A 3'-deoxy-3'-C-methylenephosphonate modified diribonucleotide is highly resistant to degradation by spleen phosphodiesterase and not cleaved at all by snake venom phosphodiesterase. The most remarkable finding is that, despite the fact that both the vicinal 2-hydroxy nucleophile and the 5'-oxyanion leaving group are intact, the 3'-methylenephosponate RNA modification is also highly resistant towards the action of RNase A.
Oligoribonucleotides/chemistry , Phosphorous Acids/chemistry , RNA/chemistry , Ribonuclease, Pancreatic/metabolism , Phosphoric Diester Hydrolases/metabolism , RNA/metabolism , Snake Venoms/enzymology
4'-Azido-2'-deoxy-2'-methylcytidine (14) is a potent nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase, displaying an EC(50) value of 1.2 µM and showing moderate in vivo bioavailability in rat (F=14%). Here we describe the synthesis and biological evaluation of 4'-azido-2'-deoxy-2'-methylcytidine and prodrug derivatives thereof.
Antiviral Agents/chemistry , Cytidine/analogs & derivatives , Deoxycytidine/analogs & derivatives , Hepacivirus/drug effects , Prodrugs/pharmacology , Animals , Antiviral Agents/pharmacology , Cytidine/pharmacology , Deoxycytidine/pharmacology , Drug Discovery , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Rats , Viral Nonstructural Proteins/antagonists & inhibitors , Virus Replication/drug effects
The discovery of 4'-azidocytidine (3) (R1479) (J. Biol. Chem. 2006, 281, 3793; Bioorg. Med. Chem. Lett. 2007, 17, 2570) as a potent inhibitor of RNA synthesis by NS5B (EC(50) = 1.28 microM), the RNA polymerase encoded by hepatitis C virus (HCV), has led to the synthesis and biological evaluation of several monofluoro and difluoro derivatives of 4'-azidocytidine. The most potent compounds in this series were 4'-azido-2'-deoxy-2',2'-difluorocytidine and 4'-azido-2'-deoxy-2'-fluoroarabinocytidine with antiviral EC(50) of 66 nM and 24 nM in the HCV replicon system, respectively. The structure-activity relationships within this series were discussed, which led to the discovery of these novel nucleoside analogues with the most potent compound, showing more than a 50-fold increase in antiviral potency as compared to 4'-azidocytidine (3).
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Azides/chemical synthesis , Azides/pharmacology , Deoxycytidine/analogs & derivatives , Drug Design , Hepacivirus/physiology , Virus Replication/drug effects , Antiviral Agents/chemistry , Azides/chemistry , Cell Line, Tumor , Deoxycytidine/chemical synthesis , Deoxycytidine/chemistry , Deoxycytidine/pharmacology , Hepacivirus/drug effects , Humans
4'-Azidocytidine 3 (R1479) has been previously discovered as a potent and selective inhibitor of HCV replication targeting the RNA-dependent RNA polymerase of hepatitis C virus, NS5B. Here we describe the synthesis and biological evaluation of several derivatives of 4'-azidocytidine by varying the substituents at the ribose 2' and 3'-positions. The most potent compound in this series is 4'-azidoarabinocytidine with an IC(50) of 0.17 microM in the genotype 1b subgenomic replicon system. The structure-activity relationships within this series of nucleoside analogues are discussed.
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Cytarabine/analogs & derivatives , Drug Design , Hepacivirus/drug effects , Virus Replication/drug effects , Antiviral Agents/chemistry , Cell Line , Cytarabine/chemical synthesis , Cytarabine/chemistry , Cytarabine/pharmacology , Inhibitory Concentration 50 , Molecular Structure
