Carbohydrate-derived nitrones as synthetic tools for the discovery of novel classes of iminosugars

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1st EuroCarb Young Researcher (ECYR) Workshop

CarboMet Workshop

Mini symposium: Glycobiology at the LUMC and beyond

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Carbohydrate-derived nitrones as synthetic tools for the discovery of novel classes of iminosugars

Anaïs Vieira Da Cruz 1,2 , Liang Wu 3 , Salia Tangara 1,2 , Alice Kanazawa 1,2 , Jean-Bernard Behr 4 , Gideon J. Davies 3 , Sandrine Py 1,2

1 Univ. Grenoble Alpes, DCM, Grenoble, France, 2 CNRS, DCM, Grenoble, France, 3 York Structural Biology Laboratory, Department of Chemistry, University of York, York, United Kingdom, 4 Univ. Reims Champagne-Ardenne, ICMR, CNRS UMR 7312, Reims, France

Due to their stability in vivo and their activity as glycosidase inhibitors or activators, iminosugars are among the most promising drug candidates for the treatment of diseases such as diabetes, viral infections and lysosomal storage disorders.[1] Recently, our group has identified a series of iminosugars (i.e. compounds 1 and 2), exhibiting a quaternary center in α-position of their nitrogen atom, which proved to be excellent inhibitors (nanomolar Ki) of α-glucosidases with exquisite selectivity.[2]

In this communication, the synthesis of novel iminosugars from carbohydrate-derived nitrones will be presented. The variety of synthetic methods that can be applied to nitrones to prepare bioactive molecules will be emphasized by successful syntheses of original iminosugar scaffolds.[3] Investigation of the biological activities of these new molecules will also be presented, and discussed in light of crystallographic analyses of iminosugar-glycosidase complexes.[4]

α-glucosidase inhibiting iminosugars

a) Compain, P.; Martin O. R. in Iminosugars: From synthesis to therapeutic applications, Wiley, 2007. b) Nash, R. J.; Kato, A.; Yu, C.-Y.; Fleet, G. W. Future Med. Chem. 2011, 3, 1513. c) Horne, G.; Wilson, F. X.; Tinsley, J.; Williams, D. H.; Storer, R. Drug Discovery Today 2011, 16, 107. d) Bras, N. F.; Cerqueira, N. M. F. S. A.; Ramos, J.; Fernandes, P. A. Opin. Ther. Patents 2014, 24, 857.

a) Boisson, J.; Thomasset, A.; Racine, E.; Cividino, P.; Banchelin Sainte-Luce, T.; Poisson, J.-F.; Behr, J.-B.; Py, S. Org. Lett. 2015, 17, 3662. b) Vieira Da Cruz, A.; Kanazawa, A.; Poisson, J.-F.; Behr, J.-B.; Py, S. J. Org. Chem. 2017, 82, 9866.

a) Tangara, S.; Aupic, C.; Kanazawa, A.; Poisson, J.-F.; Py, S. Org. Lett. 2017, 19, 4842. b) Lieou Kui, E.; Kanazawa, A.; Behr, J.-B.; Py, S. Eur. J. Org. Chem. 2018, 2178. c) Tangara, S.; Kanazawa, A.; Fayolle, M.; Philouze, C.; Poisson, J.-F.; Behr, J.-B.; Py, S. New J. Chem. 2018, 42, 16735.

Vieira Da Cruz, A.; Wu, L.; Tangara, S.; Harbison, A. M.; Boisson, J.; Lieou Kui, E.; Kanazawa, A.; Mantynen, B. E.; Nava, N. E.; Rose, D. R.; Fadda, E.; Behr, J.-B.; Davies, G. J.; Py, S. Manuscript in preparation.

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