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Special Issue "Carbohydrates 2018"

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A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (15 June 2019) | Viewed by 45020

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Prof. Dr. Amélia Pilar Rauter

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Departamento de Química e Bioquímica (DQB) e Centro de Química e Bioquímica (CQB), Faculdade de Ciências, Universidade de Lisboa (FCUL), Rua Ernesto de Vasconcelos, Campo Grande,Edifício C8, 5º Piso, 1749-016 Lisboa, Portugal
Interests: carbohydrate small molecule synthesis; organic and biomolecular chemistry developments towards new therapeutic approaches for diabetes; Alzheimer’s disease and other amyloid diseases and carbohydrate-based antibiotics
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Dr. Nuno Manuel Xavier

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Centro de Química Estrutural, Institute of Molecular Sciences, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
Interests: organic chemistry; medicinal chemistry; carbohydrate and nucleos(t)ide chemistry; bioactive molecules; enzyme inhibitors; anticancer agents; antimicrobial agents; anti-Alzheimer’s agents
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Special Issue Information

Dear Colleagues,

Carbohydrates play a major role in a diversity of processes, which are encompassed in the areas of chemistry, biochemistry, biology and medicinal chemistry. Among the topics covered at the 29^th International Carbohydrate Symposium (ICS2018), special attention is given to recent advances and emerging trends in carbohydrate research towards medical applications, including carbohydrates in therapeutics and diagnosis, glycosylation and disease, carbohydrates in inflammation and disease, glycosciences and personalized medicine and carbohydrate vaccines. The growing knowledge on the importance of carbohydrates in health and in disease progress, driving new therapeutic strategies, is the motto for this Special Issue. Contributions arising from the presentations at the Symposium within the context of the previously mentioned topics are welcome.

Speakers at the symposium are cordially invited to submit original research manuscripts to this Special Issue of Pharmaceuticals.

Prof. Dr. Amélia Pilar Rauter
Dr. Nuno Manuel Xavier
Guest Editors

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. Pharmaceuticals is an international peer-reviewed open access monthly 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 2900 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

glycosylation-related diseases/disorders
disease-associated carbohydrate-processing enzymes
carbohydrate-based therapeutics
carbohydrate-based lead molecules
medicinal glycochemistry

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Glycomimetics and Glycoconjugates in Drug Discovery in Pharmaceuticals (7 articles)

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Editorial

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Open AccessEditorial

Special Issue “Carbohydrates 2018”

Amélia Pilar Rauter

and

Nuno Manuel Xavier

Pharmaceuticals 2020, 13(1), 5; https://doi.org/10.3390/ph13010005 - 29 Dec 2019

Cited by 2 | Viewed by 2075

Abstract

This special issue of Pharmaceuticals has been dedicated to Carbohydrates on the occasion of the 29th International Carbohydrate Symposium, held at the Universidade de Lisboa from 15–19 July 2018 [...] Full article

(This article belongs to the Special Issue Carbohydrates 2018)

Research

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Open AccessArticle

Iminosugars: Effects of Stereochemistry, Ring Size, and N-Substituents on Glucosidase Activities

by Luís O. B. Zamoner,

Valquiria Aragão-Leoneti

and

Ivone Carvalho

Pharmaceuticals 2019, 12(3), 108; https://doi.org/10.3390/ph12030108 - 12 Jul 2019

