NOVEL SERIES OF TSAO-T DERIVATIVES - SYNTHESIS AND ANTI-HIV-1 ACTIVITY OF 4-SUBSTITUTED, 5-SUBSTITUTED, AND 6-SUBSTITUTED PYRIMIDINE ANALOGS

Several 4-, 5-, and 6-substituted pyrimidine analogues of the new anti -HIV-1 lead compound thymine]-3'-spiro-5''-(4''-amino-1'',2''-oxathiol e 2'',2''-dioxide) (TSAO-T) have been prepared and evaluated as inhibi tors of HIV-1 and HIV-2 replication in cell cultures. Reaction of tyl- 5-O-benzoyl-3-C-cyano-3-O-mesyl-D-ribofuranose with 5-substituted pyri midine bases, followed by treatment with Cs2CO3, afforded, stereoselec tively, beta-D-ribofuranosyl-3'-spironucleosides. 2',5'-O-Deacylation and subsequent treatment with tert-butyldimethylsilyl chloride gave th e TSAO-5-substituted pyrimidine derivatives. Reaction of 5-halogen-TSA O derivatives with nucleophiles gave 6-substituted-TSAO analogues, Tre atment of TSAO-pyrimidine analogues with POCl3/1,2,4-triazole and meth ylamine or dimethylamine afforded the 4-substituted pyrimidine compoun ds, Several substituted TSAO-thymine, TSAO-uracil, and TSAO-cytosine d erivatives were found to be superior to their unsubstituted TSAO conge ners with regard to their antiviral and/or cytotoxic properties.