Synthesis and antiviral evaluation of 3′-C-trifluoromethyl nucleoside derivatives bearing adenine as the base

Article abstract of DOI:10.1081/NCN-100002423

3′-deoxy-3′-C-trifluoromethyl-(3), 2′,3′-dideoxy-3′-C-trifluoromethyl-(5) and 2′,3′-dideoxy-2′,3′-didehydro-3′- C-trifluoromethyladenosine (6) derivatives have been synthesized and their antiviral properties examined. All these derivatives were stereospecifically prepared by glycosylation of adenine with a trifluoromethyl sugar precursor (1), followed by appropriate chemical modifications. The prepared compounds were tested for their activity against HIV, but they did not show an antiviral effect.

Full text of DOI:10.1081/NCN-100002423

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SYNTHESIS AND ANTIVIRAL EVALUATION OF 3′-
C-TRIFLUOROMETHYL NUCLEOSIDE DERIVATIVES
BEARING ADENINE AS THE BASE
Frédéric Jeannot a , Christophe Mathé a & Gilles Gosselin a
a 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: Frédéric Jeannot , Christophe Mathé & Gilles Gosselin (2001) SYNTHESIS AND ANTIVIRAL EVALUATION
OF 3′-C-TRIFLUOROMETHYL NUCLEOSIDE DERIVATIVES BEARING ADENINE AS THE BASE, Nucleosides, Nucleotides and
Nucleic Acids, 20:4-7, 755-758, DOI: 10.1081/NCN-100002423
To link to this article: http://dx.doi.org/10.1081/NCN-100002423
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 755–758 (2001)
SYNTHESIS AND ANTIVIRAL EVALUATION
OF 3ꢀ-C-TRIFLUOROMETHYL NUCLEOSIDE
DERIVATIVES BEARING ADENINE AS THE BASE
Fre´de´ric Jeannot, 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
3ꢀ-deoxy-3ꢀ-C-trifluoromethyl- (3), 2ꢀ,3ꢀ-dideoxy-3ꢀ-C-trifluoromethyl- (5) and
2ꢀ,3ꢀ-dideoxy-2ꢀ,3ꢀ-didehydro-3ꢀ-C-trifluoromethyladenosine (6) derivatives
have been synthesized and their antiviral properties examined. All these deriva-
tives were stereospecifically prepared by glycosylation of adenine with a triflu-
oromethyl sugar precursor (1), followed by appropriate chemical modifications.
The prepared compounds were tested for their activity against HIV, but they
did not show an antiviral effect.
INTRODUCTION
It has been found that many 2ꢀ,3ꢀ-dideoxynucleosides and their 2ꢀ,3ꢀ-unsatura-
ted counterparts show potent activity against human immunodeficiency virus (HIV)
(1). In order to discover new nucleoside derivatives with antiviral activity, modifica-
tions of the base and/or sugar moiety of natural nucleosides can be attempted. As a
part of our ongoing research on this topic, we have synthesized, from a common tri-
fluoromethyl sugar precursor, various 3ꢀ-C-trifluoromethyl nucleoside derivatives
bearing adenine as the base. Many advantages can be expected from the presence
of a CF3 group on the sugar moiety of nucleosides, including high lipophilicity
and increased chemical and/or enzymatic stability. Herein, we report the synthesis
(in a stereospecific manner), chemical stability studies as well as the results of
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Copyright 2001 by Marcel Dekker, Inc.
www.dekker.com

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JEANNOT, MATHE, AND GOSSELIN
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the biological evaluations of hitherto unknown 3ꢀ-deoxy- 3ꢀ-C-CF3, 2ꢀ,3ꢀ-dideoxy-
3ꢀ-C-CF3 and 2ꢀ,3ꢀ-unsaturated-3ꢀ-C-CF3 nucleoside derivatives of adenine (3, 5
and 6).
SYNTHESIS
The synthesis began with the preparation of the trifluoromethyl sugar pre-
cursor, namely, 1,2-di-O-acetyl-5-O-benzoyl-3-deoxy-3-C-trifluoromethyl-β-D-
ribofuranose (1) which was obtained in 37% overall yield from commercially
available diacetone-D-glucose following a modified procedure initially developed
by Portella et al. (2) (Scheme). A glycosylation reaction with adenine and the suit-
ably 1,2-di-O-acetyl-5-O-benzoyl-3-deoxy-3-C-trifluoromethyl-β-D-ribofuranose
(1) using stannic [tin(IV)] chloride as a catalyst afforded the protected deriva-
tive 2. Deprotection of 2 with methanolic ammonia provided the desired nucle-
oside 3. In order to prepare the target compounds 5 and 6, regioselective 2ꢀ-O-
deacylation of 2 was accomplished to give the intermediate 4. The latter was
then converted to the 2ꢀ,3ꢀ-dideoxy-3ꢀ-C-CF3-nucleoside derivative 5 via a rad-
ical reductive process and subsequent deprotection with methanolic ammonia.
On the other hand, introduction of a double bound between the 2ꢀ and 3ꢀ po-
sitions was achieved from 4 via a base-promoted β-elimination of the corre-
sponding 2ꢀ-O-mesylate derivative by treatment with TBAF in THF. Finally,
treatment with methanolic ammonia gave the 2ꢀ,3ꢀ-unsaturated-3ꢀ-C-CF3-nucleo-
side derivative 6.
Scheme.