Cited by 22 | Viewed by 4353

Abstract

N-substituted iminosugar analogues are potent inhibitors of glucosidases and glycosyltransferases with broad therapeutic applications, such as treatment of diabetes and Gaucher disease, immunosuppressive activities, and antibacterial and antiviral effects against HIV, HPV, hepatitis C, bovine diarrhea (BVDV), Ebola (EBOV) and Marburg viruses (MARV), influenza, Zika, and dengue virus. Based on our previous work on functionalized isomeric 1,5-dideoxy-1,5-imino-D-gulitol (L-gulo-piperidines, with inverted configuration at C-2 and C-5 in respect to glucose or deoxynojirimycin (DNJ)) and 1,6-dideoxy-1,6-imino-D-mannitol (D-manno-azepane derivatives) cores N-linked to different sites of glucopyranose units, we continue our studies on these alternative iminosugars bearing simple N-alkyl chains instead of glucose to understand if these easily accessed scaffolds could preserve the inhibition profile of the corresponding glucose-based N-alkyl derivatives as DNJ cores found in miglustat and miglitol drugs. Thus, a small library of iminosugars (14 compounds) displaying different stereochemistry, ring size, and N-substitutions was successfully synthesized from a common precursor, D-mannitol, by utilizing an S_N2 aminocyclization reaction via two isomeric bis-epoxides. The evaluation of the prospective inhibitors on glucosidases revealed that merely D-gluco-piperidine (miglitol, 41a) and L-ido-azepane (41b) DNJ-derivatives bearing the N-hydroxylethyl group showed inhibition towards α-glucosidase with IC₅₀ 41 µM and 138 µM, respectively, using DNJ as reference (IC₅₀ 134 µM). On the other hand, β-glucosidase inhibition was achieved for glucose-inverted configuration (C-2 and C-5) derivatives, as novel L-gulo-piperidine (27a) and D-manno-azepane (27b), preserving the N-butyl chain, with IC₅₀ 109 and 184 µM, respectively, comparable to miglustat with the same N-butyl substituent (40a, IC₅₀ 172 µM). Interestingly, the seven-membered ring L-ido-azepane (40b) displayed near twice the activity (IC₅₀ 80 µM) of the corresponding D-gluco-piperidine miglustat drug (40a). Furthermore, besides α-glucosidase inhibition, both miglitol (41a) and L-ido-azepane (41b) proved to be the strongest β-glucosidase inhibitors of the series with IC₅₀ of 4 µM. Full article

(This article belongs to the Special Issue Carbohydrates 2018)

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Synthesis and Biological Evaluation of Structurally Varied 5′-/6′-Isonucleosides and Theobromine-Containing N-Isonucleosidyl Derivatives

and

M. Conceição Oliveira

Pharmaceuticals 2019, 12(3), 103; https://doi.org/10.3390/ph12030103 - 02 Jul 2019

Cited by 6 | Viewed by 3456

Abstract

Isonucleosides are rather stable regioisomeric analogs of nucleosides with broad therapeutic potential. We have previously demonstrated the ability of 5′ and 6′-isonucleosides to inhibit the activity of acetylcholinesterase, a major target for Alzheimer’s disease therapy. Continuing with our research on this topic, we report herein on the synthesis and biological evaluation of a variety of novel terminal isonucleosides and theobromine isonucleotide analogs. Xylofuranose-based purine or uracil 5′-isonucleosides and xylofuranos-5′-yl or glucos-6′-yl theobromine derivatives were accessed via Mitsunobu coupling between partially protected xylofuranose or glucofuranose derivatives with a nucleobase using conventional or microwave-assisted heating conditions. Theobromine-containing N-isonucleosidyl sulfonamide and phosphoramidate derivatives were synthesized from isonucleosidyl acetate precursors. The most active compounds in the cholinesterase inhibition assays were a glucopyranose-based theobromine isonucleosidyl acetate, acting as a dual inhibitor of acetylcholinesterase (AChE, K_i = 3.1 µM) and butyrylcholinesterase (BChE, K_i = 5.4 µM), and a 2-O,4-O-bis-xylofuranos-5′-yl uracil derivative, which displayed moderate inhibition of AChE (K_i = 17.5 µM). Docking studies revealed that the active molecules are positioned at the gorge entrance and at the active site of AChE. None of the compounds revealed cytoxic activity to cancer cells as well as to non-malignant mouse fibroblasts. Full article

(This article belongs to the Special Issue Carbohydrates 2018)

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Open AccessArticle

Design and Synthesis of CNS-targeted Flavones and Analogues with Neuroprotective Potential Against H₂O₂- and Aβ_1-42-Induced Toxicity in SH-SY5Y Human Neuroblastoma Cells

Maria Conceição Oliveira

Óscar López

José G. Fernandez-Bolaños

Philipp Dätwyler

Beat Ernst

M. Paula Macedo

Marialessandra Contino

Nicola A. Colabufo

and

Amélia P. Rauter

Pharmaceuticals 2019, 12(2), 98; https://doi.org/10.3390/ph12020098 - 21 Jun 2019

