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Glycomimetics: Design, Synthesis and Therapeutic Applications
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Glycomimetics: Design, Synthesis and Therapeutic Applications

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

Deadline for manuscript submissions: closed (30 January 2018) | Viewed by 50652

Special Issue Editor

Prof. Dr. Philippe Compain

E-Mail Website
Guest Editor
École Européenne de Chimie, Polymères et Matériaux, Université de Strasbourg, Strasbourg, France
Interests: organic synthesis; glycomimetics; synthetic methodologies; C-H functionalization; multivalency; enzyme inhibitors; carbohydrate-processing enzymes; rare genetic diseases

Special Issue Information

Dear Colleagues,

Glycomimetics, as structurally altered analogues of sugars, offer the opportunity to emulate carbohydrate activities while circumventing their drawbacks as credible drugs. Structural modifications are performed not only to enhance target affinity and selectivity but also to improve drug-like properties, including oral bioavailability and in vivo stability. Beyond their biological interest, glycomimetics are an amazing playground for organic chemists. Creatively imagining new chemical structures that compete with one of the most important classes of biomolecules is a strong driving force. To paraphrase Marcellin Berthelot, organic chemists are indeed always eager to create their own objects of study. The high density of functional groups and asymmetric centers present in carbohydrate structures provide a rich source of inspiration. Beyond rational thinking, a kind of quest for molecular beauty via simplicity or symmetry is part of the design process. With regards to synthetic methodologies, the relative structural complexity of glycomimetics also provides a formidable testing ground for known reactions while permitting accidental discoveries in synthesis. In this Special Issue we intend to collect reviews, original research articles and short communications covering all current aspects of glycomimetic chemistry from innovative synthesis to potential therapeutic applications. Original research works on iminosugars, C-glycosides, square sugars or other sweet objects are therefore welcome, whether these glycomimetics were designed for the synthetic challenges they provide, for tackling fundamental questions in glycobiology, or for drug discovery.

Prof. Dr. Philippe Compain
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • glycomimetics
  • iminosugars
  • carbasugars
  • C-glycosides
  • thiosugars
  • multivalency
  • inhibitors
  • lectins
  • carbohydrate-processing enzymes
  • carbohydrate-mediated biological recognition

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Published Papers (9 papers)

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Editorial

Jump to: Research, Review

3 pages, 163 KiB  
Editorial
Glycomimetics: Design, Synthesis, and Therapeutic Applications
by Philippe Compain
Molecules 2018, 23(7), 1658; https://doi.org/10.3390/molecules23071658 - 7 Jul 2018
Cited by 17 | Viewed by 3885
Abstract
n/a Full article
(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)

Research

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18 pages, 2327 KiB  
Article
Probing the Inhibitor versus Chaperone Properties of sp2-Iminosugars towards Human β-Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease
by Teresa Mena-Barragán, M. Isabel García-Moreno, Alen Sevšek, Tetsuya Okazaki, Eiji Nanba, Katsumi Higaki, Nathaniel I. Martin, Roland J. Pieters, José M. García Fernández and Carmen Ortiz Mellet
Molecules 2018, 23(4), 927; https://doi.org/10.3390/molecules23040927 - 17 Apr 2018
Cited by 30 | Viewed by 5668
Abstract
A series of sp2-iminosugar glycomimetics differing in the reducing or nonreducing character, the configurational pattern (d-gluco or l-ido), the architecture of the glycone skeleton, and the nature of the nonglycone substituent has been synthesized and [...] Read more.
A series of sp2-iminosugar glycomimetics differing in the reducing or nonreducing character, the configurational pattern (d-gluco or l-ido), the architecture of the glycone skeleton, and the nature of the nonglycone substituent has been synthesized and assayed for their inhibition properties towards commercial glycosidases. On the basis of their affinity and selectivity towards GH1 β-glucosidases, reducing and nonreducing bicyclic derivatives having a hydroxylation profile of structural complementarity with d-glucose and incorporating an N′-octyl-isourea or -isothiourea segment were selected for further evaluation of their inhibitory/chaperoning potential against human glucocerebrosidase (GCase). The 1-deoxynojirimycin (DNJ)-related nonreducing conjugates behaved as stronger GCase inhibitors than the reducing counterparts and exhibited potent chaperoning capabilities in Gaucher fibroblasts hosting the neuronopathic G188S/G183W mutation, the isothiourea derivative being indeed one of the most efficient chaperone candidates reported up to date (70% activity enhancement at 20 pM). At their optimal concentration, the four selected compounds promoted mutant GCase activity enhancements over 3-fold; yet, the inhibitor/chaperoning balance became unfavorable at much lower concentration for nonreducing as compared to reducing derivatives. Full article
(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)
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Graphical abstract

