A Versatile Synthetic Approach toward Diversity Libraries using Monosaccharide Scaffolds
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Author(s)
Abbenante, Giovanni
Adamson, George
Becker, Bernd
Clark, Chris
Condie, Glenn
Falzun, Tania
Grathwohl, Matthias
Gupta, Praveer
Hanson, Michael
Huynh, Ngoc
Katavic, Peter
Kuipers, Krystle
Lam, Ann
Liu, Ligong
Mann, Maretta
Mason, Jeff
McKeveney, Declan
Muldoon, Craig
Pearson, Andrew
Rajaratnam, Premraj
Ryan, Sarah
Tornetzki, Gerry
Verquin, Geraldine
Waanders, Jennifer
West, Michael
Wilcox, Neil
Wimmer, Norbert
Yau, Annika
Zuegg, Johannes
Meutermans, Wim
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C. Dale Poulters
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Abstract
The pyranose scaffold is unique in its ability to position pharmacophore substituents in various ways in 3D space, and unique pharmacophore scanning libraries could be envisaged that focus on scanning topography rather than diversity in the type of substituents. Approaches have been described that make use of amine and acid functionalities on the pyranose scaffolds to append substituents, and this has enabled the generation of libraries of significant structural diversity. Our general aim was to generate libraries of pyranose-based drug-like mimetics, where the substituents are held close to the scaffold, in order to obtain molecules with better defined positions for the pharmacophore substituents. Here we describe the development of a versatile synthetic route toward peptide mimetics build on 2-amino pyranose scaffolds. The method allows introduction of a wide range of substituent types, it is regio- and stereospecific, and the later diversity steps are performed on solid phase. Further, the same process was applied on glucose and allose scaffolds, in the exemplified cases, and is likely adaptable to other pyranose building blocks. The methods developed in this work give access to molecules that position the three selected binding elements in various 3D orientations on a pyranose scaffold and have been applied for the production of a systematically diverse library of several hundred monosaccharide-based mimetics.
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Journal of Organic Chemistry
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75
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1
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Medicinal and biomolecular chemistry
Organic chemistry
Organic chemical synthesis