Scheme 1
Scheme 2
Lakshman, Johnson, Hopkins and Sigurdsson, and others
demonstrated the utility of the Buchwald-Hartwig reaction
for the synthesis of nucleoside adducts of carcinogens.13,18-32
We have previously reported the synthesis of the C8-
deoxyguanosine adduct of IQ and its subsequent incorpora-
tion into oligonucleotides via phosphoramidite-based solid-
phase synthesis.28,33 The key step was a Buchwald-Hartwig
reaction between a suitably protected 8-bromo-2′-deoxygua-
nosine derivative with IQ. We report here the synthesis of
the N2-deoxyguanosine adduct of IQ, which also uses the
Buchwald-Hartwig reaction as the key step.
Two strategies have been previously employed for the
synthesis of N2-modified deoxyguanosine derivatives utilizing
the Buchwald-Hartwig reaction. The first involved the
reaction of a suitably protected 2-bromopurine riboside with
an arylamine,23-27 while the second strategy utilized the
coupling of the N2-amino group of deoxyguanosine with
haloarenes.19,26,27 To examine both strategies, we synthesized
the protected 5-bromo- and 5-amino-IQ derivatives as shown
in Scheme 2. The electrophilic bromination of IQ was
previously reported to give the desired 5-bromo-IQ (7).34
Protection of the amine as the corresponding benzamide gave
There are multiple lines of evidence suggesting that the
C8- and N2-deoxyguanosine adducts of IQ are repaired at
different efficiencies.6 In feeding studies with rats and
monkeys, it was found that the major DNA lesion 24 h after
a single dose of IQ was the C8-adduct.12 The relative ratio
of the C8- to N2-deoxyguanosine adducts was in the range
of 6:1, which roughly parallels the natural reactivity of the
IQ nitrenium ion toward DNA. However, in chronically
treated monkeys undergoing long-term carcinogen bioassays,
a sharp increase in the proportion of N2-adduct was observed
after 3.6 years. This increase was found in slowly dividing
tissue such as the liver, pancreas, and kidney. There was no
increased persistence of the N2-adduct in colon tissue, which
divides at a high rate. These observations suggest that the
C8-adduct (5) is repaired more efficiently in slow growing
tissue. This has led to speculation that the minor N2-
deoxyguanosine adduct (6) plays a more significant role in
the tumorigenic properties of IQ and other aromatic amines.
The Buchwald-Hartwig palladium-catalyzed N-arylation
reaction has been widely used for the synthesis of modified
nucleosides.13-15 Chida and co-workers used this reaction
as the key step in the total synthesis of the nucleoside
antibiotic spicamycin.16,17 Shortly thereafter, reports by
(18) Lakshman, M. K.; Keeler, J. C.; Hilmer, J. H.; Martin, J. Q. J. Am.
Chem. Soc. 1999, 121, 6090-6091.
(19) De Riccardis, F.; Bonala, R. R.; Johnson, F. J. Am. Chem. Soc.
1999, 121, 10453-10460.
(20) Harwood, E. A.; Sigurdsson, S. T.; Edfeldt, N. B. F.; Reid, B. R.;
Hopkins, P. B. J. Am. Chem. Soc. 1999, 121, 5081-5082.
(21) Harwood, E. A.; Hopkins, P. B.; Sigurdsson, S. T. J. Org. Chem.
2000, 65, 2959-2964.
(22) De Riccardis, F.; Johnson, F. Org. Lett. 2000, 2, 293-295.
(23) Bonala, R. R.; Shishkina, I. G.; Johnson, F. Tetrahedron Lett. 2000,
41, 7281-7284.
(24) Lakshman, M. K.; Gunda, P. Org. Lett. 2003, 5, 39-42.
(25) Johnson, F.; Bonala, R.; Tawde, D.; Torres, M. C.; Iden, C. R. Chem.
Res. Toxicol. 2002, 15, 1489-1494.
(10) Turesky, R. J.; Markovic, J. Chem. Res. Toxicol. 1994, 7, 752-
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H.-G.; Mah, H. J. Org. Chem. 2003, 68, 6020-6030.
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1999, 40, 2573-2576.
(17) Suzuki, T.; Suzuki, S. T.; Yamada, I.; Koashi, Y.; Yamada, K.;
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