Carbohydrate Scaffolds Research Articles

LpxC inhibition: Potential and opportunities with carbohydrate scaffolds

Uridine diphosphate-3-O-(hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a key enzyme involved in the biosynthesis of lipid A, an essential building block, for the construction and assembly of the outer membrane (OM) of Gram-negative bacteria. The enzyme is highly conserved in almost all Gram-negative bacteria and hence has emerged as a promising target for drug discovery in the fight against multi-drug resistant Gram-negative infections. Since the first nanomolar LpxC inhibitor, L-161,240, an oxazoline-based hydroxamate, the two-decade-long ongoing search has provided valuable information regarding essential features necessary for inhibition. Although the design and structure optimization for arriving at the most efficacious inhibitor of this enzyme has made good use of different heterocyclic moieties, the use of carbohydrate scaffold is scant. This review briefly covers the advancement and progress made in LpxC inhibition. The field awaits the use of potential associated with carbohydrate-based scaffolds for LpxC inhibition and the discovery of anti-bacterial agents against Gram-negative infections.

Site-selective editing of carbohydrate scaffolds to access rare sugars enabled by photoinduced radical processes

Herein, we summarize recent achievements via photoinduced radical-mediated strategies that enable the precise modification of carbohydrates.

Sweet Synthesis

Sweet Synthesis

Growing Impact of Carbohydrate‐Based Organocatalysts

AbstractOrganocatalysis has emerged as one of the most progressive and prevailing field of organic synthesis to assist green chemistry. Constantly increasing demand of promising scaffolds to develop potent organocatalysts has impelled researchers to utilize the unique traits of carbohydrate moiety in this field. Biological significance of carbohydrates, as well as, their high natural abundance as chiral non‐racemic material, presence of multiple hydroxyl groups, several stereogenic centres, and easily modifiable structure make this moiety an appropriate skeleton to develop organocatalysts to enhance productivity and selectivity of a chemical transformation. 21st Century has witnessed the progress of carbohydrate moiety in development of organocatalysts from obscurity to eminence. This review encapsulates the importance of carbohydrate scaffolds in organocatalysis mainly dealing with the synthesis and applications carbohydrate‐derived organocatalyst in different common organic reactions with their significance and future purspectives.

Surface Modification of Porous Silica Particles with Carbohydrate Scaffolds as Receptor Components for Molecular Recognition.

Invited for this month's cover is the group of Osamu Kanie and co-workers at Tokai University. The cover picture shows the interaction of an incoming molecule and a receptor surface as the first process of a molecular sensing mechanism. For this, porous silica particles were decorated with protected carbohydrates to create artificial pocket-like structures on its surface. More information can be found in the Research Article by O. Kanie and co-workers.

Front Cover: Surface Modification of Porous Silica Particles with Carbohydrate Scaffolds as Receptor Components for Molecular Recognition (ChemPlusChem 7/2022)

The cover picture shows the interaction of an incoming molecule and a receptor surface as the first process of a molecular sensing mechanism. It is envisioned that creating stable receptor substitutes could become of prime importance in the near future. For this, porous silica particles were decorated with protected carbohydrates to create artificial pocket-like structures on its surface. The feasibility of the idea was proven by detecting interactions of protected carbohydrates and 4-nitrobenzene analogs by using a confocal laser Raman spectrometer. More information can be found in the Research Article by O. Kanie and co-workers.

Surface Modification of Porous Silica Particles with Carbohydrate Scaffolds as Receptor Components for Molecular Recognition.

Biosensors play a pivotal role in diagnosis through specific receptor-ligand interactions. However, receptor biomolecules such as proteins have inevitable stability issues due to denaturation. Alternatively, utilization of the small molecules multivalently presented on porous silica particles as receptor components is considered to address the stability issues. A series of receptor components was synthesized using carbohydrates as a chiral scaffold to support multiple functional groups. The synthesized molecules were attached on the porous silica particles. Raman spectral analyses of single silica particles in the presence of nitrobenzene derivatives revealed a specific interaction with 4-nitrophenol among others using a confocal Raman microscope. Chiral selective recognition was also accomplished for (1S,3S)- and (1R,3R)-2-amino-1-(4-nitrophenyl)-1,3-propanediols. Protected carbohydrate derivatives are shown to be useful as receptor components on porous silica particles.

