O-Alkylated heavy atom carbohydrate probes for protein X-ray crystallography: Studies towards the synthesis of methyl 2-O-methyl-L-selenofucopyranoside

• Roman Sommer,
• Dirk Hauck,
• Annabelle Varrot,
• Anne Imberty,
• Markus Künzler and
• Alexander Titz

Beilstein J. Org. Chem. 2016, 12, 2828–2833, doi:10.3762/bjoc.12.282

• are used as reactive glycosyl donors in the syntheses of oligosaccharides. In addition, such heavy atom analogs of natural glycosides are useful tools for structure determination of their lectin receptors using X-ray crystallography. Some lectins, e.g., members of the tectonin family, only bind to

• carbohydrate epitopes with O-alkylated ring hydroxy groups. In this context, we report the first synthesis of an O-methylated selenoglycoside, specifically methyl 2-O-methyl-L-selenofucopyranoside, a ligand of the lectin tectonin-2 from the mushroom Laccaria bicolor. The synthetic route required a strategic

• : carbohydrate chemistry; fucose; lectin; selenoglycoside; Introduction Since the discovery of seleno mercaptan by Siemens in 1847 [1], organoselenium compounds have attracted high attention. Besides their biological and pharmaceutical relevance, e.g., selenocysteine or ebselen [2][3][4][5], selenium-containing

Chemical probes for competitive profiling of the quorum sensing signal synthase PqsD of Pseudomonas aeruginosa

• Michaela Prothiwa,
• Dávid Szamosvári,
• Sandra Glasmacher and
• Thomas Böttcher

Beilstein J. Org. Chem. 2016, 12, 2784–2792, doi:10.3762/bjoc.12.277

• ) are the two best studied AQs (Figure 1A) [7]. A variety of virulence factors are under control of the pqs quorum sensing system, including the production of elastase, pyocyanin, PA-IL lectin, and rhamnolipids, as well as populations dynamic behaviours such as biofilm formation. However, the exact

Exploring architectures displaying multimeric presentations of a trihydroxypiperidine iminosugar

• Camilla Matassini,
• Stefania Mirabella,
• Andrea Goti,
• Inmaculada Robina,
• Antonio J. Moreno-Vargas and
• Francesca Cardona

Beilstein J. Org. Chem. 2015, 11, 2631–2640, doi:10.3762/bjoc.11.282

• (glycosidases) [1][2]. In quite sharp contrast the multivalent effect, widely investigated in the field of carbohydrate–lectin interactions [3], has remained essentially unexplored concerning glycosidase inhibition up to 2010. Indeed, the first examples of multivalent iminosugars gave disappointing results in

Are D-manno-configured Amadori products ligands of the bacterial lectin FimH?

• Tobias-Elias Gloe,
• Insa Stamer,
• Cornelia Hojnik,
• Tanja M. Wrodnigg and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2015, 11, 1096–1104, doi:10.3762/bjoc.11.123

• site of the type 1-fimbrial lectin FimH. Keywords: Amadori rearrangement; bacterial adhesion; C-mannosides; docking studies; FimH ligands; Introduction The Amadori rearrangement (AR) is the reaction in which aldohexoses react with suitable amines under acidic catalysis to 1-amino-1-deoxyketohexoses

• investigation of ligands for the bacterial lectin FimH [4] it has been our goal to investigate the Amadori rearrangement as a method to approach new FimH ligands. These are especially relevant in the context of an anti-adhesion therapy against bacterial infections [5][6]. As FimH-mediated adhesion to the

• glycosylated surface of host cells is a key step in infections caused by type 1-fimbriated bacteria, FimH antagonists that inhibit bacterial adhesion can be valuable for treatment of infectious diseases [7][8]. The structure of type 1-fimbrial lectin FimH has been elucidated in X-ray analysis [9][10][11

Multivalency as a chemical organization and action principle

• Rainer Haag

Beilstein J. Org. Chem. 2015, 11, 848–849, doi:10.3762/bjoc.11.94

• [8][9][10][11][12] and studies the scope of multivalent lectin-glycointeractions in galectins [13], with iminosugars [14] and carbohydrate mimetics [15]. This Thematic Series in the Beilstein Journal of Organic Chemistry also investigates the enhanced multivalent binding of protein scaffolds [16

