| Reference | <p style=/line-height:25px/>
<br>[1]. Klumpp, Klaus; Kalayanov, Genadiy; Ma, Han et al. 2/’-Deoxy-4/’-azido Nucleoside Analogs Are Highly Potent Inhibitors of Hepatitis C Virus Replication Despite the Lack of 2/’-α-Hydroxyl Groups. Journal of Biological Chemistry (2008), 283(4), 2167-2175.
Abstract
RNA polymerases effectively discriminate against deoxyribonucleotides and specifically recognize ribonucleotide substrates most likely through direct hydrogen bonding interaction with the 2/’-alpha-hydroxy moieties of ribonucleosides. Therefore, ribonucleoside analogs as inhibitors of viral RNA polymerases have mostly been designed to retain hydrogen bonding potential at this site for optimal inhibitory potency. Here, two novel nucleoside triphosphate analogs are described, which are efficiently incorporated into nascent RNA by the RNA-dependent RNA polymerase NS5B of hepatitis C virus (HCV), causing chain termination, despite the lack of alpha-hydroxy moieties. 2/’-deoxy-2/’-beta-fluoro-4/’-azidocytidine (RO-0622) and 2/’-deoxy-2/’-beta-hydroxy-4/’-azidocytidine (RO-9187) were excellent substrates for deoxycytidine kinase and were phosphorylated with efficiencies up to 3-fold higher than deoxycytidine. As compared with previous reports on ribonucleosides, higher levels of triphosphate were formed from RO-9187 in primary human hepatocytes, and both compounds were potent inhibitors of HCV virus replication in the replicon system (IC(50) = 171 +/- 12 nM and 24 +/- 3 nM for RO-9187 and RO-0622, respectively; CC(50) >1 mM for both). Both compounds inhibited RNA synthesis by HCV polymerases from either HCV genotypes 1a and 1b or containing S96T or S282T point mutations with similar potencies, suggesting no cross-resistance with either R1479 (4/’-azidocytidine) or 2/’-C-methyl nucleosides. Pharmacokinetic studies with RO-9187 in rats and dogs showed that plasma concentrations exceeding HCV replicon IC(50) values 8-150-fold could be achieved by low dose (10 mg/kg) oral administration. Therefore, 2/’-alpha-deoxy-4/’-azido nucleosides are a new class of antiviral nucleosides with promising preclinical properties as potential medicines for the treatment of HCV infection.
<br>[2]. Smith, David B.; Kalayanov, Genadiy; Sund, Christian et al. The Design, Synthesis, and Antiviral Activity of 4/’-Azidocytidine Analogues against Hepatitis C Virus Replication: The Discovery of 4/’-Azidoarabinocytidine. Journal of Medicinal Chemistry (2009), 52(1), 219-223.
Abstract
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.
<br>[3]. Smith, David B.; Kalayanov, Genadiy; Sund, Christian et al. The Design, Synthesis, and Antiviral Activity of Monofluoro and Difluoro Analogues of 4/’-Azidocytidine against Hepatitis C Virus Replication: The Discovery of 4/’-Azido-2/’-deoxy-2/’-fluorocytidine and 4/’-Azido-2/’-dideoxy-2/’,2/’-difluorocytidine. Journal of Medicinal Chemistry (2009), 52(9), 2971-2978.
Abstract
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).
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