当前位置： SCI文献检索 > BIOORGANIC & MEDICINAL CHEMISTRY LETTERS期刊下所有文献 > Prodrugs of imidazotriazine and pyrrolotriazine C-nucleosides can increase anti-HCV activity and enhance nucleotide triphosphate concentrations in vitro.

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).

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Tyndall EM,Draffan AG,Frey B,Pool B,Halim R,Jahangiri S,Bond S,Wirth V,Luttick A,Tilmanis D,Thomas J,Porter K,Tucker SP

doi

10.1016/j.bmcl.2014.12.069

subject

Has Abstract

pub_date

2015-02-15 00:00:00

pages

869-73

issue

4

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(14)01377-8

journal_volume

25

pub_type

杂志文章

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