Synthesis and anti-HIV activity of 4'-substituted 4'-thiothymidines: a new entry based on nucleophilic substitution of the 4'-acetoxy group.

Diacetoxylation of 1-(2,5-dideoxy-beta-L-glycero-pent-4-eno-4-thiofuranosyl)thymine (13) with Pb(OAc) 4 allowed introduction of an acetoxy leaving group to the 4'-position. Nucleophilic substitution of the resulting 4'-acetoxy derivative (14) with silicon reagents enabled us to prepare the 4'-phenylthio (17a), 4'-azido (18a), 4'-methoxy (20a), and 4'-allyl (21a) analogues of 4'-thiothymidine. 4'-Cyano ( 25a) and 4'-ethynyl (31) nucleosides were also synthesized from 3',5'-bis-O-TBDMS derivative (24). Among novel 4'-substituted 4'-thiothymidines, the 4'-azido (33), 4'-cyano (36), and 4'-ethynyl (37) derivatives were found to show potent inhibitory activity against HIV-1 and HIV-2. It is noteworthy that 36 and 37 were also inhibitory against replication of HIV variant resistant to 3TC (HIV-1 M184V), being as potent as against HIV-1 IIIB.