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Iminosugars: Beyond Glycosidase Inhibition

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 9968

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Prof. Dr. Ramón J. Estévez Cabanas

E-Mail Website1 Website2
Guest Editor

Center for Research in Biological Chemistry and Molecular Materials, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
Interests: carbohydrates; sugar mimics (including iminosugars, carbasugars and sugar amino acids); peptidomimetics; heterocycles; natural product chemistry
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. George Fleet

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Guest Editor

Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK
Interests: carbohydrate chemistry; monosaccharides; iminosugars; synthesis; sugar amino acids

Prof. Dr. Atsushi Kato

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Guest Editor

Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
Interests: iminosugars, glycobiology, phytochemistry, food chemistry, glycosidase inhibitors

Prof. Dr. Robert J. Nash

E-Mail Website
Guest Editor

1. Department of Science and Technology, University of Swansea, Sketty, Swansea SA2 8PP, UK
2. Phytoquest Limited, IBERS, Ceredigion, UK
Interests: iminosugars; sugar amino acids; pharmaceuticals; nutraceuticals; biochemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Iminosugars are analogues of carbohydrates in which the ring oxygen is replaced by nitrogen. Over 200 such sugar mimics have been isolated from plants and many thousands of analogues synthesised. Although initially recognised as one of the largest families of glycosidase inhibitors, they are increasingly being found to interact with many other biological processes involving sugars, including interacting with carbohydrate receptors without inhibiting glycosidases. Iminosugars have proven value and great potential as chemotherapeutic agents. Papers on any aspect of iminosugars are invited, including but not limited to: isolation from plants, bacteria or any natural source; synthesis by chemical, biotechnological or any other procedure; occurrence of iminosugars in food, structure of iminosugars or any enzyme associated with iminosugars, including any crystallographic or modeling studies; any aspect of production of iminosugars or of regulatory interest studies; any use or application of iminosugars, including food, medicine material etc.

Prof. Ramón J. Estévez Cabanas
Prof. Dr. George Fleet
Prof. Atsushi Kato
Prof. Robert J. Nash
Guest Editors

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Keywords

iminosugars
iminosugar synthesis
natural iminosugars
biological significance of iminosugars
pharmaceutical applications of iminosugars
pharmacological chaperones
sugar amino acids
isolation of iminosugars

Published Papers (3 papers)

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Research

11 pages, 1508 KiB

Open AccessArticle

Iminosugar Amino Acid idoBR1 Reduces Inflammatory Responses in Microglia

by Olumayokun A. Olajide, Victoria U. Iwuanyanwu, Owolabi W. Banjo, Atsushi Kato, Yana B. Penkova, George W. J. Fleet and Robert J. Nash

Molecules 2022, 27(10), 3342; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27103342 - 23 May 2022

Cited by 2 | Viewed by 2419

Abstract

(1) Background. Inflammation is reported to be a key factor in neurodegeneration. The microglia are immune cells present in the central nervous system; their activation results in the release of inflammatory cytokines and is thought to be related to aging and neurodegenerative disorders, such as Alzheimer’s disease. (2) Methods. A mouse BV-2 microglia cell line was activated using LPS and the anti-inflammatory cucumber-derived iminosugar amino acid idoBR1, (2R,3R,4R,5S)-3,4,5-trihydroxypiperidine-2-carboxylic acid, was used alongside dexamethasone as the control to determine whether it could reduce the inflammatory responses. (3) Results. A dose-dependent reduction in the LPS-induced production of the proinflammatory factors TNFα, IL-6, and nitric oxide and the transcription factor NF-κB was found. (4) Conclusions. Further investigations of the anti-inflammatory effects of idoBR1 in other models of neurodegenerative diseases are warranted. Full article

(This article belongs to the Special Issue Iminosugars: Beyond Glycosidase Inhibition)

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13 pages, 3587 KiB

Open AccessArticle

Strategy for Designing Selective Lysosomal Acid α-Glucosidase Inhibitors: Binding Orientation and Influence on Selectivity

by Atsushi Kato, Izumi Nakagome, Mizuki Hata, Robert J. Nash, George W. J. Fleet, Yoshihiro Natori, Yuichi Yoshimura, Isao Adachi and Shuichi Hirono

Molecules 2020, 25(12), 2843; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25122843 - 19 Jun 2020

Cited by 9 | Viewed by 3551

Abstract

Deoxynojirimycin (DNJ) is the archetypal iminosugar, in which the configuration of the hydroxyl groups in the piperidine ring truly mimic those of d-glucopyranose; DNJ and derivatives have beneficial effects as therapeutic agents, such as anti-diabetic and antiviral agents, and pharmacological chaperones for genetic disorders, because they have been shown to inhibit α-glucosidases from various sources. However, attempts to design a better molecule based solely on structural similarity cannot produce selectivity between α-glucosidases that are localized in multiple organs and tissues, because the differences of each sugar-recognition site are very subtle. In this study, we provide the first example of a design strategy for selective lysosomal acid α-glucosidase (GAA) inhibitors focusing on the alkyl chain storage site. Our design of α-1-C-heptyl-1,4-dideoxy-1,4-imino-l-arabinitol (LAB) produced a potent inhibitor of the GAA, with an IC₅₀ value of 0.44 µM. It displayed a remarkable selectivity toward GAA (selectivity index value of 168.2). A molecular dynamic simulation study revealed that the ligand-binding conformation stability gradually improved with increasing length of the α-1-C-alkyl chain. It is noteworthy that α-1-C-heptyl-LAB formed clearly different interactions from DNJ and had favored hydrophobic interactions with Trp481, Phe525, and Met519 at the alkyl chain storage pocket of GAA. Moreover, a molecular docking study revealed that endoplasmic reticulum (ER) α-glucosidase II does not have enough space to accommodate these alkyl chains. Therefore, the design strategy focusing on the shape and acceptability of long alkyl chain at each α-glucosidase may lead to the creation of more selective and practically useful inhibitors. Full article

(This article belongs to the Special Issue Iminosugars: Beyond Glycosidase Inhibition)

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24 pages, 17089 KiB

Open AccessArticle

Synthesis of Pyrrolidine Monocyclic Analogues of Pochonicine and Its Stereoisomers: Pursuit of Simplified Structures and Potent β-N-Acetylhexosaminidase Inhibition

by Xin Yan, Yuna Shimadate, Atsushi Kato, Yi-Xian Li, Yue-Mei Jia, George W. J. Fleet and Chu-Yi Yu

Molecules 2020, 25(7), 1498; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25071498 - 25 Mar 2020

Cited by 6 | Viewed by 2773

Abstract

Ten pairs of pyrrolidine analogues of pochonicine and its stereoisomers have been synthesized from four enantiomeric pairs of polyhydroxylated cyclic nitrones. Among the ten N-acetylamino pyrrolidine analogues, only compounds with 2,5-dideoxy-2,5-imino-d-mannitol (DMDP) and pochonicine (1) configurations showed potent inhibition of β-N-acetylhexosaminidases (β-HexNAcases); while 1-amino analogues lost almost all their inhibitions towards the tested enzymes. The assay results reveal the importance of the N-acetylamino group and the possible right configurations of pyrrolidine ring required for this type of inhibitors. Full article

(This article belongs to the Special Issue Iminosugars: Beyond Glycosidase Inhibition)

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