Mononucleoside SATE glucosyl phosphorothiolates as a new series of pronucleotides

Article abstract of DOI:10.1081/NCN-120022681

The synthesis and the study of two phosphorothiolate derivatives of 3′-azido-2′,3′-dideoxythymidine (AZT) bearing a S-pivaloyl-2-thioethyl (tBuSATE) group and glucosyl residues associated to the phosphorus atom by a 2-oxyethyl link, are reported. These derivatives could be considered as prototypes of a new series of nucleotide prodrugs (pronucleotides).

Full text of DOI:10.1081/NCN-120022681

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Mononucleoside SATE Glucosyl Phosphorothiolates as a
New Series of Pronucleotides
A. Jochum a , N. Schlienger a , G. Gosselin a , J.-L. Imbach a , A.-M. Aubertin b & C. Périgaud
a c
a Université Montpellier II, UMR 5625 CNRS , Montpellier, France
b Laboratoire de Virologie de la Faculté de Médecine , Université L. Pasteur , Unité 74
I.N.S.E.R.M., Strasbourg, France
c Laboratoire de Chimie Organique Biomoléculaire de Synthése , Université Montpellier II,
UMR 5625 CNRS , CC008, Place E. Bataillon, Montpellier Cedex 05, France
Published online: 31 Aug 2006.
To cite this article: A. Jochum , N. Schlienger , G. Gosselin , J.-L. Imbach , A.-M. Aubertin & C. Périgaud (2003)
Mononucleoside SATE Glucosyl Phosphorothiolates as a New Series of Pronucleotides, Nucleosides, Nucleotides and Nucleic
Acids, 22:5-8, 899-901, DOI: 10.1081/NCN-120022681
To link to this article: http://dx.doi.org/10.1081/NCN-120022681
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 899–901, 2003
Mononucleoside SATE Glucosyl Phosphorothiolates
as a New Series of Pronucleotides
A. Jochum,1 N. Schlienger,1 G. Gosselin,1 J.-L. Imbach,1 A.-M. Aubertin,2
1,
*
´
and C. Perigaud
1
´
Universite Montpellier II, UMR 5625 CNRS, Montpellier, France
´
2
´
´
Laboratoire de Virologie de la Faculte de Medecine, Universite L. Pasteur,
´
Unite 74 I.N.S.E.R.M., Strasbourg, France
ABSTRACT
The synthesis and the study of two phosphorothiolate derivatives of 30-azido-
20,30-dideoxythymidine (AZT) bearing a S-pivaloyl-2-thioethyl (tBuSATE) group
and glucosyl residues associated to the phosphorus atom by a 2-oxyethyl link, are
reported. These derivatives could be considered as prototypes of a new series of
nucleotide prodrugs (pronucleotides).
Key Words: Prodrug; Mononucleotide; Glucosidase.
We have previously reported that the use of mononucleoside arylphosphotriester
or phosphoramidate diester derivatives bearing one tBuSATE group (Fig. 1) leads to
the intracellular delivery of the corresponding mononucleotide.[1,2] As part of our
work in this field, the potentialities of a new series of mixed phosphorylated deriva-
tives, namely SATE glucosylphosphorothiolates (Fig. 1), have been evaluated.
´
*Correspondence: C. Perigaud, Laboratoire de Chimie Organique Biomoleculaire de Synth-
ese, Universite Montpellier II, UMR 5625 CNRS, CC008, Place E. Bataillon, F-34095
´
´
´
Montpellier Cedex 05, France; Fax: þ33 4 6704 2029; E-mail: perigaud@univ-montp2.fr.
899
DOI: 10.1081/NCN-120022681
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

900
Jochum et al.
Figure 1.
Scheme 1.
The synthesis of phosphorothiolate models 7 and 8 (Sch. 1) combined two com-
mon strategies using PIII and PV intermediates. These derivatives were evaluated for
their inhibitory effects on the replication of HIV-1 in several cell lines. In thymidine-
kinase deficient (TKꢀ) CEM cells compounds 7 and 8 exhibited, in contrast to AZT,
antiviral activity at micromolar concentration showing their ability to act as pro-
nucleotides.
This point was corroborated by stability studies in various biological media as
well as evaluation of substrate properties towards purified b-glucosidase. The pro-
posed decomposition mechanism of these mixed pronucleotides involves successively
two different enzymatic systems, i.e., esterases and glucosidases.

Mononucleoside SATE Glucosyl Phosphorothiolates
REFERENCES
901
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´
A.-M.; Perigaud, C. S-Acyl-2-thioethyl aryl phosphotriester derivatives as mono-
nucleotide prodrugs. J. Med. Chem. 2000, 43, 4570–4574.
´
2. Egron, D.; Perigaud, C.; Gosselin, G.; Aubertin, A.-M.; Imbach, J.-L. Synthesis
and study of a new series of phosphoramidate derivatives as mononucleotide
prodrugs. Nucleosides, Nucleotides & Nucleic Acids 2001, 20, 751–754.