A Unified Strategy to Access 2- and 4-Deoxygenated Sugars Enabled by Manganese-Promoted 1,2-Radical Migration.

The selective manipulation of carbohydrate scaffolds is challenging due to the presence of multiple, nearly chemically indistinguishable O-H and C-H bonds. As a result, protecting-group-based synthetic strategies are typically necessary for carbohydrate modification. Here we report a concise semisynthetic strategy to access diverse 2- and 4-deoxygenated carbohydrates without relying on the exhaustive use of protecting groups to achieve site-selective reaction outcomes. Our approach leverages a Mn2+-promoted redox isomerization step, which proceeds via sugar radical intermediates accessed by neutral hydrogen atom abstraction under visible light-mediated photoredox conditions. The resulting deoxyketopyranosides feature chemically distinguishable functional groups and are readily transformed into diverse carbohydrate structures. To showcase the versatility of this method, we report expedient syntheses of the rare sugars l-ristosamine, l-olivose, l-mycarose, and l-digitoxose from commercial l-rhamnose. The findings presented here validate the potential for radical intermediates to facilitate the selective transformation of carbohydrates and showcase the step and efficiency advantages attendant to synthetic strategies that minimize a reliance upon protecting groups.

Tetrathiomolybdate and Tetraselenotungstate as Sulfur/Selenium Transfer Reagents: Applications in the Synthesis of New Thio/Seleno Sugars

AbstractSulfur and selenium containing sugars have gained prominence in the last two decades because of their importance in several biological applications. These type of carbohydrate scaffolds are also challenging targets for synthesis. In this personal note, we have summarised the results of our investigation over the last 20 years on the use of two reagents, benzyltriethylammonium tetrathiomolybdate and tetraethylammonium tetraselenotungstate, in efficient transfer of sulfur and selenium respectively to the synthesis of a number of carbohydrate derivatives.

Generalising a Simple Methodology for the Regioselective Anomeric Deacetylation of Carbohydrates

AbstractThe use of methylamine to deprotect 1‐O‐acetyl protected carbohydrates has only attracted limited interest in the literature. Demonstrated here is an approach that is able to be generalized for a wide variety of carbohydrate scaffolds which results in a high yielding, simplified, practical, expedient and clean method to prepare hemiacetals from 1‐O‐acetyl protected carbohydrates.

One-pot construction of carbohydrate scaffolds mediated by metal catalysts.

Owing to the environmental concern worldwide and also due to cost, time and labour issues, use of one-pot reactions [domino/cascade/tandem/multi-component (MC) or sequential] has gained much attention among the scientific and industrial communities for the generation of compound libraries having different scaffolds. Inclusion of sugars in such compounds is expected to increase the pharmacological efficacy because of the possibility of better interactions with the receptors of such unnatural glycoconjugates. In many of the one-pot transformations, the presence of a metal salt/complex can improve the reaction/change the course of reaction with remarkable increase in chemo-/regio-/stereo-selectivity. On the other hand because of the importance of natural polymeric glycoconjugates in life processes, the development and efficient synthesis of related oligosaccharides, particularly utilising one-pot MC-glycosylation techniques are necessary. The present review is an endeavour to discuss one-pot transformations involving carbohydrates catalysed by a metal salt/complex.

Interactive Polymer Gels as Biomimetic Sensors for Carbohydrate Interactions and Capture–Release Devices for Pathogens

AbstractAdhesive processes mediated by carbohydrate‐decorated interfaces play a crucial role in many biological processes such as cell development or pathogen invasion. The involved carbohydrate scaffolds are soft and present multiple subsites forming complex and dynamic bonds to carbohydrate binding proteins. New tools and data are needed to understand how ligand presentation and mechanical properties drive these binding processes. This article highlights recent developments in the area of adhesion assays with a focus on soft biomimetic carbohydrate scaffolds as probes of adhesion forces. Key findings state that carbohydrate functionalized polymer networks largely show additive multivalency (statistical effects) and that the overall interaction forces are strongly affected by the stiffness of the network. These results indicate that phase transitions of carbohydrate bearing polymer gels may enable tunable affinity toward carbohydrate binding proteins. As an example, polymer networks undergoing large changes in mechanical rigidity, density, and spacing of carbohydrate ligands upon temperature stimulus are shown to bind or release carbohydrate binding bacteria such as Escherichia coli. The presented adhesion assays and the developed responsive systems can provide new insights into the mechanism through which carbohydrates mediate adhesion processes and establish new avenues toward scaffolds for the capture or release of cells or pathogens.

