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Carbohydrate-based self-assembling systems are essential for the formation of advanced biocompatible materials via a bottom-up approach. The self-assembling of sugar-based small molecules has applications encompassing many research fields and has been studied extensively. In this focused review, we will discuss the synthetic approaches for carbohydrate-based self-assembling (SA) systems, the mechanisms of the assembly, as well as the main properties and applications. This review will mainly cover recent publications in the last four years from January 2020 to December 2023. We will essentially focus on small molecule self-assembly, excluding polymer-based systems, which include various derivatives of monosaccharides, disaccharides, and oligosaccharides. Glycolipids, glycopeptides, and some glycoconjugate-based systems are discussed. Typically, in each category of systems, the system that can function as low molecular weight gelators (LMWGs) will be discussed first, followed by self-assembling systems that produce micelles and aggregates. The last section of the review discusses stimulus-responsive self-assembling systems, especially those forming gels, including dynamic covalent assemblies, chemical-triggered systems, and photoresponsive systems. The review will be organized based on the sugar structures, and in each category, the synthesis of representative molecular systems will be discussed next, followed by the properties of the resulting molecular assemblies.

Precise and selective modification of carbohydrates is a critical strategy in producing diverse carbohydrate derivatives for exploiting their functions. We disclosed a simple, efficient, and highly regioselective and stereoselective protocol to controllable amination of 2-nitroglycals under mild conditions in 5 min. A range of 3-amino-carbohydrates including 3-arylamino-2-nitro-glycals and 1,3-di-amino-carbohydrate derivatives were obtained in good to excellent yield with excellent stereoselectivity. The produced 3-amino-2-nitro-glycals can be used as a precursor for further transformation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

1,2,3-triazole is an important building block in organic chemistry. It is now well known as a bioisostere for various functions, such as the amide or the ester bond, positioning it as a key pharmacophore in medicinal chemistry and it has found applications in various fields including life sciences. Attention was first focused on the synthesis of 1,4-disubstituted 1,2,3-triazole molecules however 1,4,5-trisubstituted 1,2,3-triazoles have now emerged as valuable molecules due to the possibility to expand the structural modularity. In the last decade, methods mainly derived from the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction have been developed to access halo-triazole compounds and have been applied to nucleosides, carbohydrates, peptides and proteins. In addition, late-stage modification of halo-triazole derivatives by metal-mediated cross-coupling or halo-exchange reactions offer the possibility to access highly functionalized molecules that can be used as tools for chemical biology. This review summarizes the synthesis, the functionalization, and the applications of 1,4,5-trisubstituted halo-1,2,3-triazoles in biologically relevant molecules., (© 2024 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

Chemical tools and principles have become central to biological and medical research/applications by leveraging a range of classical organic chemistry reactions. Friedel-Crafts alkylation and acylation are arguably some of the most well-known and used synthetic methods for the preparation of small molecules but their use in biological and medical fields is relatively less frequent than the other reactions, possibly owing to the notion of their plausible incompatibility with biological systems. This review demonstrates advances in Friedel-Crafts alkylation and acylation reactions in a variety of biomolecular chemistry fields. With the discoveries and applications of numerous biomolecule-catalyzed or -assisted processes, these reactions have garnered considerable interest in biochemistry, enzymology, and biocatalysis. Despite the challenges of reactivity and selectivity of biomolecular reactions, the alkylation and acylation reactions demonstrated their utility for the construction and functionalization of all the four major biomolecules ( i.e. , nucleosides, carbohydrates/saccharides, lipids/fatty acids, and amino acids/peptides/proteins), and their diverse applications in biological, medical, and material fields are discussed. As the alkylation and acylation reactions are often fundamental educational components of organic chemistry courses, this review is intended for both experts and nonexperts by discussing their basic reaction patterns (with the depiction of each reaction mechanism in the ESI) and relevant real-world impacts in order to enrich chemical research and education. The significant growth of biomolecular Friedel-Crafts reactions described here is a testament to their broad importance and utility, and further development and investigations of the reactions will surely be the focus in the organic biomolecular chemistry fields.

Novel synthetic methods published since 2005 affording carbohydrates containing sulfur atom(s) are reviewed. The review is divided to subchapters based on the position of sulfur atom(s) in the sugar molecule. Only those methods that take advantage of substitution are discussed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Photocaged compounds are applied for implementing precise, optochemical control of gene expression in bacteria. To broaden the scope of UV-light-responsive inducer molecules, six photocaged carbohydrates were synthesized and photochemically characterized, with the absorption exhibiting a red-shift. Their differing linkage through ether, carbonate, and carbamate bonds revealed that carbonate and carbamate bonds are convenient. Subsequently, those compounds were successfully applied in vivo for controlling gene expression in E. coli via blue light illumination. Furthermore, benzoate-based expression systems were subjected to light control by establishing a novel photocaged salicylic acid derivative. Besides its synthesis and in vitro characterization, we demonstrate the challenging choice of a suitable promoter system for light-controlled gene expression in E. coli. We illustrate various bottlenecks during both photocaged inducer synthesis and in vivo application and possibilities to overcome them. These findings pave the way towards novel caged inducer-dependent systems for wavelength-selective gene expression., (© 2021 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

Taking advantage of the locked conformation of cyclic furanose form, carbohydrate derivatives have been transformed into relevant tetrahydrofuran moieties through a chemical operation commonly known as C-glycosylation reaction. Consequently, a large number of total synthesis of naturally occurring products containing this heterocycle have been accomplished by applying this reaction. In this regard, the C-allylation reaction of furanose carbohydrates provides flexible routes for stereoselective anomeric functionalization by incorporating an allyl group, which is eventually re-functionalized into advanced natural product intermediates. Therefore, this mini review deals with the description of the origin of the stereoselectivity and synthetic applications of this type of glycosylation reaction, which can be also called as: "Nucleophilic Substitution at the Anomeric Position", conducted by various research groups including our own group., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Organocatalysis is a very useful tool for the asymmetric synthesis of biologically or pharmacologically active compounds because it avoids the use of noxious metals, which are difficult to eliminate from the target products. Moreover, in many cases, the organocatalysed reactions can be performed in benign solvents and do not require anhydrous conditions. It is well-known that most of the above-mentioned reactions are promoted by a simple aminoacid, l-proline, or, to a lesser extent, by the more complex cinchona alkaloids. However, during the past three decades, other enantiopure natural compounds, the carbohydrates, have been employed as organocatalysts. In the present exhaustive review, the detailed preparation of all the sugar-based organocatalysts as well as their catalytic properties are described.

