3'-Spiro nucleosides, a new class of specific human immunodeficiency virus type 1 inhibitors: synthesis and antiviral activity of [2'-5'-bis-O-(tert-butyldimethylsilyl)-beta-D-xylo- and -ribofuranose]-3'-spiro-5"-[4"-amino-1",2"-oxathiole 2",2"-dioxide] (TSAO) pyrimidine nucleosides.
A series of 3'-spiro nucleosides have been synthesized and evaluated as anti-HIV-1 agents. Reaction of O-mesylcyanohydrins of furanos-3'-ulosyl nucleosides with base afforded [1-[2',5'-bis-O- (tert-butyldimethylsilyl)-beta-D-xylo- and -ribofuranosyl]]-3'-spiro-5"- [4"-amino-1",2"-oxathiole 2",2"-dioxide] derivatives of thymine, uracil and 4-N-acetylcytosine 11 and 12. Desilylation of 11 and 12 gave the full deprotected 3'-spiro xylo- and ribofuranosyl nucleosides 13 and 14 or the partially 5'-O-deprotected-3'-spiro beta-D-xylo- and -ribo-nucleosides 15 and 16, or 2'-O-deprotected-3'-spiro beta-D-ribo-nucleoside 17. 2'-Deoxygenation of 17 afforded 2'-deoxy-3'-spiro beta-D-erythro-pentofuranosyl derivative 18. These 3'-spiro derivatives were evaluated for their anti-HIV-1 activity. All 3'-spiro nucleosides having a xylo configuration did not show any anti-HIV-1 activity. 3'-Spiro ribo-nucleosides with none or only one silyl group at C-2' or C-5' or the 2'-deoxy derivative were also inactive at subtoxic concentrations. However, 3'-spiro ribo-nucleosides having two silyl groups at C-2' and C-5' were potent and selective inhibitors of HIV-1. None of the nucleoside analogues that showed anti-HIV-1 activity proved inhibitory to the replication of HIV-2 or SIV.
Camarasa
M J
MJ
Instituto de Química Médica, Juan de la Cierva, Madrid, Spain.
Pérez-Pérez
M J
MJ
San-Félix
A
A
Balzarini
J
J
De Clercq
E
E
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000145:classification / Q000494:pharmacology*; D002478:Cells, Cultured; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D015498:HIV-2 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D015394:Molecular Structure; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis / Q000494:pharmacology*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D011741:Pyrimidine Nucleosides