11 pages, 1157 KiB  
Communication
One-Pot, Highly Stereoselective Synthesis of Dithioacetal-α,α-Diglycosides
by Maria F. Céspedes Dávila, Jérémy P. Schneider, Amélie Godard, Damien Hazelard and Philippe Compain
Molecules 2018, 23(4), 914; https://doi.org/10.3390/molecules23040914 - 15 Apr 2018
Cited by 10 | Viewed by 5233
Abstract
A one-step access to dithioacetal-α,α-diglycosides is reported. The synthetic strategy is based on the thioacetalization of aldehydes or ketones via highly stereoselective ring-opening of 1,6 anhydrosugars with bis(trimethylsilyl)sulfide. Full article
(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)
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Graphical abstract

11 pages, 2403 KiB  
Article
Potent GH20 N-Acetyl-β-d-hexosaminidase Inhibitors: N-Substituted 3-acetamido-4-amino-5-hydroxymethyl-cyclopentanediols
by Patrick Weber, Seyed A. Nasseri, Bettina M. Pabst, Ana Torvisco, Philipp Müller, Eduard Paschke, Marion Tschernutter, Werner Windischhofer, Stephen G. Withers, Tanja M. Wrodnigg and Arnold E. Stütz
Molecules 2018, 23(3), 708; https://doi.org/10.3390/molecules23030708 - 20 Mar 2018
Cited by 8 | Viewed by 5219
Abstract
From 1,2;3,4-di-O-isopropylidene-d-galactopyranose, a preliminary series of highly functionalized amino(hydroxymethyl)cyclopentanes was easily available. These amine-containing basic carbasugars featuring the d-galacto configuration are potent inhibitors of the GH20 β-d-hexosaminidases probed and may bear potential as regulators of [...] Read more.
From 1,2;3,4-di-O-isopropylidene-d-galactopyranose, a preliminary series of highly functionalized amino(hydroxymethyl)cyclopentanes was easily available. These amine-containing basic carbasugars featuring the d-galacto configuration are potent inhibitors of the GH20 β-d-hexosaminidases probed and may bear potential as regulators of N-acetyl-d-hexosaminidase activities in vivo. Full article
(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)
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Graphical abstract

