Carbohydrates constitute the most abundant class of biomolecules on Earth. They exist as small mono- or oligo-saccharides, as large and highly complex polysaccharides, and in conjugation with, for example, proteins and lipids, forming a kingdom of glycoconjugates that are found on every cell surface. It is now generally considered important to be able to synthesize carbohydrates and glycoconjugates, to analyze their structures, and to advance our understanding of the biology of carbohydrates in living systems. The Thematic Series “Synthesis in the glycosciences” and “Synthesis in the glycosciences II” have impressively documented the state of the art in this field of research. Now, a third Thematic Series is presented in which the structural world of natural sugars has been extended towards artificial carbohydrate architectures to achieve potential innovations offered by glycoconjugates. For instance, multivalent glycoconjugates can be used as anti-adhesive drugs against microbial infections. They could be developed into bioimaging agents that can target specific tissues. Indeed, they will certainly find applications in materials science and in medicine, for example, in drug delivery or diagnostics.
See also the Thematic Series:
Multivalency as a chemical organization and action principle
Graphical Abstract
Figure 1: Examples of sucrose-based macrocycles.
Figure 2: Synthesis of higher sugar precursors by a Wittig-type methodology.
Scheme 1: Synthesis of higher sugar enone 10.
Scheme 2: Synthesis of the diol 13 containing two sucrose units.
Figure 3: CD spectra of in situ formed chiral complexes of 13 (green line), 14 (purple line) and 16 (blue lin...
Scheme 3: Synthesis of model sucrose diols.
Graphical Abstract
Figure 1: Structure of GM3-ganglioside 1, GM3-lactone 2, GM3-lactone mimetic 3, and GM3-lactone mimetic conju...
Scheme 1: Synthesis of the bifunctional multivalent glycodendron 5.
Figure 2: Upper panels: percentage of expression of dendritic cell markers (HLA-DR ECD, CD80 FITC, CD86 PE an...
Graphical Abstract
Figure 1: Our reported strategy for quick access to 3-amino-2,3-dideoxysugars via regio- and stereoselective ...
Figure 2: Synthetic modification of α-GalNAc linked glycopeptides to 3-tosylamino-2,3-dideoxyneoglycoconjugat...
Figure 3: Our proposal for access to 3-tosylamino-2,3-dideoxyneoglycoconjugates via tandem hydroamination/gly...
Scheme 1: Synthesis of propargyl 3-tosylamino-2,3-dideoxy-α-D-allohexopyranoside (2a).
Scheme 2: Synthesis of divalent 3-tosylamino-2,3-dideoxyneoglycoconjugates 6a and 6b.
Scheme 3: Synthesis of trivalent 3-tosylamino-2,3-dideoxyneoglycoconjugate 6c.
Graphical Abstract
Figure 1: The prepared lamivudine (3TC) and abacavir (ABC) potential prodrugs and the corresponding 3TC- and ...
Figure 2: Time course release of free 3TC and ABC from the corresponding GNPs in 1 N HCl, detected by HPLC–MS...
Figure 3: Cellular experiments: The two graphs show the percentage of luciferase activity decrease in the pre...
Graphical Abstract
Figure 1: Molecular structures of carbohydrates (NANA, Glc, Gal, Man) immobilized on epoxide SAMs, NANA-bindi...
Figure 2: Schematic representation of the preparation of a simple carbohydrate microarray by μCP of amine-fun...
Figure 3: Optical microscopy images of water droplets selectively condensed in the areas where (A) the NANA i...
Figure 4: (A) AFM height image (zoom) of NANA ink in 10 μm stripes on an epoxide-terminated SAM; (B) Height p...
Figure 5: Fluorescence images of bifunctional carbohydrate microarrays incubated with FITC-HisHis. (A) NANA (...
Figure 6: Overlay of fluorescence images of bifunctional carbohydrate microarrays; (A) NANA (dots 10 × 5 μm) ...
Figure 7: Fluorescence images of a microarray consisting of NANA (dots 5 × 3 μm) and Man (background). (A) In...
Figure 8: Fluorescence images of a microarray of NANA (dots 5 × 3 μm) and Glc (background), first incubated w...
Graphical Abstract
Figure 1: The structure of biantennary oligoglycines and their glyco derivatives (sp = spacer group).
Scheme 1: Synthesis of biantennary oligoglycines and their glycoderivatives.