Orthogonal dual-modification of proteins for the engineering of multivalent protein scaffolds

• Michaela Mühlberg,
• Michael G. Hoesl,
• Christian Kuehne,
• Jens Dernedde,
• Nediljko Budisa and
• Christian P. R. Hackenberger

Beilstein J. Org. Chem. 2015, 11, 784–791, doi:10.3762/bjoc.11.88

• (CuAAC) and oxime ligation. This method was applied to the conjugation of biotin and β-linked galactose residues to yield an enzymatically active thermophilic lipase, which revealed specific binding to Erythrina cristagalli lectin by SPR binding studies. Keywords: chemoselectivity; dual protein

• modification; lectin; multivalency; Introduction The chemical modification of proteins has been developed to a core discipline in chemical biology with diverse applications in all areas of the life sciences, including pharmacology, biophysics, biotechnology and cell biology [1][2][3][4]. In addition to the

• oxidative aldehyde formation at the N-terminus with NaIO4 [36][37][38][39][40][41]. With this approach, we aimed to engineer an artificial lectin-binding protein via chemical installation of several galactose moieties by CuAAC [18]. The second functionalization site at the protein’s N-terminus was

Probing multivalency in ligand–receptor-mediated adhesion of soft, biomimetic interfaces

• Stephan Schmidt,
• Hanqing Wang,
• Daniel Pussak,
• Simone Mosca and
• Laura Hartmann

Beilstein J. Org. Chem. 2015, 11, 720–729, doi:10.3762/bjoc.11.82

• water and drying. ConA (0.2 mg mL−1) in PBS buffer pH 7.4 was placed on the aldehyde-functionalized surfaces for 1 h [19]. and prior to the measurements washed with lectin binding buffer (10 mM HEPES pH 6, 50 mM NaCl, 1 mM MnCl2, 1 mM CaCl2). Reflection interference contrast microscopy (RICM) RICM on an

• domain NIH) and the mathematical software OriginPro (OriginLab, USA). 1 mL of lectin binding buffer pH 6 was added to the ConA-functionalized surface and PEG-Man SCPs were spread into the solution. The particles were sedimented and the contact radius and the particle radius were measured. Inhibition of

• the interaction was done by adding of α-methyl-D-mannose (300 µL, 1 mg mL−1) in lectin binding buffer to the suspension and well mixed so that all bound particles were detached from the surface. SCP adhesion measurement sketch (top): A mannose-functionalized PEG-SCP sediments onto a Concanavalin A

DNA display of glycoconjugates to emulate oligomeric interactions of glycans

• Alexandre Novoa and
• Nicolas Winssinger

Beilstein J. Org. Chem. 2015, 11, 707–719, doi:10.3762/bjoc.11.81

• the glycan–DNA conjugate (KA = 104–105 M−1) compared to glycan alone was observed with RCA120 lectin (Ricinus communis agglutinin) demonstrating the synergy of interactions amongst the glycan units along the DNA. As an alternative strategy to gain better control on the composition of DNA–glycan

• ]. Three galactosylated DNA conjugates with different lengths were obtained and mixed with the corresponding half-slide complementary DNA to obtain supramolecular oligomers forming galactoside clusters. The different assemblies were tested for their binding affinity to the RCA120 lectin showing a

• helical structure and thermal stability. Surface plasmon resonance (SPR) affinity measurements with murine C-type lectin receptor (mMGL) showed specific binding only for duplexes containing two or four Lewis-X units. Alternatively, Ebara and co-workers have shown that glycan–DNA conjugates can be accessed

Effects of RAMEA-complexed polyunsaturated fatty acids on the response of human dendritic cells to inflammatory signals

• Éva Rajnavölgyi,
• Renáta Laczik,
• Viktor Kun,
• Lajos Szente and
• Éva Fenyvesi

