Synthesis of a 6-Methyl-7-Deaza Analogue of Adenosine that Potently Inhibits Replication of Polio and Dengue Viruses
Smidansky, Eric D.
Oh, Hyung Suk
Cameron, Craig E.
Peterson, Blake R.
American Chemical Society
Scholarly/refereed, author accepted manuscript
This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm100593s.
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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.
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
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