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3ꢀ-C-TRIFLUOROMETHYL NUCLEOSIDES
Table.
757
Structural assignments for all the compounds synthesized in this work
were based on elemental analysis and physicochemical properties (melting point,
1H NMR, 13C NMR, 19F NMR, UV, mass spectra and optical rotation) (3).
CHEMICAL STABILITY STUDIES
Owing to the high electron withdrawing power of the CF3 group and its
potential stabilizing effect on the lability of a glycosyl-purine bound, we have
examined the stability at buffer pH 2 and 7 of the nucleosides 5 and 6 compared
to ddA and d4A (Table). These results show the benefit of the trifluoromethyl
group regarding the chemical stability of the 2ꢀ,3ꢀ-dideoxy-3ꢀ-C-CF3- and 2ꢀ,3ꢀ-
unsaturated nucleoside derivatives of adenosine.
BIOLOGICAL EVALUATIONS
The nucleosides 3, 5 and 6 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 (generally 100 µM). The anti-HIV assays on cell culture were performed by
following previously established procedures as described in ref. 4.
CONCLUSION
From this work, it appears that 3ꢀ-C-trifluoromethyl nucleoside derivatives of
adenine do not inhibit the replication of HIV. Evaluation of these compounds against
a broad range of other viruses, as well as the synthesis of 3ꢀ-C-CF3-nucleoside
derivatives bearing other purine and pyrimidine bases are currently in progress in
our laboratory. It is noteworthy that during the course of our studies, the synthesis

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JEANNOT, MATHE, AND GOSSELIN
758
and the anti-HIV evaluation of some 3ꢀ-C-CF3-nucleoside derivatives of cytosine
have been reported (5).
ACKNOWLEDGMENTS
The investigations were supported by Grants from A.N.R.S., “Agence
Nationale de Recherches sur le SIDA”, France. We gratefully acknowledge
Dr A.-M. Aubertin (Universite´ Louis Pasteur, Strasbourg, France) for the biologi-
cal results. One of us (F. J.) is particularly grateful to the Ministe`re de l’Education
Nationale, de la Recherche et de la Technologie, France, for a doctoral fellowship.
REFERENCES
1. De Clercq, E. Clin. Microb. Rev., 1995, 8, 200–239.
2. Lavaire, S.; Plantier-Royon, R.; Portella, C. Nucleosides Nucleotides, 1998, 17, 2267–
2280.
1
3. Selected NMR data. Compound 5: H NMR (DMSO-d6, 400 MHz) δ 2.66 (m, 1H),
2.95 (m, 1H), 3.45–3.74 (m, 3H), 4.22 (m, 1H), 5.37 (t, 1H, J = 5.3 Hz)), 6.30
(t, 1H, J = 6.4 Hz), 7.35 (br s, 2H), 8.13 (s, 1H), 8.36 (s, 1H); Compound 6:
1H NMR (DMSO-d6, 400 MHz) δ 3.61–3.69 (m, 2H), 5.12 (m, 1H), 5.36 (t, 1H,
J = 5. 0 Hz), 6.99 (d, 1H, J = 1.7 Hz), 7.06 (br s, 1H), 7.31 (br s, 2H), 8.14 (s, 1H),
8.20 (s, 1H).
4. Meier, C.; Aubertin, A.-M.; de Monte, M.; Faraj, A.; Sommadossi, J.-P.; Pe´rigaud, C.;
Imbach, J.-L.; Gosselin, G. Antiviral Chem. Chemother., 1998, 9, 41–51.
5. Sharma, P. K.; Nair, V. Nucleosides Nucleotides & Nucleic Acids, 2000, 19, 757–774.

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