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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• 作者：Kazuhiro Haraguchi ; Hisashi Shimada ; Hiromichi Tanaka ; Takayuki Hamasaki ; Masanori Baba ; Elizabeth A. Gullen ; Ginger E. Dutschman ; Yung-Chi Cheng
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：March 27, 2008
• 年：2008
• 卷：51
• 期：6
• 页码：1885 - 1893
• 全文大小：187K
• 年卷期：v.51,no.6(March 27, 2008)
• ISSN：1520-4804

文摘

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-1_M184V), being as potent as against HIV-1_IIIB.