title: From the chemistry of epoxy-sugar nucleosides to the discovery of anti-HIV agent 4'-ethynylstavudine-Festinavir.
abstract: Branched sugar nucleosides have attracted much attention due to their biological activities. We have demonstrated that epoxysugar nucleosides serve as versatile precursor for the stereo-defined synthesis of these nucleoside derivatives on the basis of its ring opening with organoaluminum or organosilicon reagents. In this review article, novel methods for the synthesis of nucleoside analogues branched at the 1' and 4'-position will be described. During this study, we could discover an anti-HIV agent, 4'-ethynylstavudine (Festinavir). Festinavir showed more potent anti-HIV activity than the parent compound stavudine (d4T). Other significant properties of Festinavir are as follows: 1) much less toxic to various cells and also to mitochondorial DNA synthesis than d4T, 2) better substrate for human thymidine kinase than d4T, 3) resistant not only to chemical glycosidic bond cleavage but also to catabolism by thymidine phosphorylase, 4) the activity improves in the presence of a major mutation, K103N, associated with resistance to non-nucleoside reverse transcriptase inhibitors. Detailed profile of the antiviral activities, biology and pharmacology of Festinavir are also described.
authors.affiliation: School of Pharmacy, Showa University, Japan. harakazu@pharm.showa-u.ac.jp
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Haraguchi
authors.forename: Shingo
authors.initials: S
authors.lastname: Takeda
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kubota
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kumamoto
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Tanaka
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hamasaki
authors.forename: Masanori
authors.initials: M
authors.lastname: Baba
authors.forename: Elijah
authors.initials: E
authors.lastname: Paintsil
authors.forename: Yung-Chi
authors.initials: YC
authors.lastname: Cheng
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D055808:Drug Discovery; D004852:Epoxy Compounds / Q000737:chemistry*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009705:Nucleosides / Q000737:chemistry*; D018119:Stavudine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C505960:4'-ethynylstavudine; D019380:Anti-HIV Agents; D004852:Epoxy Compounds; D009705:Nucleosides; D018119:Stavudine