Cited by 9 | Viewed by 3998

Abstract

With the lack of available drugs able to prevent the progression of Alzheimer’s disease (AD), the discovery of new neuroprotective treatments able to rescue neurons from cell injury is presently a matter of extreme importance and urgency. Here, we were inspired by the widely reported potential of natural flavonoids to build a library of novel flavones, chromen-4-ones and their C-glucosyl derivatives, and to explore their ability as neuroprotective agents with suitable pharmacokinetic profiles. All compounds were firstly evaluated in a parallel artificial membrane permeability assay (PAMPA) to assess their effective permeability across biological membranes, namely the blood-brain barrier (BBB). With this test, we aimed not only at assessing if our candidates would be well-distributed, but also at rationalizing the influence of the sugar moiety on the physicochemical properties. To complement our analysis, logD_7.4 was determined. From all screened compounds, the p-morpholinyl flavones stood out for their ability to fully rescue SH-SY5Y human neuroblastoma cells against both H₂O₂- and Aβ_1-42-induced cell death. Cholinesterase inhibition was also evaluated, and modest inhibitory activities were found. This work highlights the potential of C-glucosylflavones as neuroprotective agents, and presents the p-morpholinyl C-glucosylflavone 37, which did not show any cytotoxicity towards HepG2 and Caco-2 cells at 100 μM, as a new lead structure for further development against AD. Full article

(This article belongs to the Special Issue Carbohydrates 2018)

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Open AccessArticle

Chain-Branched Polyhydroxylated Octahydro-1H-Indoles as Potential Leads against Lysosomal Storage Diseases

and

Pharmaceuticals 2019, 12(2), 47; https://doi.org/10.3390/ph12020047 - 29 Mar 2019

Viewed by 2477

Abstract

Here, the synthesis and glycosidase inhibition properties of the two first known 3-ethyloctahydro-1H-indole-4,5,6-triols are reported. This study shows the transformation of d-glucose into polyhydroxylated 1-(2-nitrocyclohexane) acetaldehydes, followed by a protocol involving the formation of the azacyclopentane ring. Results of inhibitory potency assays and docking calculations show that at least one of them could be a lead for optimization in the search for compounds that behave like folding chaperones in lysosomal storage diseases. Full article

(This article belongs to the Special Issue Carbohydrates 2018)

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Open AccessCommunication

Development of a Microwave-assisted Chemoselective Synthesis of Oxime-linked Sugar Linkers and Trivalent Glycoclusters

and

Pharmaceuticals 2019, 12(1), 39; https://doi.org/10.3390/ph12010039 - 14 Mar 2019

Cited by 4 | Viewed by 3257

Abstract

A rapid, high-yielding microwave-mediated synthetic procedure was developed and optimized using a model system of monovalent sugar linkers, with the ultimate goal of using this method for the synthesis of multivalent glycoclusters. The reaction occurs between the aldehyde/ketone on the sugars and an aminooxy moiety on the linker/trivalent core molecules used in this study, yielding acid-stable oxime linkages in the products and was carried out using equimolar quantities of reactants under mild aqueous conditions. Because the reaction is chemoselective, sugars can be incorporated without the use of protecting groups and the reactions can be completed in as little as 30 min in the microwave. As an added advantage, in the synthesis of the trivalent glycoclusters, the fully substituted trivalent molecules were the major products produced in excellent yields. These results illustrate the potential of this rapid oxime-forming microwave-mediated reaction in the synthesis of larger, more complex glycoconjugates and glycoclusters for use in a wide variety of biomedical applications. Full article

(This article belongs to the Special Issue Carbohydrates 2018)

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Open AccessArticle

Development and Characterization of Chitosan Microparticles-in-Films for Buccal Delivery of Bioactive Peptides

and

Pharmaceuticals 2019, 12(1), 32; https://doi.org/10.3390/ph12010032 - 20 Feb 2019

Cited by 47 | Viewed by 4399

Abstract

Nowadays, bioactive peptides are used for therapeutic applications and the selection of a carrier to deliver them is very important to increase the efficiency, absorption, release, bioavailability and consumer acceptance. The aim of this study was to develop and characterize chitosan-based films loaded with chitosan microparticles containing a bioactive peptide (sequence: KGYGGVSLPEW) with antihypertensive properties. Films were prepared by the solvent casting method, while the microparticles were prepared by ionic gelation. The final optimized chitosan microparticles exhibited a mean diameter of 2.5 µm, a polydispersity index of 0.46, a zeta potential of +61 mV and a peptide association efficiency of 76%. Chitosan films were optimized achieving the final formulation of 0.79% (w/v) of chitosan, 6.74% (w/v) of sorbitol and 0.82% (w/v) of citric acid. These thin (±0.100 mm) and transparent films demonstrated good performance in terms of mechanical and biological properties. The oral films developed were flexible, elastic, easy to handle and exhibited rapid disintegration (30 s) and an erosion behavior of 20% when they came into contact with saliva solution. The cell viability (75–99%) was proved by methylthiazolydiphenyl-tetrazolium bromide (MTT) assay with TR146 cells. The chitosan mucoadhesive films loaded with peptide–chitosan microparticles resulted in an innovative approach to perform administration across the buccal mucosa, because these films present a larger surface area, leading to the rapid disintegration and release of the antihypertensive peptide under controlled conditions in the buccal cavity, thus promoting bioavailability. Full article

