Synthesis of C8-modified 2′-deoxyadenosine with carcinogenic arylamines

Article abstract of DOI:10.1080/15257770701527976

The synthesis of phosphoramidites of C8-modified 2′-deoxyadenosine with carcinogenic arylamines p-anisidine and 4-aminobiphenyl is described. Two different methods were studied related to the glycon and base protection groups. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770701527976

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Nucleosides, Nucleotides and Nucleic
Acids
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Synthesis of C8-Modified 2″-
Deoxyadenosine with Carcinogenic
Arylamines
M. I. Jacobsen a & C. Meier a
a Department of Chemistry , Organic Chemistry, Faculty of Science,
University of Hamburg , Hamburg, Germany
Published online: 05 Dec 2007.
To cite this article: M. I. Jacobsen & C. Meier (2007) Synthesis of C8-Modified 2″-Deoxyadenosine
with Carcinogenic Arylamines, Nucleosides, Nucleotides and Nucleic Acids, 26:10-12, 1217-1220, DOI:
10.1080/15257770701527976
To link to this article: http://dx.doi.org/10.1080/15257770701527976
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Nucleosides, Nucleotides, and Nucleic Acids, 26:1217–1220, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701527976
SYNTHESIS OF C8-MODIFIED 2ꢀ-DEOXYADENOSINE
WITH CARCINOGENIC ARYLAMINES
M. I. Jacobsen and C. Meier
Department of Chemistry, Organic Chemistry, Faculty
2
of Science, University of Hamburg, Hamburg, Germany
The synthesis of phosphoramidites of C8-modified 2 ꢁ-deoxyadenosine with carcinogenic ary-
2
lamines p-anisidine and 4-aminobiphenyl is described. Two different methods were studied related
to the glycon and base protection groups.
Keywords 2ꢁ-Deoxyadenosine; carcinogens; aromatic amines; c8-adducts
INTRODUCTION
Some aromatic amines are known carcinogens. Monocyclic aromatic
amines such as aniline or p-anisidine are classified as borderline carcino-
gens, whereas polycyclic aromatic amines like 2-aminofluorene belong to
the group of strong carcinogens. Poly- and monocyclic aromatic amines
form covalently bonded adducts with DNA after metabolic activation and
therefore may cause mutations and possible lead to cancer.[1] Predomi-
nantly, adduct formation was found with purine nucleosides. In in vivo stud-
6
ies C8- and N -arylamine adducts of 2ꢁ-deoxyadenosine (dA) 1, 2 were de-
tected although the corresponding adducts of 2ꢁ-deoxyguanosine (dG) 3
were found to higher extents (Figure 1).[2a,b]
The synthesis of the adducted dA-nucleoside phosphoramidites is a
prerequisite for the preparation of site-specifically C8-dA adduct modified
oligonucleotides. These oligonucleotides can then be used to study the mu-
tagenic effects, structure and DNA-repair of these lesions. In contrast to dG-
adducts, no synthetic route towards these dA-adducts is known until today.[3]
In 2001, Schoffers reported on the synthesis of C8-adducts of adenosine with
several arylamines using the Buchwald-Hartwig-reaction, but neither phos-
phoramidites nor oligonucleotides were prepared.[4]
Address correspondence to C. Meier, Department of Chemistry, Organic Chemistry, University
of Hamburg, Martin-Luther-King-Platz 6, Hamburg, D-20146, Germany. E-mail: chris.meier@chemie.
uni-hamburg.de
1217

1218
M.I. Jacobsen and C. Meier
FIGURE 1 In vivo detected adducts of dA and dG.
RESULTS AND DISCUSSION
The first approach toward C8-adducted 2ꢁ-deoxyadenosine with car-
cinogenic arylamines was accomplished by using tert-butyldimethylsilyl
(TBDMS) groups for blocking the 3ꢁ- and 5ꢁ-hydroxyl moieties in the
Pd-catalyzed cross coupling reaction. Starting from the literally known
silyl protected C8-brominated dA-derivative 4[5,6] 8-N-(arylamino)-3ꢁ,5ꢁ-
bis(TBDMS)-2ꢁ-dA 5a,b were synthesized by a Pd-catalyzed reaction using
10 mol% tris(dibenzylidenacetone)-palladium(0), 30 mol% racemic BINAP,
1.5 equivalents of caesium carbonate and 1.5 equivalents of p-anisidine or
4-aminobiphenyl in refluxing 1,2-dimethoxyethane. Protection of the N6-
amino function could be achieved using benzoylchloride in pyridine fol-
lowed upon treatment with a mixture of pyridine, water and 25% aq. ammo-
nia (4:2:1).
Surprisingly, the limiting step in this reaction sequence was the desily-
lation of the 3ꢁ,5ꢁ-hydroxyl groups. A complete deprotection could not be
achieved neither with tetrabutylammoniumfluoride nor triethylamine trihy-
drofluoride as deprotecting agent (Scheme 1).
In contrast to the benzoyl protected adducts 6, the adducts with un-
blocked N6-amino group 5 could be deprotected in nearly quantitative yields
within 12 h (Scheme 2). Nevertheless, this proves that fully deprotected C8-
adducts of 2ꢁ-deoxyadenosine with carcinogenic arylamines are accessible by
this method. Such compounds, of which 1 is known from in vivo[2a] and in
vitro studies but was never synthesized chemically before, are important as
analytical standards.
The fully deblocked adducts were then N-protected with the dimethyl-
formamidine group which is used in the so called “fast deprotection chem-
istry” in oligonucleotide synthesis. After dimethoxytritylation, phosphity-
lation of 10 led to the corresponding phosphoramidite 11 in 70% yield
(Scheme 3).
However, phosphoramidite 10 was very unstable and therefore unsuit-
able for further application in the automated DNA synthesis. In order to
avoid the problems with the TBDMS groups, these were replaced by the

