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.
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.
Haraguchi
Kazuhiro
K
School of Pharmaceutical Sciences, Showa University, Tokyo, Japan. harakazu@pharm.showa-u.ac.jp
Takeda
Shingo
S
Sumino
Masanori
M
Tanaka
Hiromichi
H
Dutschman
Ginger E
GE
Cheng
Yung-Chi
YC
Nitanda
Takao
T
Baba
Masanori
M
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002244:Carbon / Q000737:chemistry*; D002460:Cell Line; D006678:HIV / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D009705:Nucleosides / Q000138:chemical synthesis*; D010100:Oxygen / Q000378:metabolism; D018119:Stavudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D019380:Anti-HIV Agents; D009705:Nucleosides; C486840:2',3'-didehydro-3'-deoxy-4'-ethynylthymidine; D002244:Carbon; D018119:Stavudine; D010100:Oxygen