This article describes studies on the regioselective acetal protection of monosaccharide-based diols using chiral phosphoric acids (CPAs) and their immobilized polymeric variants, ( R )-Ad-TRIP-PS and ( S )-SPINOL-PS, as the catalysts. These catalyst-controlled regioselective acetalizations were found to proceed with high regioselectivities (up to >25:1 rr) on various d-glucose-, d-galactose-, d-mannose-, and l-fucose-derived 1,2-diols and could be carried out in a regiodivergent fashion depending on the choice of chiral catalyst. The polymeric catalysts were conveniently recycled and reused multiple times for gram-scale functionalizations with catalytic loadings as low as 0.1 mol %, and their performance was often found to be superior to the performance of their monomeric variants. These regioselective CPA-catalyzed acetalizations were successfully combined with common hydroxyl group functionalizations as single-pot telescoped procedures to produce 32 regioisomerically pure differentially protected mono- and disaccharide derivatives. To further demonstrate the utility of the polymeric catalysts, the same batch of ( R )-Ad-TRIP-PS catalyst was recycled and reused to accomplish single-pot gram-scale syntheses of 6 differentially protected d-glucose derivatives. The subsequent exploration of the reaction mechanism using NMR studies of deuterated and nondeuterated substrates revealed that low-temperature acetalizations happen via a syn -addition mechanism and that the reaction regioselectivity exhibits strong dependence on the temperature. The computational studies indicate a complex temperature-dependent interplay of two reaction mechanisms, one involving an anomeric phosphate intermediate and another via concerted asynchronous formation of an acetal, that results in syn -addition products. The computational models also explain the steric factors responsible for the observed C2 selectivities and are consistent with experimentally observed selectivity trends.

A series of sulfonamides containing glucosamine moieties had been prepared and investigated for the inhibition of the zinc enzyme carbonic anhydrases (CAs, EC 4.2.1.1). Compared to their parent compound p-sulfamoylbenzoic acid, target compounds showed two order of magnitude improvement in their binding affinities against hCA II in vitro. Moreover, they also showed great selectivity toward hCA II enzyme with the ratios for inhibiting hCA II over hCA I in the range 20-96 and for inhibiting hCA II over hCA IX in the range 4.3-9. Due to the introduction of glucosamine moieties, all of compounds displayed good water solubility (in the range of 2.0-2.5%) and the pH values of the obtained solutions is neutral (7.0-7.2). Compared to the clinically available and relatively highly acidic dorzolamide (pH 5.5), target compounds are more likely to be less irritating to the eye when applied to topical glaucomatous drugs. Then, cytotoxicity evaluation suggested that all target compounds did not display any appreciable toxicity against human cornea epithelial cell. In addition, molecular docking studies elucidated the binding modes of those compounds toward hCA II. Collectively, these results suggest that target compounds represented a promising scaffold to treat glaucoma without major topical side effects., (Copyright © 2021. Published by Elsevier Ltd.)

Developing (chemo)enzymatic cascades is very attractive for green synthesis, because they streamline multistep synthetic processes. In this Feature Article, we have summarized the recent advances in in vitro or whole-cell cascade reactions with a focus on the use of renewable bio-based resources as starting materials. This includes the synthesis of rare sugars (such as ketoses, L-ribulose, D-tagatose, myo -inositol or aminosugars) from readily available carbohydrate sources (cellulose, hemi-cellulose, starch), in vitro enzyme pathways to convert glucose to various biochemicals, cascades to convert 5-hydroxymethylfurfural and furfural obtained from lignin or xylose into novel precursors for polymer synthesis, the syntheses of phenolic compounds, cascade syntheses of aliphatic and highly reduced chemicals from plant oils and fatty acids, upgrading of glycerol or ethanol as well as cascades to transform natural L-amino acids into high-value (chiral) compounds. In several examples these processes have demonstrated their efficiency with respect to high space-time yields and low E -factors enabling mature green chemistry processes. Also, the strengths and limitations are discussed and an outlook is provided for improving the existing and developing new cascades.

NK1R antagonists, investigated for the treatment of several pathologies, have shown encouraging results in the treatment of several cancers. In the present study, we report on the synthesis of carbohydrate-based NK1R antagonists and their evaluation as anticancer agents against a wide range of cancer cells. All of the prepared compounds, derived from either d-galactose or l-arabinose, have shown high affinity and NK1R antagonistic activity with a broad-spectrum anticancer activity and an important selectivity, comparable to Cisplatin. This strategy has allowed us to identify the galactosyl derivative 14α , as an interesting hit exhibiting significant NK1R antagonist effect ( k inact 0.209 ± 0.103 μM) and high binding affinity for NK1R (IC 50 = 50.4 nM, K i = 22.4 nM by measuring the displacement of [ 125 I] SP from NK1R). Interestingly, this galactosyl derivative has shown marked selective cytotoxic activity against 12 different types of cancer cell lines.

