Synthesis and anti-HIV activity of 4′-substituted 4′-thiothymidines:: A new entry based on nucleophilic substitution of the 4′-acetoxy group
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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DOI：
10.1021/jm070824s
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发表时间：
2008-03-27
影响因子：
7.3
通讯作者：
Cheng, Yung-Chi
中科院分区：
文献类型：
--
作者：
Haraguchi, Kazuhiro;Shimada, Hisashi;Cheng, Yung-Chi
1-（2，5-二脱氧-β-L-甘油基-β-4-烯-4-硫代呋喃糖基）胸腺嘧啶（13）与Pb（OAc）（4）的二乙酰氧基化允许在4 ′-位引入乙酰氧基离去基团。用硅试剂对4 '-乙酰氧基衍生物（14）进行亲核取代，制备了4'-硫代胸苷的4 '-苯硫基（17 a）、4 '-叠氮基（18 a）、4 '-甲氧基（20 a）和4 '-烯丙基（21 a）类似物。还从3 '，5'-双-O-TBDMS衍生物（24）合成了4 '-氰基（25 a）和4 '-乙炔基（31）核苷。在新的4 ′-取代的4 ′-硫代胸苷中，发现4 ′-叠氮基（33）、4 ′-氰基（36）和4 ′-乙炔基（37）衍生物显示出对HIV-1和HIV-2的有效抑制活性.值得注意的是，36和37还抑制对3 TC具有抗性的HIV变体（HIV-1（M184 V））的复制，与抗HIV-1（IIIB）一样有效。
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).