Synthesis and antiviral evaluation of C-4-hydrazide derivatives of 2′,3′-dideoxycytidine

Article abstract of DOI:10.1081/NCN-100002484

Syntheses of three hitherto unknown derivatives of 2′,3′-dideoxycytidine, namely C-4-(salicylic hydrazide)-ddC, C-4-(N-butyloxycarbonyl-isoleucine hydrazide)-ddC and its N-unprotected chlorhydrate salt have been carried out. These compounds do not induce inhibition of HIV-1 replication in cell culture experiments. Nevertheless, the modifications on the base moiety increased in all cases the lipophilicity of the parent molecule with an acceptable water solubility compared to ddC.

Full text of DOI:10.1081/NCN-100002484

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SYNTHESIS AND ANTIVIRAL EVALUATION OF C-4-
HYDRAZIDE DERIVATIVES OF 2′,3′-DIDEOXYCYTIDINE
Valérie Boudou-Vivet a , Christophe Mathé a & Gilles Gosselin b
a Université Montpellier II , Laboratoire de Chimie Organique Biomoléculaire de
Synthèse, UMR 5625 CNRS-UM II, Place E. Bataillon, Montpellier, Cedex 5, 34095, France
b Université Montpellier II , Laboratoire de Chimie Organique Biomoléculaire de
Synthèse, UMR 5625 CNRS-UM II, Place E. Bataillon, Montpellier, Cedex 5, 34095, France
Published online: 07 Feb 2007.
To cite this article: Valérie Boudou-Vivet , Christophe Mathé & Gilles Gosselin (2001) SYNTHESIS AND ANTIVIRAL
EVALUATION OF C-4-HYDRAZIDE DERIVATIVES OF 2′,3′-DIDEOXYCYTIDINE, Nucleosides, Nucleotides and Nucleic Acids,
20:4-7, 1029-1032, DOI: 10.1081/NCN-100002484
To link to this article: http://dx.doi.org/10.1081/NCN-100002484
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 1029–1032 (2001)
SYNTHESIS AND ANTIVIRAL EVALUATION
OF C-4-HYDRAZIDE DERIVATIVES OF
2ꢀ,3ꢀ-DIDEOXYCYTIDINE
Vale´rie Boudou-Vivet, Christophe Mathe´,
and Gilles Gosselin∗
Laboratoire de Chimie Organique Biomole´culaire de Synthe`se,
UMR 5625 CNRS-UM II, Universite´ Montpellier II, Place E. Bataillon,
34095 Montpellier Cedex 5, France
ABSTRACT
Syntheses of three hitherto unknown derivatives of 2ꢀ,3ꢀ-dideoxycytidine,
namely C-4-(salicylic hydrazide)-ddC, C-4-(N-butyloxycarbonyl-isoleucine
hydrazide)-ddC and its N-unprotected chlorhydrate salt have been carried out.
These compounds do not induce inhibition of HIV-1 replication in cell
culture experiments. Nevertheless, the modifications on the base moiety
increased in all cases the lipophilicity of the parent molecule with an acceptable
water solubility compared to ddC.
INTRODUCTION
During the last decade, significant progress has been accomplished in the
discovery of new antiviral agents and in the therapeutic approaches against human
immunodeficiency virus (HIV) infection (1). To date, six nucleoside analogues have
been approved by the Food and Drug Administration for the treatment of AIDS.
However, these compounds suffer from several drawbacks such as low oral bioavail-
ability, chemical or enzymatic instability or non appropriate biodistribution (2,3).
Within the framework of our research program on the improvement of phar-
macological and pharmacokinetic properties of nucleoside analogues with antiviral
∗Corresponding author.
1029
ꢁ
C
Copyright 2001 by Marcel Dekker, Inc.
www.dekker.com

