title: Synthesis and biological evaluation of 4-substituted fluoronucleoside analogs for the treatment of hepatitis B virus infection.
abstract: A series of 4-substituted fluoronucleosides have been synthesized in order to address the toxicity issue of the parent compound 7, and after in vitro evaluation, the cyclopropylamino analog 1f was selected for in vivo study. In mice, this compound exhibited a significantly improved toxicity profile. Administered orally, compound 1f was well-tolerated at a dose up to 3 g/kg and showed insignificant toxicity on white blood cells and a low mutagenic effect at dosages up to 80 mg/kg (single) or 20 mg/kg/day (5 days). In duck HBV (DHBV)-infected duck models, both the serum and liver DHBV DNA levels (74.2 and 82.1%, respectively) were markedly reduced by the treatment of 1f at a dose of 1 mg/kg/day for 10 days. In addition, both the viral DNA levels had a lower degree of recovery after withdrawal of the test compound for 3 days.
authors.affiliation: †College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, PR China.|⊥Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou 450001, PR China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Yang
authors.affiliation: †College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, PR China.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Kang
authors.affiliation: ‡Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, PR China.
authors.forename: Liyun
authors.initials: L
authors.lastname: Zheng
authors.affiliation: §Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China.
authors.forename: Xue-Jun
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: ‡Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, PR China.
authors.forename: Na
authors.initials: N
authors.lastname: Wan
authors.affiliation: †College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.affiliation: †College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: †College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, PR China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Niu
authors.affiliation: §Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China.
authors.forename: Sheng-Qi
authors.initials: SQ
authors.lastname: Wang
authors.affiliation: †College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, PR China.|‡Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, PR China.
authors.forename: Youmei
authors.initials: Y
authors.lastname: Peng
authors.affiliation: ‡Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, PR China.
authors.forename: Qingduan
authors.initials: Q
authors.lastname: Wang
authors.affiliation: †College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, PR China.
authors.forename: Wenquan
authors.initials: W
authors.lastname: Yu
authors.affiliation: †College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, PR China.|⊥Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou 450001, PR China.
authors.forename: Junbiao
authors.initials: J
authors.lastname: Chang
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003562:Cytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004261:DNA Replication / Q000187:drug effects; D004279:DNA, Viral / Q000378:metabolism; D004372:Ducks; D006509:Hepatitis B / Q000188:drug therapy* / Q000821:virology; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007958:Leukocyte Count; D051379:Mice; D008958:Models, Molecular; D009152:Mutagenicity Tests; D009705:Nucleosides / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D023382:Toxicity Tests, Acute
chemical_list: C000599946:1-(5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-(cyclopropylamino)pyrimidin-2(1H)-one; D000998:Antiviral Agents; D004279:DNA, Viral; D009705:Nucleosides; D003562:Cytidine