(This article belongs to the Special Issue Carbohydrates 2018)

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Open AccessArticle

Conformation and Cross-Protection in Group B Streptococcus Serotype III and Streptococcus pneumoniae Serotype 14: A Molecular Modeling Study

Michelle M. Kuttel

and

Neil Ravenscroft

Pharmaceuticals 2019, 12(1), 28; https://doi.org/10.3390/ph12010028 - 13 Feb 2019

Cited by 12 | Viewed by 4188

Abstract

Although the branched capsular polysaccharides of Streptococcus agalactiae serotype III (GBSIII PS) and Streptococcus pneumoniae serotype 14 (Pn14 PS) differ only in the addition of a terminal sialic acid on the GBSIII PS side chains, these very similar polysaccharides are immunogenically distinct. Our simulations of GBSIII PS, Pn14 PS and the unbranched backbone polysaccharide provide a conformational rationale for the different antigenic epitopes identified for these PS. We find that side chains stabilize the proximal

β

dGlc(1→6)

β

dGlcNAc backbone linkage, restricting rotation and creating a well-defined conformational epitope at the branch point. This agrees with the glycotope structure recognized by an anti-GBSIII PS functional monoclonal antibody. We find the same dominant solution conformation for GBSIII and Pn14 PS: aside from the branch point, the backbone is very flexible with a “zig-zag” conformational habit, rather than the helix previously proposed for GBSIII PS. This suggests a common strategy for bacterial evasion of the host immune system: a flexible backbone that is less perceptible to the immune system, combined with conformationally-defined branch points presenting human-mimic epitopes. This work demonstrates how small structural features such as side chains can alter the conformation of a polysaccharide by restricting rotation around backbone linkages. Full article

(This article belongs to the Special Issue Carbohydrates 2018)

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Review

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Developments in Carbohydrate-Based Cancer Therapeutics

Farzana Hossain

and

Peter R. Andreana

Pharmaceuticals 2019, 12(2), 84; https://doi.org/10.3390/ph12020084 - 04 Jun 2019

Cited by 70 | Viewed by 8962

Abstract

Cancer cells of diverse origins express extracellular tumor-specific carbohydrate antigens (TACAs) because of aberrant glycosylation. Overexpressed TACAs on the surface of tumor cells are considered biomarkers for cancer detection and have always been prioritized for the development of novel carbohydrate-based anti-cancer vaccines. In recent years, progress has been made in developing synthetic, carbohydrate-based antitumor vaccines to improve immune responses associated with targeting these specific antigens. Tumor cells also exhaust more energy for proliferation than normal cells, by consuming excessive amounts of glucose via overexpressed sugar binding or transporting receptors located in the cellular membrane. Furthermore, inspired by the Warburg effect, glycoconjugation strategies of anticancer drugs have gained considerable attention from the scientific community. This review highlights a small cohort of recent efforts which have been made in carbohydrate-based cancer treatments, including vaccine design and the development of glycoconjugate prodrugs, glycosidase inhibiting iminosugars, and early cancer diagnosis. Full article

(This article belongs to the Special Issue Carbohydrates 2018)

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Open AccessReview

Strategies for the Development of Glycomimetic Drug Candidates

Rachel Hevey

Pharmaceuticals 2019, 12(2), 55; https://doi.org/10.3390/ph12020055 - 11 Apr 2019

Cited by 74 | Viewed by 6749

Abstract

Carbohydrates are a structurally-diverse group of natural products which play an important role in numerous biological processes, including immune regulation, infection, and cancer metastasis. Many diseases have been correlated with changes in the composition of cell-surface glycans, highlighting their potential as a therapeutic target. Unfortunately, native carbohydrates suffer from inherently weak binding affinities and poor pharmacokinetic properties. To enhance their usefulness as drug candidates, ‘glycomimetics’ have been developed: more drug-like compounds which mimic the structure and function of native carbohydrates. Approaches to improve binding affinities (e.g., deoxygenation, pre-organization) and pharmacokinetic properties (e.g., limiting metabolic degradation, improving permeability) have been highlighted in this review, accompanied by relevant examples. By utilizing these strategies, high-affinity ligands with optimized properties can be rationally designed and used to address therapies for novel carbohydrate-binding targets. Full article

(This article belongs to the Special Issue Carbohydrates 2018)

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