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BOUDOU-VIVET, MATHE, AND GOSSELIN
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properties, we have designed hitherto unknown derivatives of 2ꢀ,3ꢀ-dideoxycytidine
(ddC). Here, we report the preparation and the studies of C-4-(salicylic hydrazide)-
ddC, (4) C-4-(N-butyloxycarbonyl-isoleucine hydrazide)-ddC (6) and its N-unpro-
tected chlorhydrate salt (7).
SYNTHESES
From a synthetic viewpoint, the target compounds (4, 6 and 7) were prepared
from commercially available 2ꢀ,3ꢀ-dideoxyuridine (ddU).
Firstly, the 5ꢀ-hydroxyl function of ddU was suitably protected with a ben-
zoyl group to afford compound (1). Then, the C-4 position of the base was ac-
tivated via triisopropylbenzene-sulfonyl chloride treatment to give (2), as a key
intermediate.
Reaction of 2 with commercially available salicylic hydrazide provided com-
pound (3), which upon treatment with methanolic ammonia gave the first desired
molecule (4) in 70% yield. Isoleucine hydrazide, (5) prepared by action of hydrazine
on N-Boc-isoleucine in the presence of BOP and triethylamine in dichloromethane)
was reacted with intermediate (2) to give a fully protected derivative which upon
treatment with methanolic ammonia afforded C-4-(N-butyloxycarbonyl-isoleucine
hydrazide)-ddC (6). Finally, removal of the Boc protecting group from 6 afforded
the last desired compound (7).
Scheme.

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C-4-HYDRAZIDE DERIVATIVES OF 2ꢀ,3ꢀ-DIDEOXYCYTIDINE
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Table.
Partition Coefficient
Solubility
P
Log P
g/l
ddC
4
6
0.04
1.19
8.19
0.077
−1.36
0.07
0.91
−1.06
63
15
4
7
55
Structural assignments for compounds 4, 6 and 7 were based on elemental
analysis and physicochemical properties.
LIPOPHILICITY AND SOLUBILITY STUDIES
Thelipophilicityofthenewcompounds(4, 6and7)wasdeterminedmeasuring
their partition coefficient between octanol and water. All of them show a higher
lipophilicity than the reference molecule ddC, with an acceptable water solubility.
ANTIVIRAL EVALUATION
Compounds 4, 6 and 7 were tested for their in vitro inhibitory effects on the
replication of HIV-1 in CEM-SS and MT-4 cell systems. None of these compounds
showed significant antiviral activity nor cytotoxicity at the highest concentration
tested (100 µM). In the same assays, ddC had EC50 of 0.023 µM in CEM-SS and
≥1 µM in MT-4 cells.
CONCLUSION
From the present work, it appears that the C-4 hydrazide derivatives of ddC
do not induce inhibition of HIV-1 replication in cell culture experiments. Among
the several hypotheses than can explain this lack of activity, the inability of these
compounds to release appropriately (intra or extra-cellularly) the parent ddC nu-
cleoside, as well as their chemical or enzymatic instability (with cleavage of the
glycosidic bond), can be proposed. Nevertheless, the modifications on the base moi-
ety increased in all cases the lipophilicity of the parent molecule with an acceptable
water solubility compared to ddC. Synthesis and antiviral evaluation of other ddC
derivatives bearing various groups on the base moiety with different linkers are
currently in progress in our laboratory.
ACKNOWLEDGMENTS
These investigations were supported by grants from the “Agence Nationale
de la Recherche sur le SIDA” (ANRS) France. We gratefully acknowledge

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BOUDOU-VIVET, MATHE, AND GOSSELIN
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Dr A. M. Aubertin (Universite´ Louis Pasteur, Strasbourg, France) for the biological
evaluations. One of us (V. B.-V.) is particularly grateful to the ANRS, France for a
postdoctoral fellowship.
REFERENCES
1. Vandamme, A.-M.; Van Vaerenbergh, K.; De Clercq, E. Antiviral Chem. & Chemother.,
1998, 9, 187–203.
2. Geleziunas, R.; Schipper, H.M.; Wainberg, M.A. AIDS, 1992, 6, 1411–1426.
3. Atwood, W.J.; Berger, J.R.; Kaderman, R.; Tornatore, C.S.; Major, E.O. Clin. Microbiol.
Rev. 1993, 6, 339–366.

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