From 1,4-Disaccharide to 1,3-Glycosyl Carbasugar: Synthesis of a Bespoke Inhibitor of Family GH99 Endo-α-mannosidase

Dan Lu; Sha Zhu; Lukasz F. Sobala; Ganeko Bernardo-Seisdedos; Oscar Millet; Yongmin Zhang; Jesus Jiménez-Barbero; Gideon J. Davies; Matthieu Sollogoub

doi:10.1021/acs.orglett.8b03260

From 1,4-Disaccharide to 1,3-Glycosyl Carbasugar: Synthesis of a Bespoke Inhibitor of Family GH99 Endo-α-mannosidase

Dan Lu, Sha Zhu, Lukasz F. Sobala, Ganeko Bernardo-Seisdedos, Oscar Millet, Yongmin Zhang, Jesus Jiménez-Barbero, Gideon J. Davies, Matthieu Sollogoub^*

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	7488-7492
Number of pages	5
Journal	Organic Letters
Volume	20
Issue number	23
Early online date	14 Nov 2018
DOIs	https://doi.org/10.1021/acs.orglett.8b03260
Publication status	Published - 7 Dec 2018

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© 2018 American Chemical Society. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

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10.1021/acs.orglett.8b03260

OL aziridine revised
© 2018 American Chemical Society. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.
Accepted author manuscript, 5.29 MB

Cite this

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title = "From 1,4-Disaccharide to 1,3-Glycosyl Carbasugar: Synthesis of a Bespoke Inhibitor of Family GH99 Endo-α-mannosidase",

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.",

author = "Dan Lu and Sha Zhu and Sobala, {Lukasz F.} and Ganeko Bernardo-Seisdedos and Oscar Millet and Yongmin Zhang and Jesus Jim{\'e}nez-Barbero and Davies, {Gideon J.} and Matthieu Sollogoub",

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AU - Sobala, Lukasz F.

AU - Bernardo-Seisdedos, Ganeko

AU - Millet, Oscar

AU - Zhang, Yongmin

AU - Jiménez-Barbero, Jesus

AU - Davies, Gideon J.

AU - Sollogoub, Matthieu

N1 - © 2018 American Chemical Society. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

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Y1 - 2018/12/7

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AB - 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.

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From 1,4-Disaccharide to 1,3-Glycosyl Carbasugar: Synthesis of a Bespoke Inhibitor of Family GH99 Endo-α-mannosidase

Abstract

Bibliographical note

Access to Document

Other files and links

Glycosylation: Programmes for Observation, Inhibition & Structure-based Exploitation of key carbohydrate-active enzymes

Diffraction images used to solve the structures published in the article "From 1,4-Disaccharide to 1,3-Glycosyl Carbasugar: Synthesis of a Bespoke Inhibitor of Family GH99 Endo-α-mannosidase"

Cite this

From 1,4-Disaccharide to 1,3-Glycosyl Carbasugar: Synthesis of a Bespoke Inhibitor of Family GH99 Endo-α-mannosidase

Abstract

Bibliographical note

Access to Document

Other files and links

Projects

Glycosylation: Programmes for Observation, Inhibition & Structure-based Exploitation of key carbohydrate-active enzymes

Datasets

Diffraction images used to solve the structures published in the article "From 1,4-Disaccharide to 1,3-Glycosyl Carbasugar: Synthesis of a Bespoke Inhibitor of Family GH99 Endo-α-mannosidase"

Cite this