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Synthesis and Anti-HIV Activity of 4′-Substituted 4′-Thiothymidines: A New Entry Based on Nucleophilic Substitution of the 4′-Acetoxy Group

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journal contribution
posted on 27.03.2008, 00:00 by Kazuhiro Haraguchi, Hisashi Shimada, Hiromichi Tanaka, Takayuki Hamasaki, Masanori Baba, Elizabeth A. Gullen, Ginger E. Dutschman, Yung-Chi Cheng
Diacetoxylation of 1-(2,5-dideoxy-β-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-1M184V), being as potent as against HIV-1IIIB.

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