17 pages, 6665 KiB  
Article
Synthesis of New C- and N-β-d-Glucopyranosyl Derivatives of Imidazole, 1,2,3-Triazole and Tetrazole, and Their Evaluation as Inhibitors of Glycogen Phosphorylase
by Sándor Kun, Éva Bokor, Ádám Sipos, Tibor Docsa and László Somsák
Molecules 2018, 23(3), 666; https://doi.org/10.3390/molecules23030666 - 15 Mar 2018
Cited by 14 | Viewed by 4605
Abstract
The aim of the present study was to broaden the structure-activity relationships of C- and N-β-d-glucopyranosyl azole type inhibitors of glycogen phosphorylase. 1-Aryl-4-β-d-gluco-pyranosyl-1,2,3-triazoles were prepared by copper catalyzed azide-alkyne cycloadditions between O-perbenzylated or O-peracetylated β- [...] Read more.
The aim of the present study was to broaden the structure-activity relationships of C- and N-β-d-glucopyranosyl azole type inhibitors of glycogen phosphorylase. 1-Aryl-4-β-d-gluco-pyranosyl-1,2,3-triazoles were prepared by copper catalyzed azide-alkyne cycloadditions between O-perbenzylated or O-peracetylated β-d-glucopyranosyl ethynes and aryl azides. 1-β-d-Gluco-pyranosyl-4-phenyl imidazole was obtained in a glycosylation of 4(5)-phenylimidazole with O-peracetylated α-d-glucopyranosyl bromide. C-β-d-Glucopyranosyl-N-substituted-tetrazoles were synthesized by alkylation/arylation of O-perbenzoylated 5-β-d-glucopyranosyl-tetrazole or from a 2,6-anhydroheptose tosylhydrazone and arenediazonium salts. 5-Substituted tetrazoles were glycosylated by O-peracetylated α-d-glucopyranosyl bromide to give N-β-d-glucopyranosyl-C-substituted-tetrazoles. Standard deprotections gave test compounds which were assayed against rabbit muscle glycogen phosphorylase b. Most of the compounds proved inactive, the best inhibitor was 2-β-d-glucopyranosyl-5-phenyltetrazole (IC50 600 μM). These studies extended the structure-activity relationships of β-d-glucopyranosyl azole type inhibitors and revealed the extreme sensitivity of such type of inhibitors towards the structure of the azole moiety. Full article
(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)
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Graphical abstract

14 pages, 1354 KiB  
Communication
Convergent Synthesis of N,S-bis Glycosylquinolin-2-ones via a Pd-G3-XantPhos Precatalyst Catalysis
by Wafa Redjdal, Nada Ibrahim, Belkacem Benmerad, Mouad Alami and Samir Messaoudi
Molecules 2018, 23(3), 519; https://doi.org/10.3390/molecules23030519 - 26 Feb 2018
Cited by 9 | Viewed by 5356
Abstract
Buchwald-Hartwig-Migita cross-coupling of 1-thiosugars with α- or β-3-iodo-N-glycosylquinolin-2-ones has been accomplished under mild and operationally simple reaction conditions through the use of a Pd-G3 XantPhos palladacycle precatalyst. This new methodology has been successfully applied to a variety of α- or β-mono-, [...] Read more.
Buchwald-Hartwig-Migita cross-coupling of 1-thiosugars with α- or β-3-iodo-N-glycosylquinolin-2-ones has been accomplished under mild and operationally simple reaction conditions through the use of a Pd-G3 XantPhos palladacycle precatalyst. This new methodology has been successfully applied to a variety of α- or β-mono-, di-, and poly-thiosugar derivatives to efficiently synthesize a series of α- or β-N,S-bis-glycosyl quinolin-2-ones, which are difficult to synthesize by classical methods. Full article
(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)
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Graphical abstract