Presented herein is the discovery that bismuth(iii) trifluoromethanesulfonate (Bi(OTf) 3 ) is an effective catalyst for the activation of glycosyl bromides and glycosyl chlorides. The key objective for the development of this methodology is to employ only one promoter in the lowest possible amount and to avoid using any additive/co-catalyst/acid scavenger except molecular sieves. Bi(OTf) 3 works well in promoting the glycosidation of differentially protected glucosyl, galactosyl, and mannosyl halides with many classes of glycosyl acceptors. Most reactions complete within 1 h in the presence of only 35% of green and light-stable Bi(OTf) 3 catalyst.

Carbohydrate chemistry is an essential component of the glycosciences and is fundamental to their progress. This Perspective takes the position that carbohydrate chemistry, or glycochemistry, has reached three crossroads on the path to the transformation of the glycosciences, and illustrates them with examples from the author's and other laboratories. The first of these potential inflexion points concerns the mechanism of the glycosylation reaction and the role of protecting groups. It is argued that the experimental evidence supports bimolecular S N 2-like mechanisms for typical glycosylation reactions over unimolecular ones involving stereoselective attack on naked glycosyl oxocarbenium ions. Similarly, it is argued that the experimental evidence does not support long-range stereodirecting participation of remote esters through bridged bicyclic dioxacarbenium ions in organic solution in the presence of typical counterions. Rational design and improvement of glycosylation reactions must take into account the roles of the counterion and of concentration. A second crossroads is that between mainstream organic chemistry and glycan synthesis. The case is made that the only real difference between glycan and organic synthesis is the formation of C-O rather than C-C bonds, with diastereocontrol, strategy, tactics, and elegance being of critical importance in both areas: mainstream organic chemists should feel comfortable taking this fork in the road, just as carbohydrate chemists should traveling in the opposite direction. A third crossroads is that between carbohydrate chemistry and medicinal chemistry, where there are equally many opportunities for traffic in either direction. The glycosciences have advanced enormously in the past decade or so, but creativity, input, and ingenuity of scientists from all fields is needed to address the many sophisticated challenges that remain, not the least of which is the development of a broader and more general array of stereospecific glycosylation reactions.

Pretreatment technology has attracted much attention as an effective method for the conversion of sugarcane bagasse into biochemicals. However, residual lignin-carbohydrate complexes (LCC) can negatively impact the subsequent enzymatic hydrolysis of bagasse. In this work, the changes in bagasse LCC after pretreatment with hot water and dilute acid were characterized by component analysis, 13 C NMR and 1 H- 13 C HSQC NMR to reveal the correlation between LCC structure and cellulase adsorption. A real-time dynamic model of LCC affecting adsorption of cellulase was constructed using a quartz crystal microbalance (QCM-D). The QCM-D results demonstrated that cellulase exhibited different adsorption characteristics on different LCCs. For example, the maximum adsorption capacities for cellulase onto the raw material LCC (RW-LCC), hot water pretreated LCC (LHW-LCC), and dilute acid pretreated LCC (AP-LCC) at 4 °C were 29.0 ng/cm 2 , 94.9 ng/cm 2 and 129.8 ng/cm 2 , respectively. In addition, the adsorption rate constants for cellulase on RM-LCC, LHW-LCC and AP-LCC at 4 °C were 0.09, 0.14 and 0.19, respectively., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A series of novel carbohydrate-based sulfonamides were designed and synthesized by the sugar-tail approach. The classical aromatic sulfonamide pharmacophore (ArSO 2 NH 2 ) was directly linked to a hydrophilic sugar-tail moiety through a rigid 1, 2, 3-triazole linker by the click chemistry reaction. The inhibitory activity against three carbonic anhydrase (CA, EC 4.2.1.1) isozymes (hCA I, hCA II and hCA IX) of all new compounds so designed were investigated in vitro and efficient inhibition against all three CA isoforms, especially the tumor-associated hCA IX, were observed. These glycoconjugate sulfonamide derivatives displayed better inhibitory efficacy in comparison with the starting segments (SA and p-hydroxybenzene sulfonamide). In particular, compound 12g was found to be the most effective and rather selective inhibitor of hCA IX with inhibitory constant (IC 50 ) value of 7 nM, being four times more potent than the clinical used agent acetazolamide (AAZ) (IC 50  = 30 nM). Meanwhile, almost all compounds showed moderate antiproliferative activities against two cancer cell lines (HT-29 and MDA-MB-231) in both hypoxic and normoxic conditions while compound 12g also exhibited the most prominent antitumor activity. Furthermore, evident recovery (20-35% reduction of IC 50 values) of cytotoxic efficiency of doxorubicin with the combination of compounds 12d, 12g and 22d as CAIs were detected on MDA-MB-231 cell line under hypoxic environment. In addition, docking studies revealed that the sugar-tail fragment of the target compounds participated in interactions with hydrophilic subpocket at the surface of hCA IX active site and supported the CA IX inhibitory activities of carbohydrate-based sulfonamide derivatives., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A single-step copolymerization strategy was developed for the preparation of carbohydrate (glucose and maltose) functionalized monoliths using click reaction. Firstly, novel carbohydrate-functionalized methacrylate monomers were synthesized through Cu(I)-catalyzed 1,3-dipolar cycloaddition (alkyne-azide reaction) of terminal alkyne with azide of carbohydrate derivatives. The corresponding carbohydrate functionalized monolithic columns were then prepared through a single-step in-situ copolymerization. The physicochemical properties and performance of the fabricated monolithic columns were evaluated using scanning electron microscopy, Fourier-transform infrared spectroscopy, and nano-liquid chromatography. For the optimized monolithic column, satisfactory column permeability and good separation performance were demonstrated for polar compounds including nucleoside, phenolic compounds and benzoic acid derivatives. The monolithic column is also highly useful for selective and efficient enrichment of glycopeptides from human IgG tryptic digests. This study not only provided a novel hydrophilic column for separation and selective trapping of polar compounds, but also proposed a facile and efficient approach for preparing carbohydrate functionalized monoliths., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Synthetic carbohydrate receptors (SCRs) that selectively recognize cell-surface glycans could be used for detection, drug delivery, or as therapeutics. Here we report the synthesis of seven new C 2h symmetric tetrapodal SCRs. The structures of these SCRs possess a conserved biaryl core, and they vary in the four heterocyclic binding groups that are linked to the biaryl core via secondary amines. Supramolecular association between these SCRs and five biologically relevant C 1 -O-octyloxy glycans, α/β-glucoside (α/β-Glc), α/β-mannoside (α/β-Man), and β-galactoside (β-Gal), was studied by mass spectrometry, 1 H NMR titrations, and molecular modeling. These studies revealed that selectivity can be achieved in these tetrapodal SCRs by varying the heterocyclic binding group. We found that SCR017 (3-pyrrole), SCR021 (3-pyridine), and SCR022 (2-phenol) bind only to β-Glc. SCR019 (3-indole) binds only to β-Man. SCR020 (2-pyridine) binds β-Man and α-Man with a preference to the latter. SCR018 (2-indole) binds α-Man and β-Gal with a preference to the former. The glycan guests bound within their SCR hosts in one of three supramolecular geometries: center-parallel, center-perpendicular, and off-center. Many host-guest combinations formed higher stoichiometry complexes, 2:1 glycan⋅SCR or 1:2 glycan⋅SCR, where the former are driven by positive allosteric cooperativity induced by glycan-glycan contacts., (© 2020 Wiley-VCH GmbH.)

