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Toward Orthopoxvirus Countermeasures: A Novel Heteromorphic Nucleoside of Unusual Structure

2006; American Chemical Society; Volume: 49; Issue: 14 Linguagem: Inglês

10.1021/jm060404n

1520-4804

Xuesen Fan, Xinying Zhang, Longhu Zhou, Kathy A. Keith, Mark N. Prichard, Earl R. Kern, Paul F. Torrence,

Virus-based gene therapy research

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) (EC50 = 4.6 ± 2.0 μM), and cowpox virus (CV) (EC50 = 2.0 ± 0.3 μM). 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.