Beilstein J. Org. Chem. 2014, 10, 3152–3160, doi:10.3762/bjoc.10.332

• for monitoring DC activation based on its glycoprotein nature and the potential to act as both an activation and supression marker of DC depending on its monomeric or dimeric forms [45]. These functional attributes of CD83 offered us a potential tool for dissecting the protein and lectin mediated

Expeditive synthesis of trithiotriazine-cored glycoclusters and inhibition of Pseudomonas aeruginosa biofilm formation

• Meriem Smadhi,
• Sophie de Bentzmann,
• Anne Imberty,
• Marc Gingras,
• Raoudha Abderrahim and
• Peter G. Goekjian

Beilstein J. Org. Chem. 2014, 10, 1981–1990, doi:10.3762/bjoc.10.206

• good affinity for Pseudomonas aeruginosa lectin lecA. They are convenient biological probes for investigating the roles of lecA and lecB in biofilm formation. Keywords: antibiotic; biofilm; glycocluster; lectin; multivalency effect; multivalent glycosystems; Introduction Pseudomonas aeruginosa (PA

• promoting its dissolution is thus particularly appealing. Because the formation of PA biofilm is a complex process partly mediated by the D-galactose-specific lectin lecA (PA-IL) [7][8][9][10] and the L-fucose-specific lectin lecB (PA-IIL) [11][12][13], lectin-carbohydrate interactions can provide a new

• . Both homo- and heterobifunctional ligands are obtained by a straightforward preparative route, as an innovative approach. Additionally, isothermal titration calorimetry (ITC) and dynamic light scattering (DLS) helped to better understand lectin–ligand interactions between lecA or lecB and these

Convergent synthetic methodology for the construction of self-adjuvanting lipopeptide vaccines using a novel carbohydrate scaffold

• Vincent Fagan,
• Istvan Toth and
• Pavla Simerska

Beilstein J. Org. Chem. 2014, 10, 1741–1748, doi:10.3762/bjoc.10.181

• gave the novel carbohydrate building block 1 in 31% overall yield (Scheme 2). Similar carbohydrates have been used for the preparation of glycoclusters for lectin binding [25][26][27][28] and as scaffold carriers of multiple peptide antigens [17][29]. However, the synthesis of the new carbohydrate

Clicked and long spaced galactosyl- and lactosylcalix[4]arenes: new multivalent galectin-3 ligands

• Silvia Bernardi,
• Paola Fezzardi,
• Gabriele Rispoli,
• Stefania E. Sestito,
• Francesco Peri,
• Francesco Sansone and
• Alessandro Casnati

Beilstein J. Org. Chem. 2014, 10, 1672–1680, doi:10.3762/bjoc.10.175

• other one in the 1,3-alternate structure. Preliminary studies of the interactions of these novel glycocalixarenes with galectin-3 were carried out by using a lectin-functionalized chip and surface plasmon resonance. These studies indicate a higher affinity of lactosyl- over galactosylcalixarenes

• . Furthermore, we confirmed that in case of this specific lectin binding the presentation of lactose units on a cone calixarene is highly preferred with respect to its isomeric form in the 1,3-alternate structure. Keywords: glycocalixarenes; cluster glycoside effect; multivalency; click chemistry; surface

• 1,3-alternate structure. This confirms the data previously obtained in a series of inhibition experiments of the same lectin in surface-immobilized asialofetuin and on cells with the lactosylthioureidocalixarenes (I–III) [20][21]. A direct comparison with ligands (I–III) was, however, not feasible

Photoswitchable precision glycooligomers and their lectin binding

• Daniela Ponader,
• Sinaida Igde,
• Marko Wehle,
• Katharina Märker,
• Mark Santer,
• David Bléger and
• Laura Hartmann

Beilstein J. Org. Chem. 2014, 10, 1603–1612, doi:10.3762/bjoc.10.166

• azobenzene unit allows for the photosensitive control of glycoligand binding to protein receptors. These stimuli-sensitive glycoligands promote the understanding of multivalent binding and will be further developed as novel biosensors. Keywords: azobenzene; glycopolymer; lectin binding; multivalency

