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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Antiviral Agents / chemical synthesis*
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacology
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Benzopyrans / chemical synthesis*
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Benzopyrans / chemistry
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Benzopyrans / pharmacology
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Cell Survival / drug effects
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Cells, Cultured
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Cowpox virus / drug effects
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Cowpox virus / enzymology
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Fibroblasts / drug effects
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Fibroblasts / virology
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Humans
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Orthopoxvirus / drug effects*
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Pyrimidine Nucleosides / chemical synthesis*
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Pyrimidine Nucleosides / chemistry
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Pyrimidine Nucleosides / pharmacology
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Skin / cytology
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Structure-Activity Relationship
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Thymidine Kinase / genetics
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Vaccinia virus / drug effects
Substances
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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
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Antiviral Agents
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Benzopyrans
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Pyrimidine Nucleosides
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Thymidine Kinase