Figure 2: Dynamics of associate formation by biantennary oligoglycines Н-Glyn-NH(СН2)10NH-Glyn-Н. a) n = 4–5,...
Figure 3: Raman spectra of a) [H-Gly7-NHCH2]4C; b) H-Gly4-NH(CH2)2NH-Gly4-H; c) H-Gly4-NH(CH2)10NH-Gly4-H. Th...
Figure 4: Model of the formation of tectomer layers by biantennary oligoglycines on a mica surface. The heigh...
Figure 5: Growth of the tectomer formed by the peptide Н-Gly4-NH(СН2)10-NHGly4-Н (concentration 0.1 mg/mL) on...
Figure 6: Growth of the tectomer formed by peptide Н-Gly4-NH(СН2)10NH-Gly4-Н (concentration 0.1 mg/mL) on a m...
Figure 7: SFM images of associates formed by peptides а) Н-Gly5-NH(СН2)2NH-Gly5-Н and b) Н-Gly5-NH(СН2)10NH-G...
Graphical Abstract
Figure 1: N-Bu-DNJ (1), azide-armed DNJ derivatives 5 and cyclopeptoid scaffolds 2–4.
Scheme 1: Sub-monomer approach for the synthesis of cyclopeptoids 2–4: DIPEA = N,N-diisopropylethylamine; DIC...
Scheme 2: Synthesis of DNJ clusters 10: (a) CuSO4·5H2O cat., sodium ascorbate, DMF/H2O (5:1), MW, 80 °C; (b) ...
Figure 2: i) Partial 1H NMR spectrum (400 MHz, CD3CN/CDCl3 9:1) of compound 9a; ii) Partial 1H NMR spectrum (...
Figure 3: Monovalent models 11 and 7-valent DNJ derivatives 12.
Graphical Abstract
Figure 1: Types of PEG utilized for derivatization of drugs and peptides.
Figure 2: Activated PEG derivatives for conjugation.
Scheme 1: Chemoenzymatic method for the preparation of PEG-CMP-SA, adapted from [32,33].
Scheme 2: GlycoPEGylation by sequential in vitro, enzyme mediated, O-glycosylation followed by transfer of PE...
Scheme 3: Chemical glycation of a protein and PEGylation after periodate oxidation, adapted from [34].
Scheme 4: PEGylation of native glycosylated proteins after modification of the glycan. (A) Enzymatic modifica...
Scheme 5: PEGylation of a pentofuranose derivative, adapted from [41].
Scheme 6: Galactosyl PEGylation of polystyrene nanoparticles, adapted from [42].
Figure 3: Mannosyl PEGylated polyethylenimine for delivery systems. (A) Mannose and PEG are independently lin...
Figure 4: PEGylated mannose derivatives, adapted from [45].
Scheme 7: PEGylation of lactose analogs [53].
Scheme 8: Conjugation of lactose analogs with dendritic PEGs [54].
Figure 5: PEGylated chitosan derivative, adapted from [61].
Figure 6: Chitosan/PEG functionalized with a mannose at the distal end, adapted from [62].
Graphical Abstract
Figure 1: Requirements on absorption and emission spectral features of the photochromic and fluorescent units...
Figure 2: Bifunctional fluorescent-photochromic molecules 1 and 2.
Scheme 1: Synthesis of multichromophoric glucopyranoside 2.
Figure 3: Absorption and fluorescence spectra of compounds 6, 9, and 2 in CH3CN: (a) absorption spectrum of 6...
Figure 4: Absorption and fluorescence changes of compound 2 (1.0 μM in CH3CN) upon UV–visible irradiation: (a...
Figure 5: Partial 1H NMR spectra of compound 2 (11 μM in CD3CN/DMSO-d6 4:1) before and after increasing irrad...
Figure 6: (a) Fluorescence decays (λexc = 475 nm, λem = 610 nm) of compound 2-OF, and 2 after irradiation at ...
Graphical Abstract
Figure 1: a) Dendrons (right) are branched fragments of dendrimers (left), featuring a functional group (FG) ...
Scheme 1: Synthesis of the starting material for postsynthetic focal point functionalization; published yield...
Scheme 2: Initial syntheses of amphiphilic glycodendrons.
Scheme 3: Postsynthetic focal modification of glycodendrons (I) using using olefin cross metathesis.
Scheme 4: Postsynthetic focal modification of glycodendrons (II) using olefin cross metathesis.
