TSAO analogs. 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

• Published in: Journal of medicinal chemistry 1992-08, Vol.35 (16), p.2988-2995
• Main Authors: Perez-Perez, Maria Jesus, San-Felix, Ana, Balzarini, Jan, De Clercq, Erik, Camarasa, Maria Jose
• Format: Article
• Language: English
• Subjects: AIDS/HIV; Antiviral Agents - analogs & derivatives; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacology; Carbohydrates. Nucleosides and nucleotides; Cells, Cultured; Chemistry; Exact sciences and technology; HIV-1 - drug effects; Humans; Nucleosides - chemical synthesis; Nucleosides - pharmacology; Nucleosides, nucleotides and oligonucleotides; Organic chemistry; Preparations and properties; Pyrimidines - chemical synthesis; Pyrimidines - pharmacology; Spiro Compounds; Structure-Activity Relationship; T-Lymphocytes - microbiology; Thymidine - analogs & derivatives; Thymidine - chemical synthesis; Thymidine - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00094a009

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.