title: Prodrugs of imidazotriazine and pyrrolotriazine C-nucleosides can increase anti-HCV activity and enhance nucleotide triphosphate concentrations in vitro.
abstract: A number of prodrugs of HCV-active purine nucleoside analogues 2'-C-methyl 4-aza-9-deaza adenosine 1, 2'-C-methyl 4-aza-7,9-dideaza adenosine 2, 2'-C-methyl 4-aza-9-deaza guanosine 3 and 2'-C-methyl 4-aza-7,9-dideaza guanosine 4 were prepared and evaluated to improve potency, selectivity and liver targeting. Phosphoramidate guanosine prodrugs (3a-3k and 4a, b) showed insufficient cell activity for further profiling. Striking enhancement in replicon activity relative to the parent was observed for phosphoramidate imidazo[2,1-f][1,2,4]triazine-4-amine adenosine prodrugs (1a-1p), but this was accompanied by an increase in cytotoxicity. Improved or similar potency without a concomitant increase in toxicity relative to the parent was demonstrated for phosphoramidate pyrrolo[2,1-f][1,2,4]triazine-4-amine adenosine prodrugs (2a-2k). Carbamate, ester and mixed prodrugs of 2 showed mixed results. Selected prodrugs of 2 were analysed for activation to the triphosphate, with most demonstrating much better activation in hepatocytes over replicon cells. The best activation was observed for a mixed phosphoramidate-3'ester (11) followed by a simple 3'-ester (10).
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Tyndall
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Alistair G
authors.initials: AG
authors.lastname: Draffan
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Barbara
authors.initials: B
authors.lastname: Frey
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Brett
authors.initials: B
authors.lastname: Pool
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Rosliana
authors.initials: R
authors.lastname: Halim
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Saba
authors.initials: S
authors.lastname: Jahangiri
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Silas
authors.initials: S
authors.lastname: Bond
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Veronika
authors.initials: V
authors.lastname: Wirth
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Angela
authors.initials: A
authors.lastname: Luttick
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Danielle
authors.initials: D
authors.lastname: Tilmanis
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Jesse
authors.initials: J
authors.lastname: Thomas
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Kate
authors.initials: K
authors.lastname: Porter
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Tucker
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D009711:Nucleotides / Q000378:metabolism*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D014227:Triazines / Q000737:chemistry*
chemical_list: D000998:Antiviral Agents; D009705:Nucleosides; D009711:Nucleotides; D011355:Prodrugs; D014227:Triazines
keywords: Antiviral; C-nucleoside; Hepatitis C; NS5B polymerase