Synthesis of new homo and heterodinucleosides containing the 2′,3′-dideoxynucleosides AZT and D4T

Article abstract of DOI:10.1081/NCN-100002468

The synthesis of new dinucleosides of AZT and D4T is described.

Full text of DOI:10.1081/NCN-100002468

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SYNTHESIS OF NEW HOMO AND
HETERODINUCLEOSIDES CONTAINING THE 2′,3′-
DIDEOXYNUCLEOSIDES AZT AND D4T
M. Taourirte , H. B. Lazrek , J. J. Vasseur a , M. Ferrero , S. Fernandez & V. Gotor
a CNRS-Université Montpellier II, Lab. Chimie Organique Biomoléculaire de Synthèse,
UMR 5625, France
Published online: 07 Feb 2007.
To cite this article: M. Taourirte , H. B. Lazrek , J. J. Vasseur , M. Ferrero , S. Fernandez & V. Gotor (2001) SYNTHESIS
OF NEW HOMO AND HETERODINUCLEOSIDES CONTAINING THE 2′,3′-DIDEOXYNUCLEOSIDES AZT AND D4T, Nucleosides,
Nucleotides and Nucleic Acids, 20:4-7, 959-962
To link to this article: http://dx.doi.org/10.1081/NCN-100002468
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 959–962 (2001)
SYNTHESIS OF NEW HOMO AND
HETERODINUCLEOSIDES CONTAINING THE
2ꢀ,3ꢀ-DIDEOXYNUCLEOSIDES AZT AND D4T
M. Taourirte,1 H. B. Lazrek,2,∗ J. J. Vasseur,3 M. Ferrero,4
S. Fernandez,4 and V. Gotor4
1Faculty of Sciences and Techniques Gueliz, BP : 618, 40 000,
Marrakech, Morocco
2Lab. of Bioorganic chemistry, Faculty of Sciences Semlalia,
Marrakech, Morocco
3Lab. Chimie Organique Biomole´culaire de Synthe`se, UMR 5625
CNRS-Universite´ Montpellier II, France
4Lab. of Bioorganic Chemistry, Faculty of Chemistry, Oviedo, Spain
ABSTRACT
The synthesis of new dinucleosides of AZT and D4T is described.
The rapid spread of the human immunodeficiency virus (VIH), mainly HIV-1,
the etiological agent of Acquired immunodeficiency syndrome (AIDS) is urging
scientists to develop new drugs that can interrupts the viral life cycle. Efficient
vaccine development is steal faced with the ongoing mutational events of HIV that
enable it to evade the immune system. Efforts are now focused on the design of
new drugs that will arrest the viral life cycle. Some drugs such as AZT, D4T, DDC
and DDI have been approved so far. These nucleosides analogues are incorporated
into the retroviral DNA by the reverse transcriptase resulting in chain termination.
In fact, the main benefits of a combination therapy against HIV-infections,
is to prevent emergence of virus drug resistance and the reduction of toxicity (1).
Other results suggest that anti-HIV activity is principally dependent on lipophilicity
∗Corresponding author.
959
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C
Copyright 2001 by Marcel Dekker, Inc.
www.dekker.com

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TAOURIRTE ET AL.
Scheme 1.
of the drug (2). The latter can easily penetrate the cell membrane either by a passive
diffusion or by structural membrane deformation if the drug contain a lipophilic
group (linker). According to these remarks, an interesting alternative approach
to combination therapy, would be the use of dimers. For these investigations we
have selected as models the homodimers (AZT-CO-NH-(CH2)n-NH-CO-AZT and
D4T-CO-NH-(CH2)n-NH-CO-D4T) and an heterodimer (AZT-CO-NH-(CH2)n-
NH-CO-D4T) in the aim to combine the inhibitory capacity of these two drugs
(AZT, D4T) and to increase their lipophilicity.
The starting nucleosides AZT and D4T were prepared according to the litera-
ture (2). A general methodology was then successfully tried to give homo dimers of
AZT (Scheme 1). The synthetic scheme is based on the 5ꢁ directed intermolecular
nucleophilic substitutions at the 5ꢁ-activated position of AZT.
To study the effect of the spacer chain on the antiviral activity and the
lipophilicity, we carried out the synthesis of some homo and heterodimers with
a higher chain-length. The preparation of these dimers was achieved as described
in Schemes 2, 3 and 4.
The methodology described here allowed us to prepare various homo and
heterodimers characterized by the presence of one or two drugs used in clinical
a: DIAD/PPh3/C6H5CO2H; b: NaN3/DMF; c: NH3/MeOH; d: vinyl chloride/Pyridine; e: MsCl/Pyridine;
f: NaOH/reflux; g: tBuOK/DMSO/TA;
Scheme 2. Synthesis of activated precursors of AZT and D4T.

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961
Scheme 3. Synthesis of the homodimer of AZT and the heterodimer of AZT and D4T.
Scheme 4. Synthesis of the homodimer of D4T.
treatment and connecting residues of various lengths with carbonate and carbamate
functionality susceptible to hydrolyze in biological environment upon esterase
activation releasing the active nucleosides.
The biological activities concerning the inhibition of the multiplication of the
HIV-1 and 2 are under investigations.
ACKNOWLEDGMENTS
We thank the CNR (Morocco), the CNRS (France) and the Moroccan-Spanish
Commission for financial support.

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REFERENCES
1. Schott, H.; Ludwig, P.S.; Immelmann, A.; Schwendener, R.A. Eur. J.Med. Chem. 1999,
34, 343–352 and references cited therein.
2. Siddiqui, A.Q.; Mc Guigan, C.; Ballatore, C.; Zuccotto, F.; Gilbert, I.H.; De Clercq, E.;
Balzarini, J. J.Med. Chem. 1999, 42, 4122–4128 and references cited therein.

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