2',5'-Bis-O-(tert-butyldimethylsilyl)-3'-spiro-5''-(4''-amino-1'',2''- oxathiole-2'',2'-dioxide)pyrimidine (TSAO) nucleoside analogues: highlyselective inhibitors of human immunodeficiency virus type 1 that are targeted at the viral reverse transcriptase.
A series of pyrimidine nucleoside analogues containing [2',5'-bis-O-(tert-butyldimethylsilyl)-3'-spiro-5''-(4''-amino- 1'',2''-oxathiole-2'',2''-dioxide)]-beta-D-ribofuranose as the pentose were found to inhibit human immunodeficiency virus type 1 [HIV-1(IIIB)] replication at a concentration of 0.06-0.8 microM but were not cytotoxic at a 1000- to 10,000-fold higher concentration. These nucleoside derivatives were also effective against various other HIV-1 strains, including those resistant to 3'-azido-3'-deoxythymidine, but not against HIV-2, simian immunodeficiency virus, Moloney murine sarcoma virus, or other RNA or DNA viruses. They proved to be highly specific inhibitors of the RNA-dependent DNA polymerase function of the HIV-1 reverse transcriptase, showing no marked inhibition of the HIV-1 reverse transcriptase-associated DNA-dependent DNA polymerase activity, HIV-2 reverse transcriptase, DNA polymerase alpha, herpes simplex virus 1 DNA polymerase, or Thermus aquaticus DNA polymerase.
Balzarini
J
J
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Pérez-Pérez
M J
MJ
San-Félix
A
A
Schols
D
D
Perno
C F
CF
Vandamme
A M
AM
Camarasa
M J
MJ
De Clercq
E
E
D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D002460:Cell Line; D003499:Cyclic S-Oxides / Q000494:pharmacology; D004279:DNA, Viral / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D008264:Macrophages / Q000502:physiology; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009000:Monocytes / Q000502:physiology; D009838:Oligodeoxyribonucleotides; D016133:Polymerase Chain Reaction; D011533:Proviruses / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D011741:Pyrimidine Nucleosides / Q000494:pharmacology*; D012194:RNA-Directed DNA Polymerase / Q000009:adverse effects*; D012825:Silicon / Q000494:pharmacology; D013141:Spiro Compounds / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D003499:Cyclic S-Oxides; D004279:DNA, Viral; D006571:Heterocyclic Compounds; D009838:Oligodeoxyribonucleotides; D011741:Pyrimidine Nucleosides; D013141:Spiro Compounds; D012194:RNA-Directed DNA Polymerase; D012825:Silicon