2. Academic Validation
  3. Synthesis and biological evaluation of a novel β-D-2'-deoxy-2'-α-fluoro-2'-β-C-(fluoromethyl)uridine phosphoramidate prodrug for the treatment of hepatitis C virus infection

Synthesis and biological evaluation of a novel β-D-2'-deoxy-2'-α-fluoro-2'-β-C-(fluoromethyl)uridine phosphoramidate prodrug for the treatment of hepatitis C virus infection

  • Eur J Med Chem. 2018 Jan 1:143:107-113. doi: 10.1016/j.ejmech.2017.11.024.
Ertong Li 1,  Yafeng Wang 2,  Wenquan Yu 1,  Zhigang Lv 1,  Youmei Peng 3,  Bingjie Liu 4,  Shiliang Li 5,  Wenzhe Ho 6,  Qingduan Wang 3,  Honglin Li 5,  Junbiao Chang 7
Affiliations

Affiliations

  • 1 College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, China.
  • 2 School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
  • 3 Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China.
  • 4 School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China.
  • 5 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
  • 6 Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
  • 7 College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, China. Electronic address: changjunbiao@zzu.edu.cn.
PMID: 29172078 DOI: 10.1016/j.ejmech.2017.11.024
Abstract

A novel β-D-2'-deoxy-2'-α-fluoro-2'-β-C-(fluoromethyl)uridine phosphoramidate prodrug (1) has been synthesized. This compound exhibits submicromolar-level Antiviral activity in vitro against HCV genotypes 1b, 1a, 2a, and S282T replicons (EC50 = 0.18-1.13 μM) with low cytotoxicity (CC50 > 1000 μM). Administered orally, prodrug 1 is well tolerated at doses of up to 4 g/kg in mice, and produces a high level of the corresponding triphosphate in rat liver.

Keywords

2′-α-fluoro-2′-β-C-(fluoromethyl)uridine; Anti-HCV; Phosphoramidate prodrug; Triphosphate.

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