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Review
. 2018 Jan-Dec:26:2040206618756788.
doi: 10.1177/2040206618756788.

Flexibility-Not just for yoga anymore!

Katherine Seley-Radtke  1
Affiliations
Review

Flexibility-Not just for yoga anymore!

Katherine Seley-Radtke. Antivir Chem Chemother. 2018 Jan-Dec.

Abstract

Over the past few years, nucleosides have maintained a prominent role as one of the cornerstones of antiviral and anticancer therapeutics, and many approaches to nucleoside drug design have been pursued. One such approach involves flexibility in the sugar moiety of nucleosides, for example, in the highly successful anti-HIV and HBV drug tenofovir. In contrast, introduction of flexibility to the nucleobase scaffold has only more recently gained significance with the invention of our fleximers. The history, development, and some biological relevance for this innovative class of nucleosides are detailed herein.

Keywords: Coronaviridae; dengue virus; filoviridae; flaviviridae; nucleoside analogues.

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Figures

Figure 1.
Figure 1.
The five most common naturally occurring nucleosides.
Figure 2.
Figure 2.
Acyclic nucleosides and nucleoside phosphonates.
Figure 3.
Figure 3.
The fleximer concept.
Figure 4.
Figure 4.
Retrosynthetic approach to the distal fleximers.
Figure 5.
Figure 5.
Retrosynthetic approach to the proximal fleximers.
Figure 6.
Figure 6.
Inhibition of SAHase and indirectly, MTases. SAM: S-adenosylmethionine; SAH: S-adenosylhomocysteine.
Figure 7.
Figure 7.
Flex-G in SAHase.
Figure 8.
Figure 8.
Syn vs. anti conformation for Flex-G in SAHase binding site vs. in solution.
Figure 9.
Figure 9.
Two pathways to GDP-fucose.
Figure 10.
Figure 10.
Differential Activities of GTP and Flex-GTP.
Figure 11.
Figure 11.
Carbocyclic “reverse” fleximers.
Figure 12.
Figure 12.
3-Deaza binding energies in SAHase.
Figure 13.
Figure 13.
Flex-3-deazaNpC and 3-deaza-NpC.
Figure 14.
Figure 14.
2′ Modified fleximers in the HCV replicon assay.
Figure 15.
Figure 15.
Acyclovir and Flex-Acyclovir analogues.
Scheme 1.
Scheme 1.
Pochet’s transglycosylation route to fleximers.
Scheme 2.
Scheme 2.
Hudson’s click fleximers.
Scheme 3.
Scheme 3.
Fleximer analogues via the Bannert Cascade reaction.
Scheme 4.
Scheme 4.
Peyrottes’ azido-fleximers.
Scheme 5.
Scheme 5.
Robins’ ring opening route to an oxadiazole fleximer.
Figure 16.
Figure 16.
Gunderson’s fleximers.
Figure 17.
Figure 17.
Various connectivities for Flex-G.
See this image and copyright information in PMC

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