Synthesis and Anti-Human Immunodeficiency Virus Activity of 4'-Branched (±)-4'-Thiostavudines

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• 作者：Hiroki Kumamoto ; Takahito Nakai ; Kazuhiro Haraguchi ; Kazuo T. Nakamura ; Hiromichi Tanaka ; Masanori Baba ; Yung-Chi Cheng
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：December 28, 2006
• 年：2006
• 卷：49
• 期：26
• 页码：7861 - 7867
• 全文大小：111K
• 年卷期：v.49,no.26(December 28, 2006)
• ISSN：1520-4804

文摘

Motivated by our recent finding that 4'-ethynylstavudine (4) is a promising anti-human immunodeficiencyvirus type 1 (HIV-1) agent, we synthesized its 4'-thio analogue, as well as other 4'-thiostavudines having acarbon substituent at the 4'-position, as racemates in this study. Methyl 3-oxo-tetrahydrothiophen-2-carboxylate(5) was used as a starting material to construct the requisite 4-thiofuranoid glycal (13). Introduction of athymine base was carried out by an electrophilic addition reaction to 13 using N-iodosuccinimide (NIS) andbis(trimethylsilyl)thymine. The desired -anomer (16) obtained as a major product in this reaction underwentready elimination with activated Zn to give the 4'-carbomethoxy derivative (18). By using 18 as a commonintermediate, 4'-carbon-substituted (CH₂OH, CO₂Me, CONH₂, CH=CH₂, CN, and CCH) 4'-thiostavudineswere prepared. Among these six compounds, 4'-cyano (28) and 4'-ethynyl (29) analogues were found toshow inhibitory activity against HIV-1 with ED₅₀ values of 7.6 and 0.74 M, respectively. The activity of29 was comparable to that of stavudine, but 29 was not as active as 4. Optical resolution of 29 was brieflyexamined.