Synthesis and study of conformationally restricted 3′-deoxy-3′, 4′-exo-methylene nucleoside analogues

Article abstract of DOI:10.1081/NCN-200059796

Hitherto unknown restricted 3′-deoxy-3′,4′-exo-methylene nucleoside derivatives bearing the nucleic acid naturally occurring pyrimidine bases have been synthesized. The compounds were tested for their activity against HIV, HBV, and several RNA viruses, bu

Full text of DOI:10.1081/NCN-200059796

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SYNTHESIS AND STUDY OF CONFORMATIONALLY
RESTRICTED 3′-DEOXY-3′,4′-EXO-METHYLENE
NUCLEOSIDE ANALOGUES
Julien Gagneron a , Gilles Gosselin a & Christophe Mathé a
a Laboratoire de Chimie Organique Biomoléculaire de Synthèse , UMR 5625 CNRS-Université
Montpellier II , Montpellier, Cedex 5, France
Published online: 15 Nov 2011.
To cite this article: Julien Gagneron , Gilles Gosselin & Christophe Mathé (2005) SYNTHESIS AND STUDY OF
CONFORMATIONALLY RESTRICTED 3′-DEOXY-3′,4′-EXO-METHYLENE NUCLEOSIDE ANALOGUES, Nucleosides, Nucleotides and
Nucleic Acids, 24:5-7, 383-385, DOI: 10.1081/NCN-200059796
To link to this article: http://dx.doi.org/10.1081/NCN-200059796
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (5--7):383–385, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200059796
SYNTHESIS AND STUDY OF CONFORMATIONALLY RESTRICTED
3’-DEOXY-3’,4’-EXO-METHYLENE NUCLEOSIDE ANALOGUES
5
´
Julien Gagneron, Gilles Gosselin, and Christophe Mathe
Laboratoire de Chimie
Organique Biomoleꢀculaire de Synth`ese, UMR 5625 CNRS-Universiteꢀ Montpellier II,
Montpellier, Cedex 5, France
5
Hitherto unknown restricted 3’-deoxy-3’,4’-exo-methylene nucleoside derivatives bearing the nucleic
acid naturally occurring pyrimidine bases have been synthesized. The compounds were tested for their
activity against HIV, HBV, and several RNA viruses, but they did not show significant antiviral effect.
Keywords Nucleoside Analogues/Antiviral Agents
INTRODUCTION
Over several decades, a large number of nucleoside analogues have been
synthesized and some of them have been shown to present potent antiviral or
antitumoral activities. In order to discover new nucleoside derivatives endowed
with biological activities, modifications of the base and/or sugar moiety of natural
nucleosides can be attempted. For our part, we chose to introduce modifications on
the sugar capable of restricting the dynamic equilibrium between the northern-type
and southern-type geometry that normally characterize the sugar moiety of
standard nucleosides in solution. In this respect, we have synthesized new
conformationally locked nucleoside analogues built on a 2-oxabicyclo[3.1.0.]hex-
ane system bearing purine and pyrimidine bases. Assuming that the conformation
and puckering[1] of the glycon moiety of nucleosides play a critical role in
modulating biological activity; for example, new conformationally restricted
nucleoside analogues could be used to obtain further information regarding the
correlation between sugar ring conformation and biological activity.
We gratefully acknowledge Pr. P. La Colla (Universit`a degli Studi di Cagliari, Italy) for the biological results.
J.G. is particularly grateful to the Minist`ere de l’Education Nationale, de la Recherche et de la Technologie, France,
for a doctoral fellowship. This work was supported by Grants from Ensemble contre le Sida, Sidaction, France, and
in part by the European Economic Community program ‘‘Flavitherapeutics’’ (QLK3-CT-2001-00506).
´
Address correspondence to Christophe Mathe, Laboratoire de Chimie Organique Biomoleꢀculaire de
Synth`ese, UMR 5625 CNRS-Universiteꢀ Montpellier II, Place Eug`ene Bataillon, Montpellier, Cedex 5 34095,
France; Fax: +33-(0)4-67-14042029; E-mail: cmathe@univ-montp2.fr
383
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384
J. Gagneron, G. Gosselin, and C. Mathe´
SCHEME 1 Synthesis of the sugar precursor 6.
SCHEME 2 Synthesis of the target nucleosides 10--12.

J. Gagneron, G. Gosselin, and C. Mathe´
385
SYNTHESIS
The synthesis of compound 1 was achieved from L-xylose in 3 steps using a
procedure previously established for D-xylose.[2] The cyclopropanation of
compound 2 was accomplished via a Simmons-Smith reaction following
Furukawa’s procedure[3] to afford a mixture of compounds 3a and 3b (ratio 3a/
3b: 98/2). Separation of compounds 3a and 3b was readily achieved on silica gel
column chromatography. Structural assignments of 3a and 3b were based upon 1H
NMR spectra and NOE effects. After cleavage of the isopropylidene group, an
oxidation-reduction process gave stereospecifically compound 5, which was finally
converted into the sugar precursor 6, obtained as a mixture of b- and a-anomers
(ratio a/b: 9/91) with an 20% overall yield from L-xylose (Scheme 1).
Coupling reactions of sugar 6 with silylated bases (uracil, thymine, and
cytosine) provided acetylated nucleosides 7--9 (Scheme 2). The deprotection of
7--9 afforded the target restricted 3’-deoxy-3’,4’-exo-methylene pyrimidine nucleo-
side analogues 10--12.
Structural assignments for all the compounds were based upon their elemental
1
analysis and physicochemical properties (melting point, H NMR, 13C NMR, UV,
mass spectra, and optical rotation).
CONFORMATIONAL ANALYSIS
We used the program Pseurot[4] for the determination of the conformation of
the furanose ring taking compound 11 as a model. After determination of
parameters A and B using FHH = Anj + B, a convergence was obtained toward a
south-type conformation with P = 158° and nmax = 23.9° (x [south = 0.69]) and
north-type conformation with P = À26.5° and nmax = 21.6°.
BIOLOGICAL EVALUATIONS
The nucleoside analogues 10--12 were tested for their in vitro inhibitory
effects on the replication of HIV, HBV, and several RNA viruses. None of these
compounds showed significant antiviral activity.
REFERENCES
1. Choi, Y.; Moon, H.R.; Yoshimura, Y.; Marquez, V.E. Recent advances in the synthesis of conformationally
locked nucleosides and their success in probing the critical question of conformational preferences by their
biological targets. Nucleosides Nucleotides Nucleic Acids 2003, 22(5--8), 547–557.
2. Ichikawa, E.; Kato, K. Sugar-modified nucleosides in past 10 years, a review. Curr. Med. Chem. 2001, 8,
385–423.
3. Lebel, H.; Marcoux, J.F.; Molinaro, C.; Charette, A.B. Stereoselective cyclopropanation reactions. Chem. Rev.
2003, 103(4), 977–1050.
4. Houseknecht, J.B.; Altona, C.; Hadad, C.M.; Lowary, T.L. Conformational analysis of furanose rings with
PSEUROT: parametrization for rings possessing the arabino, lyxo, ribo, and xylo stereochemistry and
application to arabinofuranosides. J. Org. Chem. 2002, 67(14), 4647–4651.