C8-Modified 2 ꢁ-Deoxyadenosine
1219
SCHEME 1 Synthesis of C8 adducted 2ꢁ-deoxyadenosine with carcinogenic arylamines.
SCHEME 2 Fully deprotected adducts.
SCHEME 3 Preparation of the phosphoramidite 10.

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M.I. Jacobsen and C. Meier
tetraisopropyldisilyloxane (TIPDS) protecting group in the synthesis. The
cross coupling and the following benzoylation proceeded in nearly identi-
cal yields as described in Scheme 1. The following desilylation which was
the crucial step in the first synthesis route gave the desired products in ex-
cellent yields like in the case of the desilylation of the N 6-unprotected com-
pounds 5a,b (Scheme 2). We recently reported on this new strategy that led
to the C8-modified phosphoramidites in good yields.[7] A further difficulty
was the dimethoxytritylation of the 5ꢁ-hydroxyl group of 7, which showed
only low regioselectivity and long reaction times and therefore led to an in-
creasing amount of the 3ꢁ,5ꢁ-bis-dimethoxytritylated side product. According
to Ogilvie who had similar difficulties in the dimethoxytritylation of N 6-bz-
adenosine,[8] silver nitrate and 2,4,6-collidine were added to the reaction to
enhance the regioselectivity by accelerating the reaction rate. Now yields up
to 72% instead of 42–45% were obtained.
REFERENCES
1. Beland, F.A.; Beranek, D.T.; Dooley, K.L.; Heflich, R.H.; Kadlubar, F.F. Arylamine-DNA adducts in
vitro and in vivo: Their role in bacterial mutagenesis and urinary bladder carcinogenesis. Environ.
Health Persp. 1983, 49, 125–134.
2. a) Neumann, H.G. DNA damage in chemical carcinogenesis of aromatic amines. J. Cancer Res. Clin.
Onco. 1986, 112, 100–106. b) Kadlubar, F.F.; Anson, J.F.; Dooley, K.L.; Beland, F.A. Formation of
urothelial and hepatic DNA adducts of the carcinogen 2-naphthylamine. Carcinogenesis 1981, 2, 467–
470.
3. Bo¨ge, N.; Gra¨sl, S.; Meier, C. Synthesis and properties of oligonucleotides containing C8-
deoxyguanosine arylamine adducts of borderline carcinogens. J. Org. Chem. 2006, 71, 9728–9738.
4. Schoffers, E.; Olsen, P.D.; Means, J.C. Synthesis of C8-adenosine adducts of arylamines using palla-
dium catalysis. Org. Lett. 2001, 3, 4221–4223.
5. Guy, A.; Duplaa, A.-M.; Harel, P.; Te´oule, R. Synthesis and characterization of DNA fragments bear-
ing an adenine radiation product: 7,8-Dihydroadenin-8-one. Helv. Chimica Acta 1988, 71, 1566–1572.
6. Navacchia, M.L.; Chatgilialoglu, C.; Montevecchi, P.C. C5ꢁ-Adenosyl radical cyclization. A stereo-
chemical investigation. J. Org. Chem. 2006, 71, 4445–4452.
7. Jacobsen, M.I.; Meier, C. First synthesis of C8-arylamine adducts of 2ꢁ-deoxyadenosine and incorpo-
ration of the phosphoramidite into an oligonucleotide. Synlett 2006, 15, 2411–2414.
8. Hakimelahi, G.H.; Proba, Z.A.; Ogilvie, K.K. New catalysts and procedures for dimethoxytritylation
and selective silylation of ribonucleosides. Can. J. Chem. 1982, 60, 1106–1113.