The aminated mimetics of 2-keto-3-deoxy-sugar acids such as the anti-influenza clinical drugs oseltamivir (Tamiflu) and zanamivir (Relenza) are important bioactive molecules. Development of synthetic methodologies for accessing such compound collections is highly desirable. Herein, we describe a simple, catalyst-free glycal diazidation protocol enabled by visible light-driven conditions. This new method requires neither acid promoters nor transition-metal catalysts and takes place at ambient temperature within 1-2 hours. Notably, the desired transformations could be promoted by thermal conditions as well, albeit with lower efficacy compared to the light-induced conditions. Different sugar acid-derived glycal templates have been converted into a range of 2,3-diazido carbohydrate analogs by harnessing this mild and scalable approach, leading to the discovery of new antiviral agents.

In order to explore the pathway of non-structural carbohydrate synthesis, an analysis of the pathway of non-structural carbohydrate synthesis under the network security model was proposed. Taking non-structural carbohydrates as the research object, the experimental materials and equipment were selected under the network security model. Through the establishment of detection methods, the preparation of freeze-dried carbohydrates, the influence of synthesis pathway-specific inhibitors on the synthesis of non-structural carbohydrates, the influence of precursors and intermediates in the pathway on the synthesis of non-structural carbohydrates, the effect of multiple factors on the synthesis of non-structural carbohydrates, the influence of polysaccharide synthesis, the treatment of reaction solution for detection, the preparation of detection sample, the detection conditions of a liquid phase, the detection conditions of LC-MS and the determination of carbohydrate biomass were studied. The results showed that the synthesis of nonstructural carbohydrates requires the participation of the glycolysis, shikimic acid and phenylpropane pathways, but not the polyketone pathway.

The Thomsen-Friedenreich (TF) antigen is a key target for the development of anticancer vaccines, and this ongoing challenge remains relevant due to the poor immunogenicity of the TF antigen. To overcome this challenge, we adopted a bivalent conjugate design which introduced both the TF antigen and the Thomsen-nouveau (Tn) antigen onto the immunologically relevant polysaccharide A1 (PS A1). The immunological results in C57BL/6 mice revealed that the bivalent, Tn-TF-PS A1 conjugate increased the immune response towards the TF antigen as compared to the monovalent TF-PS A1. This phenomenon was first observed with enzyme-linked immunosorbent assay (ELISA) where the bivalent conjugate generated high titers of IgG antibodies where the monovalent conjugate generated an exclusive IgM response. Fluorescence-activated cell sorting (FACS) analysis also revealed increased binding events to the tumor cell lines MCF-7 and OVCAR-5, which are consistent with the enhanced tumor cell lysis observed in a complement dependent cytotoxicity (CDC) assay. The cytokine profile generated by the bivalent construct revealed increased pro-inflammatory cytokines IL-17 and IFN-γ. This increase in cytokine concentration was matched with an increase in cytokine producing cells as observed by ELISpot. We hypothesized the mechanisms for this phenomenon to involve the macrophage galactose N -acetylgalactosamine specific lectin 2 (MGL2). This hypothesis was supported by using biotinylated probes and recombinant MGL2 to measure carbohydrate-protein interactions.

The natural occurrence of enantiomers and diastereomers is often encountered. In addition, the synthesis of these stereoisomers is important for structure determination and for the study of structure-activity relationships. Stereodivergent routes simplify the access to these molecules starting from a common material. This review is focused on the synthesis of carbohydrates, amino acids, alkaloids and terpenes using this efficient strategy. In the case of carbohydrates, such as monosaccharides, carbasugars, aminosugars and azasugars, carbohydrates are usually employed as common starting materials. As a very common strategy, configurations of hydroxy groups are inverted by SN2 methods playing with protection and deprotection processes. For the synthesis of acyclic α-AAs, diastereoselective methods using mainly Garner's aldehyde have been described. Diastereodivergent routes allowed the synthesis of β-hydroxy- and β-amino-α-amino acids, as well as of β- and γ-amino acids. Heterocyclic and cyclic amino phosphonic acids were synthesized using diastereodivergent routes. Alkaloids containing five- and six-membered saturated azaheterocycles needed multistep stereodivergent routes and other alkaloids, such as enantiomers of balanol, vincamine, anatoxin and codeine, and diastereomeric isochaetominines C and galanthamines. In the terpene field, sesquiterpenes β-santalene, α-curcumene and α-cuparenone and the diterpene scopadulcic acid A have been synthesized using enantiodivergent routes.