Carbohydrate Scaffolds for the Study of the Autism-associated Bacterium, Clostridium bolteae.

A large number of children in the autism spectrum disorder suffer from gastrointestinal (GI) conditions, such as constipation and diarrhea. Clostridium bolteae is a part of a set of pathogens being regularly detected in the stool samples of hosts affected by GI and autism symptoms. Accompanying studies have pointed out the possibility that such microbes affect behaviour through the production of neurotoxic metabolites in a so-called, gut-brain connection. As an extension of our Clostridium difficile polysaccharide (PS)-based vaccine research, we engaged in the discovery of C. bolteae surface carbohydrates. So far, studies revealed that C. bolteae produces a specific immunogenic PS capsule comprised of disaccharide repeating blocks of mannose (Manp) and rhamnose (Rhap) units: α-D-Manp-(1→[-4)-β-D-Rhap-(1→3)-α-D-Manp-(1→]n. For vaccinology and further immunogenic experiments, a method to produce C. bolteae PS conjugates has been developed, along with the chemical syntheses of the PS non-reducing end linkage, with D-Rha or L-Rha, α-D-Manp-(1→4)-α-D-Rhap-(1→O(CH2)5NH2 and α-D-Manp-(1→4)-α-L-Rhap-(1→O(CH2)5NH2, equipped with an aminopentyl linker at the reducing end for conjugation purposes. The discovery of C. bolteae PS immunogen opens the door to the creation of non-evasive diagnostic tools to evaluate the frequency and role of this microbe in autistic subjects and to a vaccine to reduce colonization levels in the GI tract, thus impeding the concentration of neurotoxins.

Carbohydrate‐Scaffolded Thymine Multimers: Scope and Limitations of the Allylation–Hydroboration Sequence

Carbohydrates serve as versatile molecular scaffolds and platforms in organic chemistry, for example in combinatorial chemistry or for the multivalent presentation of ligands. Carbohydrate scaffolds are frequently employed in the synthesis of multivalent glycoconjugates and utilized for the study of fundamental parameters of carbohydrate recognition. However, facile procedures are required to achieve a useful variety of sugar platforms. Here, we report on the synthesis of a series of divalent und tetravalent hydroxypropylated mannosides, using an allylation‐hydroboration sequence. The hydroxypropyl‐linkers were further functionalized with thymine in a Mitsunobu reaction to achieve multivalent glycothymine scaffolds for intramolecular [2+2] photocyclization. This will be of importance to further investigate the influence of the 3D orientation in carbohydrate recognition. We discuss the scope of the allylation‐hydroboration sequence comparing 2,3‐, 2,6‐, and 4,6‐difunctionalization and 2,3,4,6‐tetrafunctionalization of protected 2‐aminoethyl α‐d‐mannopyranosides.

Norovirus devours human milk oligosaccharides rich in α-fucose

Human norovirus binding to histo-blood group antigens (HBGAs) is thought to direct their entry into host cells. However, the glycan epitopes characteristic of HBGAs are also present on oligosaccharides abundant in human milk. In this issue of JBC, Hanisch et al compared norovirus binding to human gastric mucins and human milk oligosaccharides, finding those bound most avidly are rich in α-fucose. Mimicry of these epitopes with α-fucose multivalently displayed on other carbohydrate scaffolds successfully scavenged this prevalent virus, providing new insights into norovirus biology and clues for future therapeutic development.

