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

被引：0
|
作者：
Haraguchi, K
Takeda, S
Sumino, M
Tanaka, H
Dutschman, GE
Cheng, YC
Nitanda, T
Baba, M
机构：
[1] Showa Univ, Sch Pharmaceut Sci, Shinagawa Ku, Tokyo 1428555, Japan
[2] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT USA
[3] Kagoshima Univ, Fac Med, Div Antiviral Chemotherapy, Ctr Chron Viral Dis, Kagoshima 890, Japan
来源：
NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS | 2005年 / 24卷 / 5-7期
关键词：
anti-HIV; 4 '-substituted nucleosides; didehydro-3 '-deoxythymidine; dimethyldioxirane; epoxidation; organosilicon reagents; Lewis acids; organoaluminum reagents;
D O I：
10.1081/NCN-200059774
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
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.
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页码：343 / 347
页数：5
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