• synthesized. The photoswitchable behavior of all azobenzene-containing glycooligomers was evaluated along with their photoswitchable binding affinities towards PA-IL (also called LecA) as targeted lectin receptor [23]. Results and Discussion Synthesis of photoswitchable precision glycooligomers The synthesis

• )-5 Z-isomers is anticipated to be very similar since their two azo units were found to operate independently. The long-lived Z-forms of these glycoconjugates allows for a convenient handling of the PSS mixtures and a precise measurement of their binding affinities. Lectin binding studies Competition

Multivalent scaffolds induce galectin-3 aggregation into nanoparticles

• Candace K. Goodman,
• Mark L. Wolfenden,
• Pratima Nangia-Makker,
• Anna K. Michel,
• Avraham Raz and
• Mary J. Cloninger

Beilstein J. Org. Chem. 2014, 10, 1570–1577, doi:10.3762/bjoc.10.162

• solution. Taken together, these data support aggregate initiation as a response to specific carbohydrate binding interactions between lectin and glycodendrimer. They also reveal the significance of the N-terminal domain in formation of higher order aggregates. The presence of these aggregates was confirmed

• has been previously determined using turbidity and precipitation assays that carbohydrate-functionalized dendrimers induce lectin aggregation, the consistent formation of large nanoparticles has to our knowledge not been previously identified and characterized. The most likely explanation for the

• at molar ratios of 9:1 galectin:glycodendrimer were largest while 220:1 and 3:1 ratios produced smaller complexes. The difference in aggregate sizes may relate to the size and shape complementarity between dendrimer and lectin or to the interplay of enthalpic and entropic contributions to aggregate

Orthogonal dual thiol–chloroacetyl and thiol–ene couplings for the sequential one-pot assembly of heteroglycoclusters

• Michele Fiore,
• Gour Chand Daskhan,
• Baptiste Thomas and
• Olivier Renaudet

Beilstein J. Org. Chem. 2014, 10, 1557–1563, doi:10.3762/bjoc.10.160

• (Scheme 1). Such derivatives have proved to be useful in bioconjugates chemistry [25] and for the preparation of thioether-linked tetravalent glycocyclopeptides which have shown highest inhibition against a model lectin in comparison with analogues bearing oxime and triazole linkage [26]. Glycosyl thiols

Synthesis and solvodynamic diameter measurements of closely related mannodendrimers for the study of multivalent carbohydrate–protein interactions

• Yoann M. Chabre,
• Alex Papadopoulos,
• Alexandre A. Arnold and
• René Roy

Beilstein J. Org. Chem. 2014, 10, 1524–1535, doi:10.3762/bjoc.10.157

• more insight into this direction, we designed herein three families of closely related mannopyranoside clusters (glycodendrimers) aimed at evaluating their relative binding abilities against the hometetrameric leguminous lectin ConA from Canavalia ensiformis by inhibition of haemagglutination and by

• lectins such as ConA [43] and the LecA lectin from Pseudomonas aeruginosa [17]. With these closely related families of mannosylated dendrimers in hand, together with their known relative size in solution, we are now well positioned to evaluate their binding behavior against their cognate proteins and this

Bis(β-lactosyl)-[60]fullerene as novel class of glycolipids useful for the detection and the decontamination of biological toxins of the Ricinus communis family

• Hirofumi Dohi,
• Takeru Kanazawa,
• Akihiro Saito,
• Keita Sato,
• Hirotaka Uzawa,
• Yasuo Seto and
• Yoshihiro Nishida

Beilstein J. Org. Chem. 2014, 10, 1504–1512, doi:10.3762/bjoc.10.155

• notable biological and physical properties. For example, bis(α-D-mannopyranosyl)-[60]fullerene is capable of forming a liposome-like supramolecule in aqueous media and exhibits a strong binding activity to an α-mannose-binding lectin (concanavalin A, Con A) as the result not only of carbohydrate cluster

