TSAO analogues. 3. Synthesis and anti-HIV-1 activity of 2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl 3'-spiro-5''-(4''-amino-1'',2''-oxathiole 2'',2''-dioxide) purine and purine-modified nucleosides.
Several purine and purine-modified analogues of the new lead anti-HIV-1 agent [[2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl] thymine]-3'-spiro-5''-(4''-amino-1'',2''-oxathiole 2'',2''-dioxide) (TSAO-T) have been prepared and evaluated as inhibitors of HIV-1-induced cytopathicity. Reaction of O-mesylcyanohydrins of furanos-3'-ulosyladenine with Cs2CO3 afforded beta-D-xylo- and ribofuranosyladenine 3'-spiro nucleosides. Reaction of 1,2-di-O-acetyl-5-O-benzoyl-3-C-cyano-3-O-mesyl-D-ribofuranose with purine bases, followed by treatment with Cs2CO3, stereoselectively afforded beta-D-ribofuranosyl 3'-spiro nucleosides. 2',5'-O-Deacylation and subsequent treatment with tert-butyldimethylsilyl chloride gave the required TSAO derivatives. The 3'-spiro nucleosides with a xylo configuration did not show any anti-HIV activity. However, the purine ribo 3'-spiro nucleosides were potent and selective inhibitors of HIV-1 with a 50% effective concentration in the range of 0.1-1 microM and a selectivity index ranging from 2 to 3 orders of magnitude. Introduction of an alkyl function at N-1 of the purine moiety markedly decreased cytotoxicity without affecting antiviral activity.
Velázquez
S
S
Instituto de Química Médica (C.S.I.C.), Madrid, Spain.
San-Félix
A
A
Pérez-Pérez
M J
MJ
Balzarini
J
J
De Clercq
E
E
Camarasa
M J
MJ
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002478:Cells, Cultured; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D011684:Purine Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology*; D011687:Purines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013141:Spiro Compounds; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D014529:Uridine / Q000031:analogs & derivatives
D000998:Antiviral Agents; D011684:Purine Nucleosides; D011687:Purines; D013141:Spiro Compounds; D013936:Thymidine; C075132:TSAO-T; D014529:Uridine