Synthesis and biological evaluation of β-D-pentofuranonucleoside derivatives of 2-azidoadenine and 6-azidopurines

Article abstract of DOI:10.1081/NCN-120021964

β-D-pentofuranonucleoside derivatives of 2-azidoadenine and 6-azidopurines have been synthesized. The azido-tetrazolo tautomerism observed on such nucleoside analogues has been studied. The compounds were tested for their activity against HIV and HBV but they did not show significant antiviral effect.

Full text of DOI:10.1081/NCN-120021964

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Synthesis and Biological Evaluation of β-D-
Pentofuranonucleoside Derivatives of 2-Azidoadenine
and 6-Azidopurines
Christophe Mathé a c , Thierry Lioux a & Gilles Gosselin a b
a Laboratoire de Chimie Organique Biomoléculaire de Synthèse , CNRS-Université Montpellier
II , Montpellier, France
b Laboratoire Coopératif Idenix , CNRS-Université Montpellier II , Montpellier, France
c Laboratoire de Chimie Organique Biomoléculaire de Synthèse , CNRS-Université Montpellier
II , UMR 5625, Montpellier, France
Published online: 31 Aug 2006.
To cite this article: Christophe Mathé , Thierry Lioux & Gilles Gosselin (2003) Synthesis and Biological Evaluation of β-D-
Pentofuranonucleoside Derivatives of 2-Azidoadenine and 6-Azidopurines, Nucleosides, Nucleotides and Nucleic Acids, 22:5-8,
605-609, DOI: 10.1081/NCN-120021964
To link to this article: http://dx.doi.org/10.1081/NCN-120021964
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 605–609, 2003
Synthesis and Biological Evaluation of
b-D-Pentofuranonucleoside Derivatives
of 2-Azidoadenine and 6-Azidopurines
1,
Christophe Mathe, Thierry Lioux, and Gilles Gosselin
1
1,2
*
´
1
´
Laboratoire de Chimie Organique Biomoleculaire de Synthese and
Laboratoire Cooperatif Idenix, CNRS-Universite Montpellier II,
`
2
´
´
Montpellier, France
ABSTRACT
b-D-pentofuranonucleoside derivatives of 2-azidoadenine and 6-azidopurines
have been synthesized. The azido-tetrazolo tautomerism observed on such nucleo-
side analogues has been studied. The compounds were tested for their activity
against HIV and HBV but they did not show significant antiviral effect.
Key Words: Nucleoside analogues; Azido-tetrazolo tautomerism.
INTRODUCTION
Some adenosine analogues substituted at the 2-position show interesting bio-
logical properties. For instance, 2-chloroadenosine derivatives exhibit potent anti-
tumoral and antiviral activities as demonstrated with 2-chloro-20-deoxyadenosine
´
*Correspondence: Christophe Mathe, Laboratoire de Chimie Organique Biomoleculaire de
Synthese, UMR 5625 CNRS-Universite Montpellier II, Montpellier, France; E-mail: cmathe@
´
`
´
univ-montp2.fr.
605
DOI: 10.1081/NCN-120021964
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

´
Mathe, Lioux, and Gosselin
606
(Cladribine),[1] 2-chloro-20,30-dideoxyadenosine[2] and 2-chloro-20,30-dideoxy-20,30-
didehydroadenosine,[2] respectively. In order to discover new nucleoside derivatives
endowed with antiviral activity, modifications of the base and=or sugar moiety of
natural nucleosides can be attempted. As a part of our ongoing research program
on this topic, we have synthesized various b-D-pentofuranonucleoside derivatives
bearing 2-azidoadenine as the base, most of them being hitherto unknown. Herein,
we report on the synthesis of the ribo-, 20-deoxy-, 20,30-dideoxy- and 20,30-dideoxy-
20,30-didehydro-b-D-pentofuranonucleosides of 2-azidoadenine. The azido-tetrazolo
tautomerism observed on 2-azidoadenine nucleoside analogues led us to synthesize
the 6-azidopurine ribonucleoside counterparts in order to have a more thorough
investigation on such tautomerism.
SYNTHESIS
The preparation of the b-D-pentofuranonucleosides (5-8) of 2-azidoadenine
(Sch. 1) was achieved from their corresponding 2-chloro-ribo- (1), -20-deoxy- (2),
-20,30-dideoxy- (3) and -20,30-dideoxy-20,30-didehydro- (4) b-D-pentofuranonucleoside
counterparts via a methodology previously described in the case of 2-azidoadeno-
sine.[3]
Additionally, the synthesis of the 6-azidopurine nucleoside derivatives (11 and
12) was carried out from their corresponding 6-chloro ribonucleoside counterparts
by reaction of compound 9 with sodium azide in DMF or by treatment of compound
10 with hydrazine hydrate, followed by sodium nitrite in aqueous acetic acid at 0ꢀC
(Sch. 2).
Structural assignments for all the compounds were based on elemental analysis
1
and physicochemical properties (melting point, H NMR, 13C NMR, UV, IR, mass
spectra and optical rotation).
STUDIES ON THE AZIDO-TETRAZOLO TAUTOMERISM
Briefly, azido-substituted p-deficient nitrogen heterocycles may spontaneously
cyclize to give a fused tetrazolo ring or, at least, an equilibrium mixture of both forms.
Scheme 1.

2- and 6-Azidopurines b-D-Pentofuranonucleosides
607
Scheme 2.
Such azido-tetrazolo tautomerism has been previously reported for the base
2-azidoadenine.[4] The latter has been shown to exist in DMSO solution under the
azido form (A) in balance with the tetrazolo[5,1-b] and [1,5-a] form, T1 and T2
respectively (Sch. 3). The physico-chemical properties of the b-D-pentofuranonu-
cleosides (5-8) of 2-azidoadenine showed that these compounds exist in balance
between only two forms, the A and T2 form. Furthermore, analysis of this equili-
brium shown its temperature and solvent dependence. Our results are in accordance
with those previously reported for compounds 5[5] and 6.[6]
Additionally, the azido-tetrazolo tautomerism on 6-azidopurine ribonucleoside
derivatives (11 and 12) was also investigated by means of their physico-chemical
properties. Our results clearly shown that compounds 11 and 12 exist only as their
tetrazolo [5,1-i] forms (Sch. 4). These data are in agreement with those previously
reported for compound 12.[7]
Scheme 3.

´
Mathe, Lioux, and Gosselin
608
Scheme 4.
BIOLOGICAL EVALUATIONS
The b-D-pentofuranonucleoside derivatives of 2-azidoadenine (5-8) and 6-azido-
purines (11 and 12) were tested for their in vitro inhibitory effects on the replication
of HIV and HBV. None of these compounds showed significant antiviral activity.
ACKNOWLEDGMENTS
´
We gratefully acknowledge Dr A.-M. Aubertin (Universite Louis Pasteur, Stras-
bourg, France) and Pr P. La Colla (Universita degli Studi di Cagliari, Italy) for the
`
`
biological results. One of us (T. L.) is particularly grateful to the Ministere de
l’Education Nationale, de la Recherche et de la Technologie, France, for a doctoral
fellowship.
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