4′-C-methyl-β-D-ribofuranosyl purine and pyrimidine nucleosides revisited

Article abstract of DOI:10.1081/NCN-120022615

In order to evaluate their antiviral properties, a series of 4′-C-methyl-β-D-ribofuranosyl purine and pyrimidine nucleosides has been prepared. Unfortunately, none of these 4′-branched nucleosides showed any antiviral activity or cytotoxcity when tested a

Full text of DOI:10.1081/NCN-120022615

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4′- C -Methyl-β-D-ribofuranosyl Purine and Pyrimidine
Nucleosides Revisited
J.-F. Griffon a , D. Dukhan a , C. Pierra a , S. Benzaria a , A. G. Loi b , P. La Colla b , J.-P.
Sommadossi c & G. Gosselin a d
a Laboratoire Coopératif Idenix-CNRS , Université Montpellier II , France
b Idenix Pharmaceuticals-University of Cagliari Collaborative Laboratory , Cagliari, Italy
c Idenix Pharmaceuticals Inc. , Cambridge, Massachusetts, USA
d Université de Montpellier II, Laboratoire de Chimie Organique Biomoleculaire de Synthése ,
CC008, Place E. Bataillon, F-34095, Montpellier Cedex 5, France
Published online: 31 Aug 2006.
To cite this article: J.-F. Griffon , D. Dukhan , C. Pierra , S. Benzaria , A. G. Loi , P. La Colla , J.-P. Sommadossi & G. Gosselin
(2003) 4′- C -Methyl-β-D-ribofuranosyl Purine and Pyrimidine Nucleosides Revisited, Nucleosides, Nucleotides and Nucleic
Acids, 22:5-8, 707-709, DOI: 10.1081/NCN-120022615
To link to this article: http://dx.doi.org/10.1081/NCN-120022615
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 707–709, 2003
40-C-Methyl-b-D-ribofuranosyl Purine and Pyrimidine
Nucleosides Revisitedy
J.-F. Griffon,1 D. Dukhan,1 C. Pierra,1 S. Benzaria,1 A. G. Loi,2
P. La Colla,2 J.-P. Sommadossi,3 and G. Gosselin1,
*
1
´
´
Laboratoire Cooperatif Idenix-CNRS, Universite Montpellier II, France
2Idenix Pharmaceuticals-University of Cagliari Collaborative Laboratory,
Cagliari, Italy
3Idenix Pharmaceuticals Inc., Cambridge, Massachusetts, USA
ABSTRACT
In order to evaluate their antiviral properties, a series of 40-C-methyl-b-D-ribo-
furanosyl purine and pyrimidine nucleosides has been prepared. Unfortunately,
none of these 40-branched nucleosides showed any antiviral activity or cytotoxcity
when tested against HIV, HBV, and Yellow Fever virus.
Key Words: 40-C-methyl-b-D-ribofuranosyl nucleosides; HIV; HBV; Yellow
Fever virus.
yDedicated to the memory of Martin Bryant, deceased on March 4, 2002.
´
*Correspondence: G. Gosselin, Universite de Montpellier II, Laboratoire de Chimie Organi-
que Biomoleculaire de Synthese, CC008, Place E. Bataillon, F-34095 Montpellier Cedex 5,
´
France; Fax: +33 4 6754 9610; E-mail: gosselin@univ-montp2.fr.
707
DOI: 10.1081/NCN-120022615
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

708
Griffon et al.
INTRODUCTION
In the search for new antiviral agents, various 40-C-branched-20-deoxynucleo-
sides have been reported to have potent antiretroviral activity in vitro.[1] Regarding
the 40-C-methyl-b-D-ribofuranonucleoside derivatives, the synthesis of those bearing
the five natural bases has been previously described but no biological data were
reported.[2,3]
Based on these considerations, a series of 40-C-methyl-b-D-ribofuranosyl purine
and pyrimidine nucleosides 3–9 (Sch. 1) has been prepared in order to evaluate their
antiviral properties.
SYNTHESIS OF THE 40-C-METHYL-b-D-RIBOFURANOSYL
PURINE AND PYRIMIDINE NUCLEOSIDES 3–9 (SCH. 1)
5-O-Benzoyl-4-C-methyl-1-O-methyl-2,3-O-isopropylidene-b-D-ribofuranose 1
was prepared in 8 steps according to published procedures.[4–6] Cleavage of the
2,3-O-isopropylidene group of 1, followed by acetylation led to the hitherto
unknown 5-O-benzoyl-4-C-methyl-1,2,3-O-acetyl-D-ribofuranose 2. Condensation
of 2, under Vorbruggen conditions, respectively with silylated uracil, 5-fluorouracil,
¨
or thymine afforded the corresponding fully acylated 40-C-methyl-b-D-ribofuranosyl
nucleosides. Regarding the purine nucleobases, 2 was either condensed with adenine
or silylated O6-diphenylcarbamoyl-N2-isobutyrylguanine. Finally, treatment with
saturated methanolic ammonia gave the title compounds 3–7. Conversion of the
uracil and 5-fluorouracil derivatives into the corresponding cytosine and 5-fluoro-
cytosine 40-C-methyl-b-D-ribofuranosyl nucleosides 8–9 was carried out via a treat-
ment with Lawesson’s reagent, followed by a treatment with saturated methanolic
ammonia at 100ꢀC.
ANTIVIRAL EVALUATIONS
The 40-C-methyl-b-D-ribofuranosyl nucleosides 3–9 were evaluated for their
in vitro inhibitory effects on the replication of HIV-1(IIIb) in MT-4 cell system,
but none of them showed any antiviral activity or cytotoxcity (up to 100 mM, data
not shown). When evaluated in anti-HBV assays in the HBV DNA-transfected
Scheme 1. Synthesis of the 40-C-methyl-b-D-ribofuranonucleosides 3–9.

40-C-Methyl-b-D-ribofuranosyl Nucleosides
709
Hep-G2 cells (2.2.15 cells), none of the compounds tested 3–9 was active (up to a
concentration of 10 mM) or cytotoxic (up to a concentration of 100 mM). Compounds
3–9 were also inactive and non-cytotoxic (up to a concentration of 100 mM) against
Yellow Fever virus in BHK cell lines.
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1993, 29, 93–94.
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4. Jones, G.H.; Taniguchi, M.; Tegg, D.; Moffatt, J.G. 40-Substituted nucleosides.
5. Hydroxylation of nucleoside 50-aldehydes. J. Org. Chem. 1979, 44, 1309–1317.
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