Bacterial cellulose (BC) is a biosynthesized carbohydrate polymer with excellent biocompatibility and water holding capability. However, it lacks an inherent antibacterial activity that has limited its in-depth biomedical applications. This study investigated a novel strategy of adopting a simultaneous process to chemically anchor a quaternary ammonium salt (R-N(CH 3 ) + ) with a special vinyl group (2-methacryloyloxyethyl trimethylammonium chloride, METAC) onto the BC, and meanwhile, enhance the density of (R-N(CH 3 ) + ) via free radical vinyl polymerization. The results have confirmed the transition of BC surface from a negatively-charged surface to a polycationic surface via such a simultaneous reaction. As compared to chitin film (a representative of R-NH 3 + ), the resulting METAC-grafted BC (a representative of high-density R- N(CH 3 ) + ) acquired excellent water absorbability (40 times of dry weight of the BC), 99% antibacterial activity against Escherichia coli and Staphylococcus aureus, a satisfactory in-vitro biocompatibility, and a better in-vivo wound healing outcome with an excellent in-vivo antibacterial efficacy. This study has exhibited potential in utilizing a facile method to prepare a bio-safe, adaptive antibacterial surface for various biomedical applications., (Copyright © 2019 Elsevier B.V. All rights reserved.)

This article presents a selection of topics from Professor Frieder W. Lichtenthaler's scientific lifework. It describes his contributions to, and further development of, the nitromethane cyclization of dialdehydes leading to amino sugars and amino nucleosides, as well as a new coupling methodology for purine nucleosides. A number of chiral building blocks derived from sugars like the "sugar enolones," enollactones, hydroxyhexenals, and their synthetic applications in natural product syntheses are covered. The article further describes the chemistry of "ulosyl bromides" and their glycosidation reactions, including those with bifunctional acceptors, which led to the synthesis of spectinomycin and gomphoside. Lichtenthaler's work on the preparation of synthetically useful building blocks from disaccharides that are readily available in bulk quantities, and his studies on the reactivity, as well as the selective O-functionalization of sucrose, higher oligosaccharides, and cyclodextrins based on computer simulations, are highlighted. The article also presents his research on the syntheses of chiral building blocks from readily available ketoses and their synthetic applications. Finally the chapter concludes with his significant contributions in the field of the history of carbohydrate chemistry., (© 2020 Elsevier Inc. All rights reserved.)

The synthesis of a carbohydrate building block usually starts with introduction of a temporary protecting group at the anomeric center and ends with its selective cleavage for further transformation. Thus, the choice of the anomeric temporary protecting group must be carefully considered because it should retain intact during the whole synthetic manipulation, and it should be chemoselectively removable without affecting other functional groups at a late stage in the synthesis. Etherate groups are the most widely used temporary protecting groups at the anomeric center, generally including allyl ethers, MP (p-methoxyphenyl) ethers, benzyl ethers, PMB (p-methoxybenzyl) eithers, and silyl ethers. This chapter provides a comprehensive review on their formation, cleavage, and applications in the synthesis of complex carbohydrates., (© 2020 Elsevier Inc. All rights reserved.)

Glycopolymers are an important class of biomaterials which include carbohydrate moieties in their polymer structure. In addition to biological research on the interactions of glycopolymers with lectin-carbonate, glycopolymers have recently been used as a new synthetic biomaterial for direct therapeutic methods, medical adhesives, and biosensors. Thus, a comprehensive understanding of new advances in glycopolymer research is essential for the next level of biomaterial studies. This review article highlights commonly used glycopolymer synthesis methods and biomedical applications thereof. Glycopolymers can be synthesized by modern polymerization methods that can control the molecular weight, molecular weight distribution, chemical functionality, and polymer architecture. The polymerizations include free radical polymerization, atom transfer radical polymerization, reversible addition-fragmentation chain-transfer polymerization, and nitroxide-mediated polymerization. Because the carbohydrate-lectin interactions with glycopolymers are involved in many biological processes, carbohydrates containing glycopolymers are used in (1) fundamental studies to understand the specificity and strength of biological binding, (2) controllable interactions to prevent microorganism adhesion to human cells, (3) large scale bulk adhesives for medical applications, (4) biocompatible therapeutic nanoparticles, (5) direct drug delivery vehicles, and (6) precise quantitative measurement of biosensor materials that can detect physiological signals.

Asymmetrically branched precision glycooligomers are synthesized by solid-phase polymer synthesis for studying multivalent carbohydrate-protein interactions. Through the stepwise assembly of Fmoc-protected oligo(amidoamine) building blocks and Fmoc/Dde-protected lysine, straightforward variation of structural parameters such as the number and length of arms, as well as the number and position of carbohydrate ligands, is achieved. Binding of 1-arm and 3-arm glycooligomers toward lectin receptors langerin and concanavalin A (ConA) was evaluated where the smallest 3-arm glycooligomer shows the highest binding toward langerin, and stepwise elongation of one, two, or all three arms leads to decreased binding. When directly comparing binding toward langerin and ConA, we find that structural variation of the scaffold affects glycomimetic ligand binding differently for the different targets, indicating the potential to tune such ligands not only for their avidity but also for their selectivity toward different lectins.

