Synthesis of a 6-methyl-7-deaza analogue of adenosine that potently inhibits replication of polio and dengue viruses

Runzhi Wu, Eric D. Smidansky, Hyung Suk Oh, Ratree Takhampunya, Radhakrishnan Padmanabhan, Craig E. Cameron, Blake R. Peterson

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7958-7966
Number of pages9
JournalJournal of Medicinal Chemistry
Volume53
Issue number22
DOIs
StatePublished - Nov 25 2010

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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