Novel Series of TSAO-T Derivatives. Synthesis and Anti-HIV-1 Activity of 4-, 5-, and 6-Substituted Pyrimidine Analogues

Article abstract of DOI:10.1021/jm00030a004

Several 4-, 5-, and 6-substituted pyrimidine analogues of the new anti-HIV-1-lead compound <1-<2',5'-bis-O-(tert-butyldimethylsilyl)-β-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 and HIV-2 replication in cell cultures.Reaction of 1,2-di-O-acetyl-5-O-benzoyl-3-C-cyano-3-O-mesyl-D-ribofuranose with 5-substituted pyrimidinen bases, followed by treatment with Cs2CO3, afforded, stereoselectively, β-D-ribofuranosyl-3'-spironucleosides. 2',5'-O-Deacylation and subsequent treatment with tert-butyldimethylsilyl chloride gave the TSAO-5-substituted pyrimidine derivatives.Reaction of 5-halogen-TSAO derivatives with nucleophiles gave 6-substituted-TSAO analogues.Treatment of TSAO-pyrimidine analogues with POCl3/1,2,4-triazole and methylamine or dimethylamine afforded the 4-substituted pyrimidine compounds.Several substituted TSAO-thymine, TSAO-uracil, and TSAO-cytosine derivatives were found to be superior to their unsubstituted TSAO congeners with regard to their antiviral and/or cytotoxic properties.