Nowadays, sonication is a well-known technique for the fabrication and surface modification of nanomaterials with various sizes, shapes, and chemical and physical properties. In addition to conducting catalyst-mediated chemical reactions and enhancing medicinal properties, such as antibacterial and antifungal activities, nanoparticles made from biodegradable and biocompatible carbohydrate coatings and glycosidic frameworks offer exciting opportunities for the development of biomaterials, optical sensors, packaging materials, agricultural products, and food. This review article discusses the synthesis of carbohydrate-coated nanoparticles by ultrasound radiation as well as the many applications of these nanoparticles.

Discussed herein is the synthesis of partially protected carbohydrates by manipulating only one type of a protecting group for a given substrate. The first focus of this review is the uniform protection of an unprotected starting material in a way that only one (or two) hydroxyl group remains unprotected. The second focus involves regioselective partial deprotection of uniformly protected compounds in a way that only one (or two) hydroxyl group becomes liberated.

Caramel is a widely used water-soluble food pigment. The acylation of caramel was conducted by aliphatic acyl chlorides with different chain lengths. Acetyl, butyryl, octyl, lauryl, palmityl, and stearyl caramels were prepared with the ratio of acyl chloride/caramel of 6. The formation of acylated caramel was confirmed by Fourier transform infrared spectra, and the acyl mass fraction in acylcaramel was determined by potentiometric titration. Thermal analysis showed that the weight loss of acylated caramel was higher than that of raw caramel. The scanning electron microscopy analysis showed that the morphology of acylated caramel was significantly different from that of raw material. The acyl mass fraction of acylated caramel increased with the increase of acyl chain lengths. Meanwhile, the lipo-hydro partition coefficient, the solubility in corn oil, and color, red, and yellow indexes increased with the increase of the mass fraction of acyl in acylcaramel. It was found that stearyl caramel has the highest lipid solubility of 5.73 mg/mL in corn oil; however, the color, red, and yellow indexes of palmityl caramel reached 25 818.60, 1.149, and 1.757, respectively. This study provides a method to improve the solubility of caramel in lipid phase and expand the application range of caramel.

Precision glycomacromolecules have proven to be important tools for the investigation of multivalent carbohydrate-lectin interactions by presenting multiple glycan epitopes on a highly-defined synthetic scaffold. Herein, we present a new strategy for the versatile assembly of heteromultivalent glycomacromolecules that contain different carbohydrate motifs in proximity within the side chains. A new building block suitable for the solid-phase polymer synthesis of precision glycomacromolecules was developed with a branching point in the side chain that bears a free alkyne and a TIPS-protected alkyne moiety, which enables the subsequent attachment of different carbohydrate motifs by on-resin copper-mediated azide-alkyne cycloaddition reactions. Applying this synthetic strategy, heteromultivalent glycooligomers presenting fragments of histo-blood group antigens and human milk oligosaccharides were synthesized and tested for their binding behavior towards bacterial lectin LecB., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Polymer particles modified with carbohydrates on their surfaces are of significant interest, because their specific recognition abilities to biomolecules are valuable for developing promising materials in biomedical fields. Carbohydrate-decorated core-shell polymer particles are expected to be efficiently prepared by dispersion polymerization using a glycopolymer-based amphiphilic macromonomer as both a polymeric steric stabilizer and a monomer. To create glycopolymer-type macromonomers, we propose a new strategy combining living cationic polymerization of an alkynyl-functionalized vinyl ether (VE), and the click reaction for the preparation of glycopolymers having a polymerizable terminal group, and investigate their dispersion copolymerization with styrene for generating carbohydrate-decorated polymer particles. This study deals with (i) the synthesis of block copolymer-type amphiphilic macromonomers bearing a methacryloyl group at the α -terminus, and pendant alkynyl groups by living cationic polymerization of alkynyl-substituted VE (VEEP), (ii) the derivatization of maltose-carrying macromonomers by click chemistry of the pendant alkynyl groups of the precursor macromonomers with maltosyl azide without any protecting/deprotecting processes, and (iii) the preparation of maltose-decorated (Mal-decorated) polymer particles through the dispersion copolymerization of glycopolymer-type macromonomers with styrene in polar media. Moreover, this study concerns the specific interactions of the resultant polymer particles with the lectin concanavalin A (Con A).

Carbohydrates are structurally complex but functionally important biomolecules. Therefore, they have been challenging but attractive synthetic targets. While substantial progress has been made on advancing chemical glycosylation methods, incorporating enzymes into carbohydrate synthetic schemes has become increasingly practical as more carbohydrate biosynthetic and metabolic enzymes as well as their mutants with synthetic application are identified and expressed for preparative and large-scale synthesis. Chemoenzymatic strategies that integrate the flexibility of chemical derivatization with enzyme-catalyzed reactions have been extremely powerful. Briefly summarized here are our experiences on developing one-pot multienzyme (OPME) systems and representative chemoenzymatic strategies from others using glycosyltransferase-catalyzed reactions for synthesizing diverse structures of oligosaccharides, polysaccharides, and glycoconjugates. These strategies allow the synthesis of complex carbohydrates including those containing naturally occurring carbohydrate postglycosylational modifications (PGMs) and non-natural functional groups. By combining these srategies with facile purification schemes, synthetic access to the diverse space of carbohydrate structures can be automated and will not be limited to specialists., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Glycopolymers have gained increasing importance in investigating glycan-lectin interactions, as drug delivery vehicles and in modulating interactions with proteins. The synthesis of these glycopolymers is still a challenging and rigorous exercise. In this regard, the highly efficient click reaction, copper (I)-catalyzed alkyne-azide cycloaddition, has been widely applied not only for its efficiency but also for its tolerance of the appended carbohydrate groups. However, a significant drawback of this method is the use of the heavy metal catalyst which is difficult to remove completely, and ultimately toxic to biological systems. In this work, we present the synthesis of carbohydrate-grafted glycopolymers utilizing a mild and catalyst-free perfluorophenyl azide (PFPA)-mediated Staudinger reaction. Using this strategy, mannose (Man) and maltoheptaose (MH) were grafted onto the biodegradable poly(lactic acid) (PLA) by stirring a PFAA-functionalized PLA with a phosphine-derivatized Man or MH in DMSO at room temperature within an hour. The glycopolymers were characterized by ¹H-NMR, 19 F-NMR, 31 P-NMR and FTIR.

