4'-取代4'-硫代胸苷的合成及其抗HIV活性：基于4'-乙酰氧基亲核取代的新方法

Synthesis and anti-HIV activity of 4'-substituted 4'-thiothymidines: a new entry based on nucleophilic substitution of the 4'-acetoxy group.

作者信息

Haraguchi Kazuhiro, Shimada Hisashi, Tanaka Hiromichi, Hamasaki Takayuki, Baba Masanori, Gullen Elizabeth A, Dutschman Ginger E, Cheng Yung-Chi

机构信息

School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, Japan.

出版信息

J Med Chem. 2008 Mar 27;51(6):1885-93. doi: 10.1021/jm070824s. Epub 2008 Feb 27.

DOI:10.1021/jm070824s

PMID:18311897

Abstract

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.

摘要

用四乙酸铅对1-(2,5-二脱氧-β-L-甘油基-戊-4-烯-4-硫代呋喃糖基)胸腺嘧啶(13)进行二乙酰氧基化反应，可在4'-位引入乙酰氧基离去基团。用硅试剂对所得的4'-乙酰氧基衍生物(14)进行亲核取代反应，使我们能够制备4'-硫代胸苷的4'-苯硫基(17a)、4'-叠氮基(18a)、4'-甲氧基(20a)和4'-烯丙基(21a)类似物。4'-氰基(25a)和4'-乙炔基(31)核苷也由3',5'-双-O-叔丁基二甲基硅烷基衍生物(24)合成。在新型的4'-取代4'-硫代胸苷中，发现4'-叠氮基(33)、4'-氰基(36)和4'-乙炔基(37)衍生物对HIV-1和HIV-2显示出强效抑制活性。值得注意的是，36和37对耐3TC的HIV变异体(HIV-1 M184V)的复制也有抑制作用，其效力与对HIV-1 IIIB的抑制作用相同。