Graphical Abstract
Figure 1: Repeating unit of the A-band polysaccharide of P. aeruginosa.
Scheme 1: Preparation of the monomeric building blocks; reagents and conditions: i) Pyr., BzCl, 0 °C–rt; ii) ...
Figure 2: Retrosynthetic analysis.
Scheme 2: Sequential stepwise synthesis of the trisaccharide; reagents and conditions: i) TMSOTf, DCM, molecu...
Scheme 3: Synthesis of the trisaccharide by sequential one-pot glycosylation reactions; reagents and conditio...
Scheme 4: Synthesis of the target trisaccharide via global deoxygenation strategy; reagents and conditions: i...
Graphical Abstract
Figure 1: Structure of bis(β-lactosyl)-[60]fullerene (bis-Lac-C60).
Scheme 1: Synthesis of bis-Lac-C60. Reagents and conditions: (a) 6-chloro-1-hexanol, TMSOTf, CH2Cl2, −40 °C, ...
Figure 2: Precipitation assay of bis-Lac-C60 colloidal solution. The tubes were allowed to stand for 10 min a...
Figure 3: Schematic image for the quantitative analysis of ricin protein in the colloidal suspension of bis-L...
Figure 4: A modified procedure for the rapid detection and the efficient decontamination of ricin and ricin-l...
Graphical Abstract
Figure 1: Octyl α-D-mannoside (mannoside) and diaminopyrrolic tripodal receptor molecules. 2D and 3D represen...
Figure 2: Full titration curve of the receptor (a) and the correspondent percentage of protonation in each ge...
Figure 3: Diagram representing the population of all microstates at each number of titrable protons (n) prese...
Figure 4: Radius of gyration (Rg) histograms for the receptor in water at pH 1.0, 3.0, 6.0, 10.0 and in ACN. ...
Figure 5: Free energy profiles for the receptor at pH 1.0 (a), 6.0 (b), 10.0 (c) and ACN (d) using RMSD and Rg...
Figure 6: Schematic representation of the receptor arms positions. Pyrrolic nitrogen atoms positions relative...
Figure 7: Histogram of the hydrogen bonds between receptor and mannoside in ACN and water (at different proto...
Figure 8: Distance histograms between the center of mass of the last 4 atoms of the carbon chain of the manno...
Figure 9: Typical conformations in water and ACN. The selected conformations have 6 hydrogen bonds in ACN and...
Graphical Abstract
Scheme 1: Synthesis of mannosylated trimers 5 and 9 using trimesic acid core transformed into propargylated (2...
Scheme 2: Divergent CuAAc “click reaction” between propargylated core 10 and azide 3 to afford 9-mer 12.
Scheme 3: Divergent CuAAc synthesis of “extended” 9-mer 17 using phloroglucinol (13) as core, bromoacylated T...
Scheme 4: Convergent synthesis of further “extended” 9-mer 21 using mannosylated bromoacyl dendron 18 transfo...
Scheme 5: Convergent assembly of 27-mer 23 using key propargylated scaffold precursors 10 and mannosylated az...
Figure 1: a) Decay of 1H signal for the nonavalent mannosylated compound 12 in D2O during the PFGSTE experime...
Graphical Abstract
Figure 1: Reaction scheme of the synthesis of anionic, cationic, and ampholytic cellulose carbamates (substit...
Figure 2: 13C NMR spectra of (3-ethoxy-3-oxopropyl)(N-Boc-2-aminoethyl)- (4), (2-carboxyethyl)(N-Boc-2-aminoe...
Figure 3: Acid–base titration of (3-ethoxy-3-oxopropyl)(2-aminoethyl)cellulose carbamate (6, 0.4%) in 0.2 M a...
Figure 4: Acid–base titration of (2-carboxyethyl)(2-aminoethyl)cellulose carbamate (7a, 0.4%) in 0.2 M aqueou...
Figure 5: Acid–base titration of (2-carboxyethyl)(N-Boc-2-aminoethyl)-cellulose carbamate (5, 0.1%) from pH 6...
Figure 6: Acid–base titration of (2-carboxyethyl)(2-aminoethyl)cellulose carbamate (7a, 0.4% in water) from p...
Figure 7: Titration of (2-carboxyethyl)(2-aminoethyl)cellulose carbamate (7a, 0.1% in water) at pH 11.5 with ...