The methodological developments in gold(i)- and gold(iii)-catalyzed glycosylation reactions are fully surveyed, which exploit the special alkynophilicity or the Lewis acidity of the gold cationic complexes. The application of the new methods in the total synthesis of naturally occurring glycoconjugates and glycans is comprehensively reviewed, with a focus on glycosylation of various complex aglycones.

Conjugation of RNA with multiple partners to obtain mimics of complex biomolecules is limited by the identification of orthogonal reactions. Here, lipid-carbohydrate-peptidyl-RNA conjugates were obtained by post-functionalization reactions, solid-phase synthesis, and enzymatic steps, to generate molecules mimicking the substrates of FmhB, an essential peptidoglycan synthesis enzyme of Staphylococcus aureus. Mimics of Gly-tRNA Gly and lipid intermediate II (undecaprenyl-diphospho-disaccharide-pentapeptide) were combined in a single "bi-substrate" inhibitor (IC 50 =56 nm). The synthetic route was exploited to generate substrates and inhibitors containing d-lactate residue (d-Lac) instead of d-Ala at the C-terminus of the pentapeptide stem, a modification responsible for vancomycin resistance in the enterococci. The substitution impaired recognition of peptidoglycan precursors by FmhB. The associated fitness cost may account for limited dissemination of vancomycin resistance genes in S. aureus., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Carbohydrates, which are ubiquitously distributed throughout the three domains of life, play significant roles in a variety of vital biological processes. Access to unique and homogeneous carbohydrate materials is important to understand their physical properties, biological functions, and disease-related features. It is difficult to isolate carbohydrates in acceptable purity and amounts from natural sources. Therefore, complex saccharides with well-defined structures are often most conviently accessed through chemical syntheses. Two major hurdles, regioselective protection and stereoselective glycosylation, are faced by carbohydrate chemists in synthesizing these highly complicated molecules. Over the past few years, there has been a radical change in tackling these problems and speeding up the synthesis of oligosaccharides. This is largely due to the development of one-pot protection, one-pot glycosylation, and one-pot protection-glycosylation protocols and streamlined approaches to orthogonally protected building blocks, including those from rare sugars, that can be used in glycan coupling. In addition, new automated strategies for oligosaccharide syntheses have been reported not only for program-controlled assembly on solid support but also by the stepwise glycosylation in solution phase. As a result, various sugar molecules with highly complex, large structures could be successfully synthesized. To summarize these recent advances, this review describes the methodologies for one-pot protection and their one-pot glycosylation into the complex glycans and the chronological developments associated with automated syntheses of oligosaccharides.

A next-generation reagent-controlled approach for the synthesis of 2,6-dideoxy and 2,3,6-trideoxy sugar donors in good yield and high β-selectivity is reported. The use of p-toluenesulfonyl chloride and potassium hexamethyldisilazide (KHMDS) greatly simplifies deoxy-sugar glycoside construction, and can be used for gram-scale glycosylation reactions. The development of this approach and its application to the construction of β-linked deoxy-sugar oligosaccharides are described., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Review primarily covers from 1995-2018Carbohydrate function, recognized in a multitude of biological processes, provides a precedent for developing carbohydrate surrogates that mimic the structure and function of bioactive compounds. In order to constrain highly flexible oligosaccharides, synthetic tethering techniques like those exemplified by stapled peptides are utilized to varying degrees of success. Naturally occurring constrained carbohydrates, however, exist with noteworthy cytotoxic and chemosensitizing properties. This review highlights the structure, biology, and synthesis of this intriguing class of molecules.

Galactosyl and lactosyl conjugated 6A,6D-bifunctionlized β cyclodextrin derivatives were designed and synthesized as the potential liver cancer drug carriers through SN2 replacement and click reactions in order to increase liver cancer drug's targeting ability, solubility and stability. The synthetic methods and strategies to obtain the designed compounds were discussed., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Glycopolymers are synthetic-carbohydrate-containing materials capable of interacting and binding to specific targeting lectins, which are crucially important in many biologically active processes. Over the last decade, advances in synthetic chemistry and polymerization techniques have enabled the development of sequence and architecturally controlled glycopolymers for different types of bioapplications, such as drug delivery and release purposes, gene therapy, lectin-based biosensors, and much more in the future. These precision glycopolymers are able to mimic structural and functional features of the naturally existing glycocalyx. Furthermore, self-assembled glycopolymers could enhance specific and selective recognition properties on multivalent scaffolds in glycoscience. This mini-review will focus on production methods and recent advances in precision synthesis and self-assembly of glycopolymers. Additionally, possible contributions of single-chain folding in glycopolymers will be discussed as a future prospect., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Spironucleosides are a type of conformationally restricted nucleoside analogs in which the anomeric carbon belongs simultaneously to the sugar moiety and to the base unit. This locks the nucleic base in a specific orientation around the N -glycosidic bond, imposing restrictions on the flexibility of the sugar moiety. Anomeric spiro-functionalized nucleosides have gained considerable importance with the discovery of hydantocidin, a natural spironucleoside isolated from fermentation broths of Streptomyces hygroscopicus which exhibits potent herbicidal activity. The biological activity of hydantocidin has prompted considerable synthetic interest in this nucleoside and also in a variety of analogues, since important pharmaceutical leads can be found among modified nucleoside analogues. We present here an overview of the most important advances in the synthesis of spironucleosides., Competing Interests: The authors declare no conflict of interest.

