The phosphoramidate ProTide approach greatly enhances the activity of beta-2'-C-methylguanosine against hepatitis C virus.
Beta-2'-C-methyl purines (1, 2) are known inhibitors of hepatitis C virus (HCV). We herein report the synthesis, biological and enzymatic evaluation of their 5'-phosphoramidate ProTides. Described herein are seven l-alanine phosphoramidate derivatives with variations to the amino acid ester. The 1-naphthyl phosphoramidate of beta-2'-methylguanosine containing the benzyl ester (20) was the most active at 0.12microM, an 84-fold of increase in activity compared to the parent nucleoside (2) with no increase of cytotoxicity. The carboxypeptidase mediated hydrolysis of several ProTides showed a predictive correlation with their activity versus HCV in replicon.
McGuigan
Christopher
C
Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK. mcguigan@cardiff.ac.uk
Perrone
Plinio
P
Madela
Karolina
K
Neyts
Johan
J
D000577:Amides / Q000737:chemistry*; D000596:Amino Acids / Q000737:chemistry; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004952:Esters / Q000737:chemistry; D006151:Guanosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D016174:Hepacivirus / Q000378:metabolism*; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D006868:Hydrolysis; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D010756:Phosphoric Acids / Q000737:chemistry*; D011355:Prodrugs
C116616:8-methylguanosine; D000577:Amides; D000596:Amino Acids; D000998:Antiviral Agents; D004952:Esters; D010756:Phosphoric Acids; D011355:Prodrugs; D006151:Guanosine; C011067:phosphoramidic acid