title: TSAO analogues. Stereospecific synthesis and anti-HIV-1 activity of 1-[2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3'-spiro -5''- (4''-amino-1'',2''-oxathiole 2'',2''-dioxide) pyrimidine and pyrimidine-modified nucleosides.
abstract: Several analogues of a new lead for anti-HIV-1 agents [1-[2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-thymine] -3'-spiro-5''-(4''-amino-1'',2''-oxathiole 2'',2''-dioxide) (TSAO) modified at positions N-3, O-4 and C-5 of the thymine moiety, have been prepared and evaluated as inhibitors of HIV-1 replication. A new stereoselective synthetic procedure is described. Reaction of 1,2-di-O-acetyl-5-O-benzoyl-3-C-cyano-3-O-mesyl-D-ribofuranose with pyrimidine bases, followed by treatment with Cs2CO3 afforded stereoselectively, beta-D-ribofuranosyl-3'-spiro nucleosides. 2',5'-O-Deacylation and subsequent treatment with tert-butyldimethylsilyl chloride gave the TSAO derivatives. Only those analogues having a tBDMSi group at both the C-5' and C-2' positions of the ribose moiety showed potent anti-HIV-1 activity. The activity ranged from 0.060 microM to 1.0 microM. Introduction of an alkyl or alkenyl function at N-3 of the thymine ring markedly decreased cytotoxicity without affecting the antiviral activity. While markedly active against HIV-1, the TSAO derivatives had no activity against HIV-2 or SIV. They represent the first example of nucleoside analogues with an intact ribose moiety that discriminate between HIV-1 and other retroviruses.
authors.affiliation: Instituto de Química Médica, Juan de la Cierva, Madrid, Spain.
authors.forename: M J
authors.initials: MJ
authors.lastname: Pérez-Pérez
authors.forename: A
authors.initials: A
authors.lastname: San-Félix
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: M J
authors.initials: MJ
authors.lastname: Camarasa
mesh_terms: D000998:Antiviral Agents / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D002478:Cells, Cultured; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013141:Spiro Compounds; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000382:microbiology; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D014529:Uridine / Q000031:analogs & derivatives
chemical_list: D000998:Antiviral Agents; D009705:Nucleosides; D011743:Pyrimidines; D013141:Spiro Compounds; D013936:Thymidine; C075132:TSAO-T; D014529:Uridine