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 
ta2.gif" BORDER=0 ALIGN="middle">-anomer (16ta2.gif" BORDER=0 ALIGN="middle">) 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 C
tities/tbd1.gif">CH) 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 tities/mgr.gif">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.
ta2.gif" BORDER=0 ALIGN="middle">-anomer (16ta2.gif" BORDER=0 ALIGN="middle">) 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 Ctities/tbd1.gif">CH) 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 tities/mgr.gif">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.