrCl6 to afford ortho-ortho C-C-coupled polyphenols through the intermediacy of a phenoxyl radical. One can envision using
such unique chemistry to oxidatively couple strands of DNA for the generation of new biomaterials. Our results also demonstrate the potential
for phenolic adducts of DNA to undergo further oxidation reactions that may contribute to phenol-mediated cytotoxicity and genotoxicity.
Covalent attachment of electrophiles to DNA forms DNA
adducts that may induce mutations and carcinogenesis.1 The
DNA adduct can clarify the nature of the activated interme-
diate which reacted with DNA and can serve as a biomarker
for exposure to a particular carcinogen. In this regard, 7,8-
dihydro-8-oxo-2′-deoxyguanosine (8-oxo-dG, Figure 1 is the
primary oxidation product of dG and is a biomarker of
cellular oxidative damage.2 The C8-site of dG is also targeted
by arylamines that undergo bioactivation to form nitrogen
attachment of H2O to the oxidized purine ring system. The
detection of Sp lesions in vivo8 combined with their
mutagenicity9 has stimulated much interest into their mech-
anisms of formation and biological implications.10
Our interest in modified nucleobases stems from research
on DNA adduction by phenolic carcinogens that form C8-
dG adducts via radical intermediates.11 A representative
member is 8-(4′′-hydroxyphenyl)-dG 1 (X ) OH, Figure
1),12 which is structurally related to other C8-aryl adducts
formed by aryl hydrazines,13 polycyclic aromatic hydrocar-
bons,14 and estrogen derivatives.15 Like 8-oxo-dG4 and C8-
(N)-bound
C8-arylamine
adducts
that
initiate
mutagenicity.3Heteroatom attachment to the C8-site of dG
lowers the oxidation potential relative to dG,4,5 and further
oxidation of 8-oxo-dG6 and C8-arylamine adducts5,7 can
produce spiroiminodihydantoin (Sp) products following
(7) Shibutani, S.; Gentles, R. G.; Iden, C. R.; Johnson, F. J. Am. Chem.
Soc. 1990, 112, 56675668.
(8) Hailer, M. K.; Slade, P. G.; Martin, B. D.; Sudgen, K. D. Chem.
Res. Toxicol. 2005, 18, 1378–1383.
(1) Josephy, P. D.; Mannervik, B. Molecular Toxicology, 2nd ed.; Oxford
University Press, Inc.: New York, 2006; pp 46-82.
(2) Bjelland, S.; Seeberg, E. Mutat. Res. 2003, 531, 37–80.
(3) Hoffmann, G. R.; Fuchs, R. P. P. Chem. Res. Toxicol. 1997, 10,
347–359.
(9) Henderson, P. T.; Delaney, J. C.; Muller, J. G.; Neeley, W. L.;
Tannenbaum, S. R.; Burrows, C. J.; Essigmann, J. M. Biochemistry 2003,
42, 9257–9262.
(10) Neeley, W. L.; Essigmann, J. M. Chem. Res. Toxicol. 2006, 19,
491–505.
(4) Steenken, S.; Jovanovic, S. V.; Bietti, M.; Bernhard, K. J. Am. Chem.
Soc. 2000, 122, 2372–2374.
(11) (a) Dai, J.; Wright, M. W.; Manderville, R. A. J. Am. Chem. Soc.
2003, 125, 3716–3717. (b) Dai, J.; Sloat, A. L.; Wright, M. W.; Manderville,
R. A. Chem. Res. Toxicol. 2005, 18, 771–779. (c) Manderville, R. A. Can.
J. Chem. 2005, 83, 1261–1267. (d) McLaughlin, C. K.; Lantero, D. R.;
Manderville, R. A. J. Phys. Chem. A 2006, 110, 6224–6230.
(12) Kikugawa, K.; Kato, T.; Kojima, K. Mutat. Res. 1992, 268, 65–75.
(5) Stover, J. S.; Ciobanu, M.; Cliffel, D. E.; Rizzo, C. J. J. Am. Chem.
Soc. 2007, 129, 2074–2081.
(6) Luo, W.; Muller, J. G.; Rachlin, E. M.; Burrows, C. J. Org. Lett.
2000, 2, 613–616.
10.1021/ol8004694 CCC: $40.75
Published on Web 04/08/2008
2008 American Chemical Society