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Synthesis of a 6-Methyl-7-Deaza Analogue of Adenosine that Potently Inhibits Replication of Polio and Dengue Viruses
Wu, Runzhi Smidansky, Eric D. Oh, Hyung Suk Takhampunya, Ratree Padmanabhan, Radhakrishnan Cameron, Craig E. Peterson, Blake R.
Wu, Runzhi
Smidansky, Eric D.
Oh, Hyung Suk
Takhampunya, Ratree
Padmanabhan, Radhakrishnan
Cameron, Craig E.
Peterson, Blake R.
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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.
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2010-11-25
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American Chemical Society
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Peterson_2010.pdf
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Wu, R., Smidansky, E. D., Oh, H. S., Takhampunya, R., Padmanabhan, R., Cameron, C. E., & Peterson, B. R. (2010). Synthesis of a 6-Methyl-7-Deaza Analogue of Adenosine that Potently Inhibits Replication of Polio and Dengue Viruses. Journal of Medicinal Chemistry, 53(22), 7958–7966. http://doi.org/10.1021/jm100593s