Halo-1,2,3-triazoles: Valuable Compounds to Access Biologically Relevant Molecules.

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.

Synthetic approaches of carbohydrate based self-assembling systems.

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.

Friedel-Crafts reactions for biomolecular chemistry.

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.

Optochemical Control of Bacterial Gene Expression: Novel Photocaged Compounds for Different Promoter Systems.

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.

Studies of Catalyst-Controlled Regioselective Acetalization and Its Application to Single-Pot Synthesis of Differentially Protected Saccharides.

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.

En Route to the Transformation of Glycoscience: A Chemist's Perspective on Internal and External Crossroads in Glycochemistry.

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 SN2-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.

Novel carbohydrate-based sulfonamide derivatives as selective carbonic anhydrase II inhibitors: Synthesis, biological and molecular docking analysis.

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.

Bismuth(iii) triflate as a novel and efficient activator for glycosyl halides.

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.

Synthesis and Applications of Carbohydrate-Based Organocatalysts.

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.

Synthesis and Binding of Mannose-Specific Synthetic Carbohydrate Receptors.

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 C2h 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 C1 -O-octyloxy glycans, α/ß-glucoside (α/ß-Glc), α/ß-mannoside (α/ß-Man), and ß-galactoside (ß-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 ß-Glc. SCR019 (3-indole) binds only to ß-Man. SCR020 (2-pyridine) binds ß-Man and α-Man with a preference to the latter. SCR018 (2-indole) binds α-Man and ß-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.

Stereodivergent routes in organic synthesis: carbohydrates, amino acids, alkaloids and terpenes.

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 ß-hydroxy- and ß-amino-α-amino acids, as well as of ß- 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 ß-santalene, α-curcumene and α-cuparenone and the diterpene scopadulcic acid A have been synthesized using enantiodivergent routes.

A light- and heat-driven glycal diazidation approach to nitrogenous carbohydrate derivatives with antiviral activity.

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.

"One-Pot" Protection, Glycosylation, and Protection-Glycosylation Strategies of Carbohydrates.

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.

The synthesis of non-structural carbohydrates under the network security model.

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.

Design, synthesis and biological evaluation of novel carbohydrate-based sulfonamide derivatives as antitumor agents.

A series of novel carbohydrate-based sulfonamides were designed and synthesized by the sugar-tail approach. The classical aromatic sulfonamide pharmacophore (ArSO2NH2) 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 (IC50) value of 7 nM, being four times more potent than the clinical used agent acetazolamide (AAZ) (IC50 = 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 IC50 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.

Enhanced Immune Response Against the Thomsen-Friedenreich Tumor Antigen Using a Bivalent Entirely Carbohydrate Conjugate.

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.

Heteromultivalent Glycooligomers as Mimetics of Blood Group Antigens.

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.

Selective in vivo metabolic cell-labeling-mediated cancer targeting.

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 (Ac4ManAz) 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 Ac4ManAz 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.

Asymmetrically Branched Precision Glycooligomers Targeting Langerin.

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.

Synthesis of carbohydrate building blocks via regioselective uniform protection/deprotection strategies.

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.