title: Synthesis and biological activity of 7-deaza-7-ethynyl-2'-deoxy-2'-fluoro-2'-C-methyladenosine and its 2'-C-methyl-ribo analogue.
abstract: In our search for improved therapeutic agents against HCV we synthesized 7-deaza-7-ethynyl-2'-C-methyladenosine (1) and its 2'-deoxy-2'-fluoro analogue 2. The corresponding nucleoside triphosphates were efficient chain terminators of the HCV NS5b polymerase with IC(50)'s of 0.75 microM and 0.4 microM respectively. However, only the ribo-nucleoside 1 exhibited activity in a Huh7 cell based replicon assay with an EC(50) of 0.09 microM. In order to overcome the lack of activity of the fluoro analogue 2 we synthesised several phosphoroamidate prodrugs.
authors.affiliation: Genelabs Technologies, Inc., 505 Penobscot Drive, Redwood City, CA 94063, USA. marijap@genelabs.com
authors.forename: Marija
authors.initials: M
authors.lastname: Prhavc
authors.forename: Natalia
authors.initials: N
authors.lastname: Dyatkina
authors.forename: Jesse
authors.initials: J
authors.lastname: Keicher
authors.forename: Sebastian
authors.initials: S
authors.lastname: Liehr
authors.forename: Samantha
authors.initials: S
authors.lastname: Koo-McCoy
authors.forename: Derek
authors.initials: D
authors.lastname: Latour
authors.forename: Kevin
authors.initials: K
authors.lastname: Fung
authors.forename: Kevin
authors.initials: K
authors.lastname: Dunlop
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Pouliot
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.forename: Wenbao
authors.initials: W
authors.lastname: Li
authors.forename: Lillian
authors.initials: L
authors.lastname: Lou
authors.forename: Christopher
authors.initials: C
authors.lastname: Roberts
authors.forename: Ronald
authors.initials: R
authors.lastname: Griffith
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014372:Tubercidin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D011355:Prodrugs; D014372:Tubercidin; D017361:Viral Nonstructural Proteins; C541642:7-deaza-7-ethynyl-2'-C-methyladenosine; C541637:7-deaza-7-ethynyl-2'-deoxy-2'-fluoro-2'-C-methyladenosine; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase