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
  • 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: [email protected].
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.