18 pages, 3034 KiB  
Article
Probing the Influence of Linker Length and Flexibility in the Design and Synthesis of New Trehalase Inhibitors
by Giampiero D’Adamio, Matilde Forcella, Paola Fusi, Paolo Parenti, Camilla Matassini, Xhenti Ferhati, Costanza Vanni and Francesca Cardona
Molecules 2018, 23(2), 436; https://doi.org/10.3390/molecules23020436 - 16 Feb 2018
Cited by 11 | Viewed by 4182
Abstract
This work aims to synthesize new trehalase inhibitors selective towards the insect trehalase versus the porcine trehalase, in view of their application as potentially non-toxic insecticides and fungicides. The synthesis of a new pseudodisaccharide mimetic 8, by means of a stereoselective α-glucosylation [...] Read more.
This work aims to synthesize new trehalase inhibitors selective towards the insect trehalase versus the porcine trehalase, in view of their application as potentially non-toxic insecticides and fungicides. The synthesis of a new pseudodisaccharide mimetic 8, by means of a stereoselective α-glucosylation of the key pyrrolizidine intermediate 13, was accomplished. The activity of compound 8 as trehalase inhibitor towards C. riparius trehalase was evaluated and the results showed that 8 was active in the μM range and showed a good selectivity towards the insect trehalase. To reduce the overall number of synthetic steps, simpler and more flexible disaccharide mimetics 9–11 bearing a pyrrolidine nucleus instead of the pyrrolizidine core were synthesized. The biological data showed the key role of the linker chain’s length in inducing inhibitory properties, since only compounds 9 (α,β-mixture), bearing a two-carbon atom linker chain, maintained activity as trehalase inhibitors. A proper change in the glucosyl donor-protecting groups allowed the stereoselective synthesis of the β-glucoside 9β, which was active in the low micromolar range (IC50 = 0.78 μM) and 12-fold more potent (and more selective) than 9α towards the insect trehalase. Full article
(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)
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Review

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30 pages, 13466 KiB  
Review
Glycoside Mimics from Glycosylamines: Recent Progress
by Cyril Nicolas and Olivier R. Martin
Molecules 2018, 23(7), 1612; https://doi.org/10.3390/molecules23071612 - 2 Jul 2018
Cited by 29 | Viewed by 6644
Abstract
Glycosylamines are valuable sugar derivatives that have attracted much attention as synthetic intermediates en route to iminosugar-C-glycosyl compounds. Iminosugars are among the most important glycomimetics reported to date due to their powerful activities as inhibitors of a wide variety of glycosidases [...] Read more.
Glycosylamines are valuable sugar derivatives that have attracted much attention as synthetic intermediates en route to iminosugar-C-glycosyl compounds. Iminosugars are among the most important glycomimetics reported to date due to their powerful activities as inhibitors of a wide variety of glycosidases and glycosyltransferases, as well as for their use as pharmacological chaperones. As they provide ready access to these important glycoside mimics, we have reviewed the most significant glycosylamine-based methodologies developed to date, with a special emphasis on the literature reported after 2006. The groups of substrates covered include N-alkyl- and N-benzyl-glycosylamines, N-glycosylhydroxylamines, N-(alkoxycarbonyl)-, and N-tert-butanesulfinyl-glycosylamines. Full article
(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)
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Graphical abstract

15 pages, 3723 KiB  
Review
Synthesis of O-Amino Sugars and Nucleosides
by Na Chen and Juan Xie
Molecules 2018, 23(3), 641; https://doi.org/10.3390/molecules23030641 - 12 Mar 2018
Cited by 5 | Viewed by 8849
Abstract
Nucleic acids and carbohydrates are essential biomolecules involved in numerous biological and pathological processes. Development of multifunctional building blocks based on nucleosides and sugars is in high demand for the generation of novel oligonucleotide mimics and glycoconjugates for biomedical applications. Recently, aminooxyl-functionalized compounds [...] Read more.
Nucleic acids and carbohydrates are essential biomolecules involved in numerous biological and pathological processes. Development of multifunctional building blocks based on nucleosides and sugars is in high demand for the generation of novel oligonucleotide mimics and glycoconjugates for biomedical applications. Recently, aminooxyl-functionalized compounds have attracted increasing research interest because of their easy derivatization through oxime ligation or N-oxyamide formation reactions. Various biological applications have been reported for O-amino carbohydrate- and nucleoside-derived compounds. Here, we report our efforts in the design and synthesis of glyco-, glycosyl, nucleoside- and nucleo-aminooxy acid derivatives from readily available sugars and amino acids, and their use for the generation of N-oxyamide-linked oligosaccharides, glycopeptides, glycolipids, oligonucleosides and nucleopeptides as novel glycoconjugates or oligonucleotide mimics. Delicate and key points in the synthesis will be emphasized. Full article
(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)
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