Figure 8: Titration of (2-carboxyethyl)(2-aminoethyl)cellulose carbamate (7a, 0.1% in water) and polyDADMAC (...
Graphical Abstract
Figure 1: Chemical strategy for the construction of heteroglycoclusters.
Scheme 1: Stepwise (Route A) and sequential one-pot (Route B) synthesis of hGCs.
Scheme 2: Synthesis of hGCs 11 and 13.
Figure 2: RP-HPLC profile of the one-pot synthesis of hGC 11 (linear A–B gradient: 5 to 100% B in 20 min, λ =...
Graphical Abstract
Scheme 1: Synthesis of isothiocyanato-functionalized lactoside 1.
Scheme 2: Synthesis of carbohydrate-functionalized PAMAM dendrimers. (Values for m and for x equivalents adde...
Figure 1: Effective diameter of galectin-3/glycodendrimer aggregates (DLS). Final concentration of galectin-3...
Figure 2: Schematic representation of galectin-3/glycodendrimer aggregates at varying stoichiometries.
Figure 3: Fluorescence microscopy images of labelled particles. Microbead standards at similar exposure times...
Figure 4: Aggregate diameter distribution of fluorescence microscopy images; 31 μM galectin-3 and 0.14 μM (a) ...
Graphical Abstract
Figure 1: Synthesis of photoswitchable precision glycooligomers via stepwise addition of building blocks on s...
Figure 2: Characterization of the E → Z photoisomerization (λ = 360 nm) of Azo-Gal(1,3,5)-5 in buffer solutio...
Figure 3: Structural models of Azo-Gal(1,3)-3 and Azo-Gal(1,3,5)-5 in (a) E- and (b) all-Z-configurations of ...
Graphical Abstract
Figure 1: Lactosylthioureidocalix[4]arenes I–III used to inhibit Gal-3 [20,21].
Figure 2: The new glycocalix[4]arenes 1–4 synthesized in this study.
Scheme 1: Synthesis of the cone galactosylcalix[4]arenes 1. Reaction conditions: (i) DCC, DMAP, CH2Cl2, under...
Scheme 2: Synthesis of the cone galactosylcalix[4]arenes 2. Reaction conditions: (i) DIPEA, CH2Cl2, rt, 6 h, ...
Scheme 3: Synthesis of the cone lactosylcalix[4]arenes 3. Reaction conditions: (i) NaN3, n-Bu4NI, DMF, 90 °C,...
Scheme 4: Synthesis of the 1,3-alternate lactosylcalix[4]arenes 4. Reaction conditions: (i) EDC, CH2Cl2/py (7...
Figure 3: SPR sensorgrams of binding experiment between immobilized Gal-3 and glycocalixarenes 1, 3 and 4.
Figure 4: a) Relative affinities of glycocalixarene 1, 3, 4 (1 mM) towards Gal-3, expressed in terms of the i...
Graphical Abstract
Figure 1: Synthesized G0, G1 and G2 dendrons and functionalized saccharides used for carbonyl conjugation.
Scheme 1: Schematic depiction of dendron conjugation to saccharides by carbonyl chemistry.
Scheme 2: Synthesis of the dendrons.
Scheme 3: Dendron conjugation to fucose moieties by reductive amination. Reagents and conditions: a) 4, 3 M Na...
Scheme 4: Dendron conjugation to fucose via oxime ligation (buffer = citrate buffer).
Graphical Abstract
Scheme 1: Convergent construction of self-adjuvanting vaccines bearing multiple copies of a B cell epitope.
Scheme 2: Synthesis of carbohydrate building block 1.
Scheme 3: (A) Lipidation of Fmoc-Lys-OH with lauroyl chloride: (B) Lipidation of Fmoc-Lys-OH with sulfonic-ca...
Scheme 4: Convergent synthesis of self-adjuvanting vaccine candidate 10 consisting of lipidic adjuvanting moi...
Figure 1: Analytical HPLCs of copper-catalyzed alkyne–azide cycloaddition reaction at the start (top) and aft...
Scheme 5: Convergent synthesis of self-adjuvanting vaccine candidate 12 consisting of lipidic adjuvanting moi...
Graphical Abstract
Scheme 1: Approach to divalent carbohydrate mimetics 1 with rigid spacer and monovalent analogues 2.
Scheme 2: Synthesis of (Z)-nitrone 6. Conditions: a) LiAlH4, THF, 1 h, rt; b) 1. NaIO4, CH3CN/H2O, 1 h, rt; 2...
