4'-碳取代核苷合成的新方法：高活性抗HIV药物2',3'-二脱氢-3'-脱氧-4'-乙炔基胸腺嘧啶的研发
A new approach to the synthesis of 4'-carbon-substituted nucleosides: development of a highly active anti-HIV agent 2', 3'-didehydro-3'-deoxy-4'-ethynylthymidine.
作者信息
Haraguchi Kazuhiro, Takeda Shingo, Sumino Masanori, Tanaka Hiromichi, Dutschman Ginger E, Cheng Yung-Chi, Nitanda Takao, Baba Masanori
机构信息
School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
出版信息
Nucleosides Nucleotides Nucleic Acids. 2005;24(5-7):343-7. doi: 10.1081/ncn-200059774.
Oxidation of 3'-O-TBDMS-4',5-unsaturated thymidine 3 with dimethyldioxirane (DMDO) allowed the isolation of the epoxide 4. Upon reacting with organosilicon reagents in the presence of SnCl4, 4 underwent stereoselective ring opening to give 4'-alpha-allyl (6), 4'-alpha-(2-bromoallyl) (7), 4'-alpha-(cyclopenten-3-yl) (8), and 4'-alpha-cyano (9) derivatives of thymidine. Reactions of the 3'-epimer 12 with organoaluminum reagents gave 4'-alpha-methyl (13), 4'-alpha-vinyl (14), and 4'-alpha-ethynyl (15) analogues. Compounds 13-15 were transformed into corresponding 2',3'-didehydro-3'-deoxy derivatives. Evaluation of their ability to inhibit the replication of HIV in cell culture showed that 4'-ethynyl-d4T (19) is more potent and less toxic than the parent compound d4T.
用二甲基二氧杂环丙烷（DMDO）氧化3'-O-叔丁基二甲基硅烷基-4',5-不饱和胸苷3可分离得到环氧化物4。在SnCl4存在下与有机硅试剂反应时，4发生立体选择性开环，得到胸苷的4'-α-烯丙基（6）、4'-α-（2-溴烯丙基）（7）、4'-α-（环戊-3-烯基）（8）和4'-α-氰基（9）衍生物。3'-差向异构体12与有机铝试剂反应得到4'-α-甲基（13）、4'-α-乙烯基（14）和4'-α-乙炔基（15）类似物。化合物13 - 15被转化为相应的2',3'-二脱氢-3'-脱氧衍生物。对它们在细胞培养中抑制HIV复制能力的评估表明，4'-乙炔基-d4T（化合物19）比母体化合物d4T更有效且毒性更小。
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