The non-hydrolyzable S-linked azasugars, 1,6-α-mannosylthio- and 1,6-α-mannobiosylthioisofagomine, were synthesized and shown to bind with high affinity to a family 76 endo-1,6-α-mannanase from Bacillus circulans. X-ray crystallography showed an atypical interaction of the isofagomine nitrogen with the catalytic acid/base. Molecular dynamics simulations reveal that the atypical binding results from sulfur perturbing the most stable form away from the nucleophile interaction preferred for the O-linked congener.

Among other classes of biomolecules, carbohydrates and glycoconjugates are widely involved in numerous biological functions. In addition to addressing the related synthetic challenges, glycochemists have invested intense efforts in providing access to structures that can be used to study, activate, or inhibit these biological processes. Over the past few decades, aminooxylated carbohydrates have been found to be key building blocks for achieving these goals. This review provides the first in-depth overview covering several aspects related to the syntheses and applications of aminooxylated carbohydrates. After a brief introduction to oxime bonds and their relative stabilities compared to related C═N functions, synthetic aspects of oxime ligation and methodologies for introducing the aminooxy functionality onto both glycofuranosyls and glycopyranosyls are described. The subsequent section focuses on biological applications involving aminooxylated carbohydrates as components for the construcion of diverse architectures. Mimetics of natural structures represent useful tools for better understanding the features that drive carbohydrate-receptor interaction, their biological output and they also represent interesting structures with improved stability and tunable properties. In the next section, multivalent structures such as glycoclusters and glycodendrimers obtained through oxime ligation are described in terms of synthetic design and their biological applications such as immunomodulators. The second-to-last section discusses miscellaneous applications of oxime-based glycoconjugates, such as enantioselective catalysis and glycosylated oligonucleotides, and conclusions and perspectives are provided in the last section.

NMR of a uniformly 13 C-labeled carbohydrate was used to elucidate the atomic details of a sugar-protein complex. The structure of the 13 C-labeled Manα(1-2)Manα(1-2)ManαOMe trisaccharide ligand, when bound to cyanovirin-N (CV-N), was characterized and revealed that in the complex the glycosidic linkage torsion angles between the two reducing-end mannoses are different from the free trisaccharide. Distances within the carbohydrate were employed for conformational analysis, and NOE-based distance mapping between sugar and protein revealed that Manα(1-2)Manα(1-2)ManαOMe is bound more intimately with its two reducing-end mannoses into the domain A binding site of CV-N than with the nonreducing end unit. Taking advantage of the 13 C spectral dispersion of 13 C-labeled carbohydrates in isotope-filtered experiments is a versatile means for a simultaneous mapping of the binding interactions on both, the carbohydrate and the protein.

Distinguishing cancer cells from normal cells through surface receptors is vital for cancer diagnosis and targeted therapy. Metabolic glycoengineering of unnatural sugars provides a powerful tool to manually introduce chemical receptors onto the cell surface; however, cancer-selective labeling still remains a great challenge. Herein we report the design of sugars that can selectively label cancer cells both in vitro and in vivo. Specifically, we inhibit the cell-labeling activity of tetraacetyl-N-azidoacetylmannosamine (Ac 4 ManAz) by converting its anomeric acetyl group to a caged ether bond that can be selectively cleaved by cancer-overexpressed enzymes and thus enables the overexpression of azido groups on the surface of cancer cells. Histone deacetylase and cathepsin L-responsive acetylated azidomannosamine, one such enzymatically activatable Ac 4 ManAz analog developed, mediated cancer-selective labeling in vivo, which enhanced tumor accumulation of a dibenzocyclooctyne-doxorubicin conjugate via click chemistry and enabled targeted therapy against LS174T colon cancer, MDA-MB-231 triple-negative breast cancer and 4T1 metastatic breast cancer in mice.

Combining nanoparticles with carbohydrate has triggered an exponential growth of research activities for the design of novel functional bionanomaterials, nano-carbohydrates. Recent advances in versatile synthesis of glycosylated nanoparticles have paved the way towards diverse biomedical applications. The accessibility of a wide variety of these structured nanosystems, in terms of shape, size, and organization around stable nanoparticles, has readily contributed to their development and application in nanomedicine. Glycosylated gold nanoparticles, glycosylated quantum dots, fullerenes, single-wall nanotubes, and self-assembled glyconanoparticles using amphiphilic glycopolymers or glycodendrimers have received considerable attention for their application in powerful imaging, therapeutic, and biodiagnostic devices. Recently, nano-carbohydrates were used for different types of microarrays to detect proteins and nucleic acids., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Professional health bodies such as the World Health Organization (WHO), the American Academy of Pediatrics (AAP), and the U.S. Department of Health and Human Services (HHS) recommend breast milk as the sole source of food during the first year of life. This position recognizes human milk as being uniquely suited for infant nutrition. Nonetheless, most neonates in the West are fed alternatives by 6 months of age. Although inferior to human milk in most aspects, infant formulas are able to promote effective growth and development. However, while breast-fed infants feature a microbiota dominated by bifidobacteria, the bacterial flora of formula-fed infants is usually heterogeneous with comparatively lower levels of bifidobacteria. Thus, the objective of any infant food manufacturer is to prepare a product that results in a formula-fed infant developing a breast-fed infant-like microbiota. The goal of this focused review is to discuss the structure, synthesis, and function of carbohydrate additives that play a role in governing the composition of the infant microbiome and have other health benefits., (Copyright © 2016 Elsevier Ltd. All rights reserved.)