Synthesis of some acyclonucleosides α-(pyrazolo[3,4-d]pyrimidin-4-ylthio)-alkylamides

Article abstract of DOI:10.1081/NCN-100002467

The synthesis of some acyclic α-(pyrazolo[3,4-d]pyrimidin-4-ylthio)alkylamide nucleosides is described.

Full text of DOI:10.1081/NCN-100002467

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SYNTHESIS OF SOME ACYCLONUCLEOSIDES
α-(PYRAZOLO[3,4-d]PYRIMIDIN-4-YLTHIO)-
ALKYLAMIDES
a
a
M. L. Taha , O. Moukha-Chafiq , H. B. Lazrek , J. J. Vasseur & J. L. Imbach
a
Université Montpellier II , Lab. de Chimie Organique Biomoléculaire de Synthèse, UMR
625 CNRS-UM II, Montpellier, France
5
Published online: 07 Feb 2007.
To cite this article: M. L. Taha , O. Moukha-Chafiq , H. B. Lazrek , J. J. Vasseur & J. L. Imbach (2001) SYNTHESIS OF SOME
ACYCLONUCLEOSIDES α-(PYRAZOLO[3,4-d]PYRIMIDIN-4-YLTHIO)-ALKYLAMIDES, Nucleosides, Nucleotides and Nucleic Acids,
20:4-7, 955-958, DOI: 10.1081/NCN-100002467
To link to this article: http://dx.doi.org/10.1081/NCN-100002467
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 955–958 (2001)
SYNTHESIS OF SOME ACYCLONUCLEOSIDES
α-(PYRAZOLO[3,4-d]PYRIMIDIN-4-YLTHIO)-
ALKYLAMIDES
1
1
2,∗
M. L. Taha, O. Moukha-Chafiq, H. B. Lazrek,
3
3
J. J. Vasseur, and J. L. Imbach
1
Lab. de Chimie Bio-Organique, Facult e´ des Sciences, Agadir, Morroco
2
Lab. de Chimie Bio-Organique, Facult e´ des Sciences Semlalia,
Marrakech, Morocco
Lab. de Chimie Organique Biomol e´ culaire de Synth e` se, UMR 5625
3
CNRS-UM II, Universit e´ Montpellier II, Montpellier, France
ABSTRACT
Thesynthesisofsomeacyclicα-(pyrazolo[3,4-d]pyrimidin-4-ylthio)alkylamide
nucleosides is described.
In the search for potent and selective chemotherapeutic agents, nucleosides
and their derivatives are among the most widely explored types of compounds.
The convenient general approach for their preparation involves the modification
of the base and/or sugar residue of the nucleoside building blocks of desoxyri-
bonucleic and ribonucleic acids (DNA and RNA respectively). Accordingly, the
replacement of furanose ring by the appropriate pseudo-sugar moiety, e.g. (2-
hydroxyethoxy)methyl, 4-hydroxybutyl or (2,3-dihydroxy-1-propoxy)methyl, is of
particularinterestsincetheresultingacyclovir(1)(ACV), HBG(2)orIso-DHPG(3)
(Fig. 1) have showed a potential anti-herpetic activity. In connection with our stud-
ies on acyclic nucleosides (4–6), we aimed through the synthesis of some acyclic
α-(pyrazolo[3,4-d]pyrimidin-4-ylthio)alkylamide nucleosides (14–16)a-c (Fig. 1)
∗
Corresponding author.
955
Copyright ꢀC 2001 by Marcel Dekker, Inc.
www.dekker.com

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56
TAHA ET AL.
Figure 1.
in order to determine the biological activities of the resulting base-modified deriva-
tives of acyclovir, HBG and Iso-DHPG.
The 4-mercaptopyrazolo[3,4-d]pyrimidine 5, depicted in scheme 1, was pre-
pared in five steps according to the literature procedure from malononitrile and
triethyl orthoformate as starting materials (7,8). The C4 sulfur atom of the base
was alkylated with ethyl bromoacetate 6a, (DL)-ethyl-2-bromopropionate 6b or
(DL)-ethyl-2-bromobutyrate 6c in a sodium hydroxide solution at room tempera-
ture to give α-(pyrazolo[3,4-d]pyrimidin-4-ylthio)ethylalkylates 7a-c, in 85%, 83%
and 82% yield, respectively.
Then the preparation of compounds (11–13)a-c (Scheme 2) was achieved us-
ing the same conditions previously described for the synthesis of the 4-substituted
pyrazolo[3,4-d]pyrimidine N -acyclonucleosides (4–6). Thus, the alkylation of het-
1
erocycles 7a, 7b or 7c with alkylating agents 8 (9), 9 (6,10), or 10 (4), using potas-
sium carbonate as base and N,N-dimethylforamide (DMF) as solvent, afforded
regioselectively the N -regioisomers (11–13)a-c in 89%, 80% and 80%, respec-
1
tively. It was reported that N -nucleoside (acyclonucleoside) formation occurred
2
during glycosylation (alkylation) of the pyrazolo[3,4-d]pyrimidines (4,11–15). In
our case presumed N -regioisomers of (11–13)a-c were detected but not isolated.
2
Finally, the treatment of N1-protected acyclic nucleosides (11–13)a-c with
methanol saturated with ammonia at room temperature gave the acyclic nucle-
osides (14–16)a-c (Scheme 2) in quantitative yield, through deprotection of the
Scheme 1.

