title: Toward orthopoxvirus countermeasures: a novel heteromorphic nucleoside of unusual structure.
abstract: Two privileged drug scaffolds have been hybridized to create the novel heteromorphic nucleoside 5-(2-amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)-1-(2-deoxypentofuranosyl)pyrimidine-2,4(1H,3H)-dione (2). Compound 2 inhibited the replication of two orthopoxviruses, vaccinia virus (VV) (EC(50) = 4.6 +/- 2.0 microM), and cowpox virus (CV) (EC(50) = 2.0 +/- 0.3 microM). Compound 2 exhibited reduced activity against a thymidine kinase (TK) negative strain of CV, implying a requirement for 5'-monophosphorylation for antiorthopoxvirus activity. Compound 2 was efficiently phosphorylated by VV TK, establishing that VV TK is more promiscuous than previously believed.
authors.affiliation: Department of Chemistry and Biochemistry, Northern Arizona University, Flagstaff, 86011, USA.
authors.forename: Xuesen
authors.initials: X
authors.lastname: Fan
authors.forename: Xinying
authors.initials: X
authors.lastname: Zhang
authors.forename: Longhu
authors.initials: L
authors.lastname: Zhou
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Keith
authors.forename: Mark N
authors.initials: MN
authors.lastname: Prichard
authors.forename: Earl R
authors.initials: ER
authors.lastname: Kern
authors.forename: Paul F
authors.initials: PF
authors.lastname: Torrence
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015608:Cowpox virus / Q000187:drug effects / Q000201:enzymology; D005347:Fibroblasts / Q000187:drug effects / Q000821:virology; D006801:Humans; D018155:Orthopoxvirus / Q000187:drug effects*; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012867:Skin / Q000166:cytology; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000235:genetics; D014616:Vaccinia virus / Q000187:drug effects
chemical_list: C513149:5-(2-amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)-1-(2-deoxypentofuranosyl)pyrimidine-2,4-(1H,3H)-dione; D000998:Antiviral Agents; D001578:Benzopyrans; D011741:Pyrimidine Nucleosides; D013937:Thymidine Kinase