• , precipitation tests were conducted with Ricinus communis agglutinin (RCA120) [27], ricin and concanavalin A (Con A) [28]. RCA120 is a ricin-like lectin and able to bind β-galactose residues. Con A is an α-mannose-specific lectin. When RCA120 (10 μL, 20 μg mL−1) was added to this suspension (0.1 mL, 300 μM), the

• suspension soon gave rise to dark brown precipitate (Figure 2a). The precipitate was collected by centrifugation, washed thoroughly with water, and then applied to SDS-PAGE. A clear band was observed at the region matching with RCA120, supporting that this lectin was directly associated with the

Synthesis of the first examples of iminosugar clusters based on cyclopeptoid cores

• Mathieu L. Lepage,
• Alessandra Meli,
• Anne Bodlenner,
• Céline Tarnus,
• Francesco De Riccardis,
• Irene Izzo and
• Philippe Compain

Beilstein J. Org. Chem. 2014, 10, 1406–1412, doi:10.3762/bjoc.10.144

• to 2 orders of magnitude more efficient as CFTR correctors than the clinical candidate miglustat (N-Bu-DNJ, 1, Figure 1). The mechanisms underlying the inhibitory multivalent effect were studied with different methods such as isothermal titration calorimetry, competitive lectin-enzyme assays, X-ray

Molecular recognition of surface-immobilized carbohydrates by a synthetic lectin

• Melanie Rauschenberg,
• Eva-Corrina Fritz,
• Christian Schulz,
• Tobias Kaufmann and
• Bart Jan Ravoo

Beilstein J. Org. Chem. 2014, 10, 1354–1364, doi:10.3762/bjoc.10.138

• wide range of physiological processes and the development of synthetic carbohydrate receptors (“synthetic lectins”) constitutes a key advance in biomedical technology. In this article we report a synthetic lectin that selectively binds to carbohydrates immobilized in a molecular monolayer. Inspired by

• our previous work, we prepared a fluorescently labeled synthetic lectin consisting of a cyclic dimer of the tripeptide Cys-His-Cys, which forms spontaneously by air oxidation of the monomer. Amine-tethered derivatives of N-acetylneuraminic acid (NANA), β-D-galactose, β-D-glucose and α-D-mannose were

• microcontact printed on epoxide-terminated self-assembled monolayers. Successive prints resulted in simple microarrays of two carbohydrates. The selectivity of the synthetic lectin was investigated by incubation on the immobilized carbohydrates. Selective binding of the synthetic lectin to immobilized NANA and

Human dendritic cell activation induced by a permannosylated dendron containing an antigenic GM₃-lactone mimetic

• Renato Ribeiro-Viana,
• Elena Bonechi,
• Javier Rojo,
• Clara Ballerini,
• Giuseppina Comito,
• Barbara Richichi and
• Cristina Nativi

Beilstein J. Org. Chem. 2014, 10, 1317–1324, doi:10.3762/bjoc.10.133

• persistence, the timing and the pathways essential for enhancing DC maturation and for licensing the antigen-loaded DCs in the T cell zone of lymph nodes [10]. Concerning the DCs maturation step, triggering C-type lectin receptors (CLRs) is crucial to enhance the antitumor immunity [10][20]. In particular

• mannose for DC targeting and one residue of the mimetic 3 as a carbohydrate melanoma-associated antigen. We have previously demonstrated that a glycodendron bearing nine copies of the monosaccharide mannose can be taken up by DCs in a receptor-dependent manner by means of the lectin DC-SIGN [34]. This

Molecular architecture with carbohydrate functionalized β-peptides adopting 3₁₄-helical conformation

• Nitin J. Pawar,
• Navdeep S. Sidhu,
• George M. Sheldrick,
• Dilip D. Dhavale and
• Ulf Diederichsen

Beilstein J. Org. Chem. 2014, 10, 948–955, doi:10.3762/bjoc.10.93

• , xylose) as sugar-β-amino acids in a 314-helix. Up to three sugar units were linearly aligned with 5 Å distance (Figure 1). This kind of sugar organization will be of later relevance, e.g., in lectin binding studies and with respect to the investigation of multivalency effects [21][22][23]. The use of