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ACYCLONUCLEOSIDE SYNTHESIS
957
Scheme 2.
acetyl group and concomitant conversion of the ester into the amide moiety. All
1
structures of the synthetic products were identified by H-NMR, mass spectra, UV
and elemental analysis.
Compounds (14–16)a-c were evaluated for their cytotoxycity and their in-
hibitory effect on HIV-1(III ) and HIV-2(ROD) replication in MT-4 cells (16,17).
B
No significant activity was found against the replication of HIV-1(III ) and HIV-
B
2(ROD) at subtoxic concentrations.
In conclusion, we have regioselectively synthesized some N1-acyclic α-(pyra-
zolo[3,4-d]pyrimidin-4-ylthio)alkylamide nucleosides with the alkyl chain of acy-
clovir, HBG and Iso-DHPG. They were characterized on the basis of their physical
and spectroscopic properties. Their anti-tumor and anti-tuberculosis evaluations are
in progress.
ACKNOWLEDGMENTS
This work has been supported by ꢁꢁ Recherches men e´ es dans le cadre du
ꢂ
◦
Programme Th e´ matique d Appui a` la Recherche Scientifique (PROTARS N P1T2/
02)ꢃꢃ . We thank Pr. E. De Clercq (Belgium) for the evaluation of the antiviral activity.
REFERENCES
1.
Schaeffer, H. J.; Beauchamp, L.; De miranda, P.; Elion, G. B.; Bauer, D. J.; Collins,
P. Nature, 1978, 272, 583–585.
Larsson, A.; Alenius, S.; Johansson, N. G.; Oberg, B. Antiviral Res., 1983, 3, 77–86.
¨
2.
3.
4.
5.
Lin, T. S.; Liu, M. C. Tetrahedron Lett., 1984, 25, 905–906.
Taha, M. L.; Lazrek, H. B. Bull. Soc. Chim. Belg., 1997, 106, 163–168.
Taha, M. L.; Lazrek, H. B.; Barascut, J. L.; Imbach, J. L. Bull. Soc. Chim. Belg., 1996,
105, 279–285.

ORDER
REPRINTS
9
58
TAHA ET AL.
6.
7.
8.
9.
Taha, M. L.; Lazrek, H. B. Bull. Soc. Chim. Belg., 1995, 104, 647–652.
Robins, R. K. J. Am. Chem. Soc., 1956, 78, 784–790.
Huber, W., This Journal, 1943, 65, 2222–2226.
Robin, M. J.; Hatfield, P. W. Can. J. Chem., 1982, 60, 547–553.
10. Lazrek, H. B.; Taourirte, M.; Barascut, J. L.; Imbach, J. L. Bull. Soc. Chim. Belg.,
1996, 105, 391–395.
11. Seela, F.; Zulauf, M.; Recher, G. Nucleosides & Nucleotides, 1997, 16, 305–314.
12. Seela, F.; Winter, H.; Moller, M. Helv. Chim. Acta, 1993, 76, 1450–1458.
13. Oertel, F.; Winter, H.; Kazimierczuk, Z.; Vilpo, J. A.; Richter, P.; Seela, F. Liebigs.
Ann. Chem., 1992, 1165–1170.
1
1
1
1
4. Saxena, N. K.; Coleman, L. A.; Drach, J. C.; Townsend, J. C. J. Med. Chem., 1990,
3
3 (7), 1980–1983.
5. Kazimierczuk, Z.; Cottam, H. B.; Revankar, G. R.; Robins, R. K. J. Am. Chem. Soc.,
984, 106, 6379–6382.
1
6. Pauwels, R.; Balzarini, J.; Baba, M.; Sneock, R.; Schols, D.; Herdewijn, P.; Desmyter,
J.; De Clercq, E. J. Virol. Methods, 1988, 20, 309–321.
7. Witvrouw, M.; Balzarini, J.; Pannecouque, C.; Jhaumar-Laullo, S.; Est e´ , J.; Schols, D.;
Cherepanov, P.; Schmit, J-C.; Debyser, Z.; Vandamme, A-M.; Desmyter, J.; Ramadas,
R.; De Clercq, E. Antimicrob. Agents Chemother., 1997, 41, 262–268.

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