PDF herunterladen
Synthesis 2009(5): 841-847  
DOI: 10.1055/s-0028-1083369
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of New Cyclic and Acyclic 5-Halouridine Derivatives as Potential Antiviral Agents

Mohamed F. Elshehrya,b, Jan Balzarinic, Chris Meier*a
a Organic Chemistry, Department of Chemistry, Faculty of Sciences, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
Fax: +49(40)428385592; e-Mail: chris.meier@chemie.uni-hamburg.de;
b Pesticides Department, National Research Centre, 12622 Dokki, Cairo, Egypt
c Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium
Weitere Informationen

Publikationsverlauf

Received 4 September 2008
Publikationsdatum:
11. Februar 2009 (online)

    Lizenzen und Reprints Alle Artikel dieser Rubrik

Abstract

The synthesis of new cyclic and acyclic nucleoside analogues was achieved by alkylation of 5-halogenated 6-(2,4-dichlorophenoxymethyl)pyrimidine-2,4-dione following the Vorbrüggen coupling procedure. Nucleoside analogues of the 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT)-type were obtained as well as analogues of ganciclovir, acyclovir, and ribonucleosides. All compounds were tested against a variety of viruses. Three of the new compounds were potent and selective anti-HIV-1 inhibitors.

Key words

bioorganic chemistry - drugs - antiviral agents - nucleosides - glycosylation

    References

  • 1 Richman DD. Fischl MA. Grieco MH. Gottieb MS. Volberding PA. Lasin OL. Leedon JM. Groopman JE. Mildran D. Hirsch MS. Jackson GG. Durack DT. Lehrman NS. and the AZT Collaborative Working GroupN. Engl. J. Med.  1987,  317:  192 
    CrossrefGoogle Scholar
  • 2 Yarchoan R. Mitsuya H. Thamas RV. Pluda J. Hartman NR. Perno CF. Marczyck KS. Allain JP. Johns DG. Broder S. Science  1989,  245:  412 
    CrossrefGoogle Scholar
  • 3 Larder BA. Darby G. Richman DV. Science  1989,  243:  1731 
    CrossrefGoogle Scholar
  • 4a Roy-Burman P. Analogues of Nucleic Acid Components   Springer-Verlag; New York: 1970. 
    Google Scholar
  • 4b Goodman L. In Basic Principles in Nucleic Acid Chemistry   Vol. 1:  Ts’V POP. Academic Press; New York: 1974.  p.146 
    Google Scholar
  • 4c Uesugi S. Ikehara M. Chem. Pharm. Bull.  1978,  26:  3040 
    Google Scholar
  • 5a Baba M. De Clercq E. Tanaka H. Ubasawa M. Takashima H. Sekiya K. Nitta I. Umezu K. Walker RT. Mori S. Ito M. Shigeta S. Miyasaka T. Mol. Pharmacol.  1993,  39:  805 
    Google Scholar
  • 5b Pontkis R. Benhida R. Aubertin AM. Grierson DS. Monneret C. J. Med. Chem.  1997,  40:  1845 
    Google Scholar
  • 5c Kim DK. Gam J. Kim YW. Lim J. Kim HT. Kim KH. J. Med. Chem.  1997,  40:  2363 
    Google Scholar
  • 6a Niedballa U. Vorbrüggen H. J. Org. Chem.  1974,  39:  3654 
    Google Scholar
  • 6b Niedballa U. Vorbrüggen H. J. Org. Chem.  1976,  41:  2084 
    Google Scholar
  • 6c Vorbrüggen H. Krolikiewiecz K. Bennua B. Chem. Ber.  1981,  114:  1234 
    Google Scholar
  • 7a Andersen GW. Halverstadt IF. Miller WH. Roblin RO. J. Am. Chem. Soc.  1945,  67:  2197 
    Google Scholar
  • 7b El-telbani EM. Elshehry MF. Nawwar GAM. Monatsh. Chem.  2008,  139:  685 
    Google Scholar
  • 8 Johnson TB. Ambelang JC. J. Am. Chem. Soc.  1938,  60:  2941 
    CrossrefGoogle Scholar
  • 9 Donleavy JJ. Kise MA. Org. Synth. Coll. Vol. II   Wiley; New York: 1943.  p.422 ; Org. Synth. 1937, 17, 63
    Google Scholar
  • 10 Asakura J.-I. Robins MJ. J. Org. Chem.  1990,  55:  4928 
    CrossrefGoogle Scholar
  • 11 Jourdan F. Laduree D. Robba M. J. Heterocycl. Chem.  1994,  31:  305 
    CrossrefGoogle Scholar
  • 13 Balzarini J. Karlsson A. De Clercq E. Mol. Pharmacol.  1993,  44:  694 
    Google Scholar
12

All new compounds were evaluated concerning their ability to inhibit the replication of HIV in T-lymphocytes cells. Briefly, a CEM cell suspension was infected with HIV-1 or HIV-2. The mutant thymidine kinase-deficient CEM cell cultures were only infected with HIV-2. Then, 100 µL of the infected cell suspensions was transferred into 96-well microtiter plate wells and mixed with 100 µL of the appropriate dilutions of the test compounds. After 4-5 days, giant cell formation was recorded microscopically in the HIV-infected cell cultures.