Scheme 3: [3 + 3]-Cyclization of (Z)-nitrone 6 with lithiated allene 9. Conditions: a) n-BuLi, THF, 15 min, −...
Scheme 4: Synthesis of 1,2-oxazine 4 by acetal formation from 10. Conditions: a) 1-bromo-4-(dimethoxymethyl)b...
Scheme 5: Synthesis of bicyclic ketone 11 by Lewis acid-induced rearrangement and reduction to alcohols 12a a...
Scheme 6: Synthesis of bicyclic diols 15 and of trityl-protected bicyclic 1,2-oxazine 16. Conditions: a) SnCl4...
Scheme 7: Hydrogenolyses of bicyclic 1,2-oxazine derivatives 15a and 15b. Conditions: a) H2, Pd/C, MeOH, EtOA...
Scheme 8: Suzuki cross-coupling of 15a leading to biphenyl derivative 18 and hydrogenolysis to 19. Conditions...
Scheme 9: Synthesis of N-benzylated p-terphenyl derivative 21 by Suzuki cross-coupling of 12a with 20 and sub...
Scheme 10: Attempted reductive cleavage of the N–O bond of compound 21 by samarium diiodide and reaction of 12a...
Scheme 11: Deprotection of compound 21 and samarium diiodide-mediated reaction of 26. Conditions: a) TBAF, THF...
Scheme 12: Suzuki cross-coupling of compound 16. Conditions: Pd(PPh3)2Cl2, 2 M Na2CO3, DMF, 80 °C, 3 d.
Scheme 13: Hydrogenolysis of compound 27 and samarium diiodide-mediated reaction leading to compounds 30 and 31...
Graphical Abstract
Figure 1: Previously reported low-valent glycoasterisk α-D-Man ligand based on a persulfurated benzene core [30] ...
Scheme 1: Synthesis of trivalent trithiotriazine-based glycoclusters.
Scheme 2: Synthesis of mixed triazine-based glycoclusters.
Figure 2: Dynamic light scattering experiments of bis-D-galactosyl proparyl cluster 16 with lecA. Distributio...
Figure 3: Typical ITC measurements representing the raw ITC data (top) and integrated titration curves (botto...
Figure 4: Inhibition of PAO1 biofilm formation by D-galactose cluster 1, L-fucose cluster 14, and D-glucose c...
Graphical Abstract
Scheme 1: Functionalization of carbohydrates; reagents and conditions: (a) In, allyl bromide, EtOH/H2O, ultra...
Scheme 2: Deprotection sequence; reagents and conditions: (a): HCl/MeOH, rt, 16–24 h, then MeOH, CH2Cl2, O3, ...
Graphical Abstract
Scheme 1: Principle of MOE with Ac4GlcNCyoc (1) and subsequent ligation by a DAinv reaction: The chemically m...
Figure 1: Hexosamine derivatives with cyclopropene tags. Cyoc = (2-methylcycloprop-2-en-1-yl)methoxycarbonyl,...
Scheme 2: Synthesis of the cyclopropene-modified hexosamine derivatives 1 and 2.
Scheme 3: Labeling strategy for metabolically incorporated monosaccharides.
Figure 2: Labeling of metabolically engineered cell-surface glycoconjugates. HEK 293T cells were grown for 48...
Figure 3: Western blot analysis of soluble glycoproteins. HeLa S3 cells were grown for 48 h with 100 µM cyclo...
Graphical Abstract
Figure 1: Structures of the repeating unit of MenX CPS and synthetic oligomers 1–3.
Scheme 1: Reagents and conditions: a) NiCl2/NaBH4, MeOH; b) Ac2O, 86% over 2 steps; c) TBAF, THF, −40 °C to r...
Scheme 2: Reagents and conditions: a) PivCl in pyridine, then I2 in 19:1 pyridine/H2O, then 1 M TEAB (45%); b...
Scheme 3: Reagents and conditions: a) SIDEA, Et3N, DMSO: 11 (64%), 12 (49%), 13 (51%); b) CRM197, 100 mM NaPi...
Figure 2: IgG levels detected at OD = 1 in individual post 3 sera (sera collected two weeks after the third i...
Figure 3: A) IgG levels detected at OD = 1 in individual post 3 sera of BALB/c mice immunization at 0.3 μg sa...