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Glycomimetics
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Glycomimetics

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

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 5136

Special Issue Editor

Prof. Dr. László Somsák

E-Mail Website
Guest Editor
Department of Organic Chemistry, University of Debrecen, P.O. Box 400, H-4002 Debrecen, Hungary
Interests: organic synthesis; carbohydrates; c-glycosyl derivatives; anomeric spirocycles; lectine antagonists; glycoenzyme inhibitors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Carbohydrates are ubiquitous molecules in nature and play pivotal roles in living organisms. In addition to being long-known nutrients and components of skeletal and connective tissues, they are general mediators of recognition processes and signaling in their mono-, oligo-, and polymeric forms. This widespread occurrence and participation in a vast number of biological events is also reflected by the fact that close to 2% of the human genes are related to transformations of glycans. The above phenomena take place in most cases via interactions with proteins (lectins, glycoenzymes, transporters). Though natural sugar derivatives, due to their highly specific interactions, could be valuable drug candidates, their hydrophilicity, metabolic instability, and unavailability in larger amounts frequently prevent such a utilization. These drawbacks can be overcome by the design and synthesis of glycomimetics (compounds that resemble carbohydrate molecules in their chemical structure and/or biological effect). Indeed, in recent decades, an ever-growing number of carbohydrate-based/glycomimetic drugs have been approved, and sugar-based drug design is becoming a field of utmost importance in drug discovery.

Glycomimetics are frequently designed and synthesized on the basis of natural sugar molecules by replacing the acetalic oxygens (responsible for the metabolic instability) by other atoms such as sulfur, nitrogen, and carbon, just to mention the preponderant ones. Many other design principles can obviously be applicable, and these are limited only by the imagination of the chemist. Contemporary design, synthesis, and evaluation of glycomimetic molecules can be and most often are performed in close collaboration of chemists with structural biologists, biochemists, and molecular modeling and computational experts. This truly interdisciplinary working method may lead to novel chemical entities of unprecedented biological actions and, ultimately, new drugs against otherwise hardly treatable diseases such as cancer, neurodegenerative disorders, bacterial infections, and diabetes.

This Special Issue is devoted to glycomimetics in the broadest sense, and all aspects of the field are considered to be included as original research articles and reviews. In addition, the issue will incorporate works presented at the Debrecen Colloquium on Carbohydrates 2020 in 2022—Rezső Bognár Memorial Conference on Glycomimetics (August 24-27, 2022, Debrecen, Hungary; https://konferencia.unideb.hu/en/debcarb2020).

Prof. Dr. László Somsák
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
  • design
  • synthesis
  • biological evaluation
  • application
  • computational methods

  • structural biology

  •  C-glycosyl compound

  •  enzyme inhibitor

  •  lectin antagonist

  •  transporter inhibitor

  •  drug design

  •  medicinal chemistry

  •  structure-activity relationship

  •  glyconanomaterial

  •  antimicrobial glycan

Published Papers (3 papers)