Synthesis of homo- and heteromultivalent carbohydrate-functionalized oligo(amidoamines) using novel glyco-building blocks

• Felix Wojcik,
• Sinaida Lel,
• Alexander G. O’Brien,
• Peter H. Seeberger and
• Laura Hartmann

Beilstein J. Org. Chem. 2013, 9, 2395–2403, doi:10.3762/bjoc.9.276

• branched) [18] and biocompatible with a decreased risk of inherent immunogenicity [19]. Recently, we showed that monodisperse, sequence-defined glycooligomers obtained by sequential addition of building blocks on solid support are valuable tools for tuning and understanding carbohydrate–lectin interactions

Synthesis and testing of the first azobenzene mannobioside as photoswitchable ligand for the bacterial lectin FimH

• Vijayanand Chandrasekaran,
• Katharina Kolbe,
• Femke Beiroth and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2013, 9, 223–233, doi:10.3762/bjoc.9.26

• powerful antagonists is highly desirable, however, ideally on demand, that is, in a specific and spatially as well as temporally resolved way. Often bacterial adhesion depends on the interaction of adhesive organelles called fimbriae. They project from the surface of bacteria and contain lectin domains to

• -mannosyl-specific lectin FimH at the tip of the fimbrial shaft. FimH antagonists are currently considered as new therapeutics for the treatment of urinary tract infections [6]. The carbohydrate specificity of FimH has been investigated in great detail [7] and its structure is well-known from several X-ray

• both isomers of 2 are equally potent inhibitors of type 1 fimbriae-mediated bacterial adhesion, similar to the power of the well-known mannoside pNPMan. In order to support the interpretation of the obtained test results, binding of (E)-2 and (Z)-2 to the bacterial lectin FimH was investigated by

Efficient synthesis of phenylene-ethynylene rods and their use as rigid spacers in divalent inhibitors

• Francesca Pertici,
• Norbert Varga,
• Arnoud van Duijn,
• Matias Rey-Carrizo,
• Anna Bernardi and
• Roland J. Pieters

Beilstein J. Org. Chem. 2013, 9, 215–222, doi:10.3762/bjoc.9.25

• phenylene units. Preliminary applications of these rods in divalent systems are shown. Inhibition studies with Pseudomonas Aeruginosa lectin LecA showed that the rigid spacer proved greatly beneficial for the inhibitory potency. Keywords: multivalent carbohydrates; LecA inhibition; phenylene ethynylene

• of aromatic rings. One of the spacers was incorporated into the structure of a divalent galactoside ligand and was used to inhibit the virulence-linked lectin LecA of Pseudomonas aeruginosa [27][28]. Results and Discussion Synthetic strategies Depending on the number of units in the spacer, two

• obtained after deprotection of the alkyne moieties with K2CO3. Preliminary application As part of our program on bacterial adhesion inhibition by multivalent carbohydrates, the bacterial lectin LecA, a virulence factor of the problematic pathogen Pseudomonas aeruginosa is a target of interest [30][31

Mannose-decorated cyclodextrin vesicles: The interplay of multivalency and surface density in lectin–carbohydrate recognition

• Ulrike Kauscher and
• Bart Jan Ravoo

Beilstein J. Org. Chem. 2012, 8, 1543–1551, doi:10.3762/bjoc.8.175

• be modified by host–guest interactions with functional guest molecules. In this article, we investigate the multivalent interaction of the lectin concanavalin A (ConA) with cyclodextrin vesicles decorated with mannose–adamantane conjugates with one, two or three adamantane units as well as one or two

• mannose units. The carbohydrate–lectin interaction in this artificial, self-assembled glycocalyx was monitored in an agglutination assay by the increase of optical density at 400 nm. It was found that there is a close relation between the carbohydrate density at the cyclodextrin vesicle surface and the

• multivalent interaction with ConA, and the most efficient interaction (i.e., fastest agglutination at lowest concentration) was observed for mannose–adamantane conjugates, in which both the cyclodextrin–adamantane and the lectin–mannose interaction is inherently multivalent. Keywords: carbohydrates