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From 1,4-disaccharide to 1,3-glycosyl carbasugar: Synthesis of a bespoke inhibitor of family GH99 endo-α-mannosidase

DOI: 10.1021/acs.orglett.8b03260 DOI Help

Authors: Dan Lu (Sorbonne Université, CNRS) , Sha Zhu (Sorbonne Université, CNRS) , Lukasz F. Sobala (University of York) , Ganeko Bernardo-seisdedos (CIC bioGUNE) , Oscar Millet (CIC bioGUNE) , Yongmin Zhang (Sorbonne Université, CNRS) , Jesus Jiménez-barbero (Ikerbasque, Basque Foundation for Science) , Gideon J. Davies (University of York) , Matthieu Sollogoub (Sorbonne Université, CNRS)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Organic Letters

State: Published (Approved)
Published: November 2018
Diamond Proposal Number(s): 9948

Abstract: Understanding the enzyme reaction mechanism can lead to the design of enzyme inhibitors. A Claisen rearrangement was used to allow conversion of an α-1,4-disaccharide into an α-1,3-linked glycosyl carbasugar to target the endo-α-mannosidase from the GH99 glycosidase family, which, unusually, is believed to act through a 1,2-anhydrosugar “epoxide” intermediate. Using NMR and X-ray crystallography, it is shown that glucosyl carbasugar α-aziridines can act as reasonably potent endo-α-mannosidase inhibitors, likely by virtue of their shape mimicry and the interactions of the aziridine nitrogen with the conserved catalytic acid/base of the enzyme active site.

Subject Areas: Chemistry


Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography