Synthesis of a 6-Methyl-7-deaza Analogue of Adenosine That Potently Inhibits Replication of Polio and Dengue Viruses

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• 作者：Runzhi Wu ; Eric D. Smidansky ; Hyung Suk Oh ; Ratree Takhampunya ; Radhakrishnan Padmanabhan ; Craig E. Cameron ; Blake R. Peterson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：November 25, 2010
• 年：2010
• 卷：53
• 期：22
• 页码：7958-7966
• 全文大小：998K
• 年卷期：v.53,no.22(November 25, 2010)
• ISSN：1520-4804

文摘

Bioisosteric deaza analogues of 6-methyl-9-β-d-ribofuranosylpurine, a hydrophobic analogue of adenosine, were synthesized and evaluated for antiviral activity. Whereas the 1-deaza and 3-deaza analogues were essentially inactive in plaque assays of infectivity, a novel 7-deaza-6-methyl-9-β-d-ribofuranosylpurine analogue, structurally related to the natural product tubercidin, potently inhibited replication of poliovirus (PV) in HeLa cells (IC₅₀ = 11 nM) and dengue virus (DENV) in Vero cells (IC₅₀ = 62 nM). Selectivity against PV over cytotoxic effects to HeLa cells was >100-fold after incubation for 7 h. Mechanistic studies of the 5′-triphosphate of 7-deaza-6-methyl-9-β-d-ribofuranosylpurine revealed that this compound is an efficient substrate of PV RNA-dependent RNA polymerase (RdRP) and is incorporated into RNA mimicking both ATP and GTP.