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Research

19 pages, 5258 KiB  
Article
Design and Synthesis of 3-(β-d-Glucopyranosyl)-4-amino/4-guanidino Pyrazole Derivatives and Analysis of Their Glycogen Phosphorylase Inhibitory Potential
by Sándor Kun, Rachel T. Mathomes, Tibor Docsa, László Somsák and Joseph M. Hayes
Molecules 2023, 28(7), 3005; https://doi.org/10.3390/molecules28073005 - 28 Mar 2023
Cited by 2 | Viewed by 998
Abstract
Glycogen phosphorylase (GP) is a key regulator of glucose levels and, with that, an important target for the discovery of novel treatments against type 2 diabetes. β-d-Glucopyranosyl derivatives have provided some of the most potent GP inhibitors discovered to date. In [...] Read more.
Glycogen phosphorylase (GP) is a key regulator of glucose levels and, with that, an important target for the discovery of novel treatments against type 2 diabetes. β-d-Glucopyranosyl derivatives have provided some of the most potent GP inhibitors discovered to date. In this regard, C-β-d-glucopyranosyl azole type inhibitors proved to be particularly effective, with 2- and 4-β-d-glucopyranosyl imidazoles among the most potent designed to date. His377 backbone C=O hydrogen bonding and ion–ion interactions of the protonated imidazole with Asp283 from the 280s loop, stabilizing the inactive state, were proposed as crucial to the observed potencies. Towards further exploring these features, 4-amino-3-(β-d-glucopyranosyl)-5-phenyl-1H-pyrazole (3) and 3-(β-d-glucopyranosyl)-4-guanidino-5-phenyl-1H-pyrazole (4) were designed and synthesized with the potential to exploit similar interactions. Binding assay experiments against rabbit muscle GPb revealed 3 as a moderate inhibitor (IC50 = 565 µM), but 4 displayed no inhibition at 625 µM concentration. Towards understanding the observed inhibitions, docking and post-docking molecular mechanics—generalized Born surface area (MM-GBSA) binding free energy calculations were performed, together with Monte Carlo and density functional theory (DFT) calculations on the free unbound ligands. The computations revealed that while 3 was predicted to hydrogen bond with His377 C=O in its favoured tautomeric state, the interactions with Asp283 were not direct and there were no ion–ion interactions; for 4, the most stable tautomer did not have the His377 backbone C=O interaction and while ion–ion interactions and direct hydrogen bonding with Asp283 were predicted, the conformational strain and entropy loss of the ligand in the bound state was significant. The importance of consideration of tautomeric states and ligand strain for glucose analogues in the confined space of the catalytic site with the 280s loop in the closed position was highlighted. Full article
(This article belongs to the Special Issue Glycomimetics)
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13 pages, 2452 KiB  
Article
Alginate–Gelatin Self-Healing Hydrogel Produced via Static–Dynamic Crosslinking
by Francesca Cadamuro, Valeria Ardenti, Francesco Nicotra and Laura Russo
Molecules 2023, 28(6), 2851; https://doi.org/10.3390/molecules28062851 - 22 Mar 2023
Cited by 1 | Viewed by 2639
Abstract
Alginate–gelatin hydrogels mimicking extracellular matrix (ECM) of soft tissues have been generated by static–dynamic double crosslinking, allowing fine control over the physical and chemical properties. Dynamic crosslinking provides self-healing and injectability attributes to the hydrogel and promotes cell migration and proliferation, while the [...] Read more.
Alginate–gelatin hydrogels mimicking extracellular matrix (ECM) of soft tissues have been generated by static–dynamic double crosslinking, allowing fine control over the physical and chemical properties. Dynamic crosslinking provides self-healing and injectability attributes to the hydrogel and promotes cell migration and proliferation, while the static network improves stability. The static crosslinking was performed by enzymatic coupling of the tyrosine residues of gelatin with tyramine residues inserted in the alginate backbone, catalyzed by horseradish peroxidase (HRP). The dynamic crosslinking was obtained by functionalizing alginate with 3-aminophenylboronic acid which generates a reversible bond with the vicinal hydroxyl groups of the alginate chains. Varying the ratio of alginate and gelatin, hydrogels with different properties were obtained, and the most suitable for 3D soft tissue model development with a 2.5:1 alginate:gelatin molar ratio was selected. The selected hydrogel was characterized with a swelling test, rheology test, self-healing test and by cytotoxicity, and the formulation resulted in transparent, reproducible, varying biomaterial batch, with a fast gelation time and cell biocompatibility. It is able to modulate the loss of the inner structure stability for a longer time with respect to the formulation made with only covalent enzymatic crosslinking, and shows self-healing properties. Full article
(This article belongs to the Special Issue Glycomimetics)
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10 pages, 2005 KiB  
Article
A Structural-Reporter Group to Determine the Core Conformation of Sialyl Lewisx Mimetics
by Beatrice Wagner, Florian P. C. Binder, Xiaohua Jiang, Tobias Mühlethaler, Roland C. Preston, Said Rabbani, Martin Smieško, Oliver Schwardt and Beat Ernst
Molecules 2023, 28(6), 2595; https://doi.org/10.3390/molecules28062595 - 13 Mar 2023
Cited by 2 | Viewed by 1035
Abstract
The d-GlcNAc moiety in sialyl Lewisx (sLex, 1) acts predominantly as a linker to position the d-Gal and the l-Fuc moieties in the bioactive spatial orientation. The hypothesis has been made that the NHAc [...] Read more.
The d-GlcNAc moiety in sialyl Lewisx (sLex, 1) acts predominantly as a linker to position the d-Gal and the l-Fuc moieties in the bioactive spatial orientation. The hypothesis has been made that the NHAc group of GlcNAc pushes the fucose underneath the galactose and, thus, contributes to the stabilization of the bioactive conformation of the core of sLex (1). To test this hypothesis, GlcNAc mimetics consisting of (R,R)-1,2-cyclohexanediols substituted with alkyl and aryl substituents adjacent to the linking position of the fucose moiety were synthesized. To explore a broad range of extended and spatially demanding R-groups, an enzymatic approach for the synthesis of 3-alkyl/aryl-1,2-cyclohexanediols (3b-n) was applied. These cyclohexanediol derivatives were incorporated into the sLex mimetics 2b-n. For analyzing the relationship of affinity and core conformation, a 1H NMR structural-reporter-group concept was applied. Thus, the chemical shift of H-C5Fuc proved to be a sensitive indicator for the degree of pre-organization of the core of this class of sLex mimetics and therefore could be used to quantify the contribution of the R-groups. Full article
(This article belongs to the Special Issue Glycomimetics)
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