Glycosyloxymethylfurfural (GMF) in Multicomponent Aza-Morita-Baylis-Hillman Reaction: Rapid Access to Highly Functionalized Carbohydrate Scaffolds

Aim and Objective: The use of glycosyloxymethylfurfural (GMF), the dehydration product of isomaltulose, in the one-step multicomponent aza-Morita-Baylis-Hillman (aza-MBH) reaction, was studied. Materials and Methods: The reaction conditions and scope were investigated with respect to solvent, combinations of catalysts (Lewis acids and nucleophilic base), and the nature of the amine and the acrylic partners. Results: The three-components one step aza-MBH reaction using GMF, sulfonamides and a Michael acceptor provides carbohydrate-based a-methylene-b-amino carbonyl derivatives in moderate to good yields. Optimized conditions are the use of La(OTf)3 and 3-HQD in methanol. The use of diphenylphosphinamide, though requiring the use of a protected GMF and a two-step protocol, offers alternatives in the type of activated imine involved the classical sulfonyl substitution. Conclusion: A wide structural range of adducts were obtained in fair to good yields, showing the synthetic efficiency of the strategy able to provide highly functionalized carbohydrate-containing new molecules in an unique step from very available starting materials. These explorations show that GMF can be transformed in very short sequences to rather elaborated new compounds using the MBH and aza-MBH strategy.

Diversity‐Oriented Synthesis of Carbohydrate Scaffolds through the Prins Cyclization of Differently Protected d‐Mannitol‐Derived Homoallylic Alcohols

A diversity‐oriented synthesis of a variety of carbohydrate scaffolds, including sugar‐fused isochroman derivatives, bicyclic vinyl halide derivatives, fluorine‐substituted tetrahydropyrans, and a furan derivative, is reported. This was achieved through the Prins reaction of d‐mannitol‐derived homoallylic alcohols in which the allylic alcohol bears a different protecting group, leading to structural variation in the products. Some of the products were also converted into more functionalized scaffolds of wider utility and of possible biological importance. Appropriate mechanisms have been proposed to account for the product formation.

A Study of Intramolecular Hydrogen Bonding in Levoglucosan Derivatives.

Organofluorine is a weak hydrogen-bond (HB) acceptor. Bernet et al. have demonstrated its capability to perturb OH···O intramolecular hydrogen bonds (IMHBs), using conformationally rigid carbohydrate scaffolds including levoglucosan derivatives. These investigations are supplemented here by experimental and theoretical studies involving six new levoglucosan derivatives, and complement the findings of Bernet et al. However, it is shown that conformational analysis is instrumental in interpreting the experimental data, due to the occurrence of non-intramolecular hydrogen-bonded populations which, although minor, cannot be neglected and appears surprisingly significant. The DFT conformational analysis, together with the computation of NMR parameters (coupling constants and chemical shifts) and wavefunction analyses (AIM, NBO), provides a full picture. Thus, for all compounds, the most stabilized structures show the OH groups in a conformation allowing IMHB with O5 and O6, when possible. Furthermore, the combined approach points out the occurrence of various IMHBs and the effect of the chemical modulations on their features. Thus, two-center or three-center IMHB interactions are observed in these compounds, depending on the presence or absence of additional HB acceptors, such as methoxy or fluorine.

Synthesis of AB4-type carbohydrate scaffolds as branching units in the glycosciences

Carbohydrate scaffolds, functionalised according to an AB4-type, were prepared on the basis of α-d-mannopyranosides with various ethyl aglycone moieties, functionalised with ‘A’. Four functional groups ‘B’ were installed at positions 2, 3, 4, and 6 of the sugar ring. In particular, we were interested in preparing N3(NH2)4-functionalised mannosides as multifunctional branching units for further orthogonal derivatisation or immobilisation on surfaces. A detailed synthetic study was performed which revealed that an azido function ‘A’ had to be installed at an advanced stage of the synthesis for successful preparation of the desired AB4-type carbohydrate scaffolds. The most successful synthetic sequence involved tetra-cyanoethylation of a 2-benzyloxyethyl mannopyranoside and subsequent reduction with in situ Boc protection to achieve (NHBoc)4 functionalisation. Finally, the benzyloxyethyl aglycon was converted into the corresponding azidoethyl moiety to gain access to the desired N3(NHBoc)4-functionalised carbohydrate scaffold. Its utilisation was exemplified by straightforward synthesis of a photosensitive glycoconjugate and a tetravalent glycocluster. Such compounds may be immobilised on functional surfaces to serve as tools in cell adhesion studies.

Construction of quaternary stereocentres on carbohydrate scaffolds

This review describes a glimpse of the various strategies for constructing stereo-defined quaternary centres in densely functionalised carbohydrates moiety of structurally intriguing and biologically potent natural products and building blocks.