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

• carbohydrate ligands to the protein barstar [18]. In the current study, we aimed to extend this approach to the dual modification of proteins using a combination of two chemoselective, orthogonal conjugation reactions for the introduction of glycan ligands and biotin to a protein. Our main objective in this

• conjugated with biotin using oxime ligation, by which the protein scaffold was immobilized on a streptavidin gold chip to monitor carbohydrate–protein binding studies by surface plasmon resonance (SPR). This immobilization strategy allowed easy handling and reproducible orientation, which are notable

• , different linker lengths should be probed to allow better binding of multiple carbohydrate units of one protein scaffold with multiple binding sites of one lectin molecule. Conclusion In conclusion, we succeeded in the incorporation of two unnatural functional groups, namely azides and aldehydes, into a

Glycodendrimers: tools to explore multivalent galectin-1 interactions

• Jonathan M. Cousin and
• Mary J. Cloninger

Beilstein J. Org. Chem. 2015, 11, 739–747, doi:10.3762/bjoc.11.84

• activity through multivalent interactions with cell surface glycoconjugates [1][2][3][4]. Galectin-1 is a non-covalent homodimer that belongs to a family of β-galactoside binding proteins called galectins [5][6][7]. The monomeric units are oriented such that the two carbohydrate recognition domains are

• very effectively used to organize proteins into biologically active arrays. Results Nanoparticle formation Poly(amidoamine) (PAMAM) dendrimers were used as a multivalent framework to study multivalent protein–carbohydrate interactions. The PAMAM structure is shown in Figure 2a. Second, third, fourth

• lactose endgroups on the dendrimers and the carbohydrate recognition site of galectin-1 occurs when nanoparticles are formed (Figure 6). Control experiments were performed with different functional groups on the multivalent framework. No aggregates were detected upon the addition of a polyhydroxylated

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

• , Institut für Organische und Makromolekulare Chemie, Universitätsstr. 1, 40225 Düsseldorf, Germany 10.3762/bjoc.11.82 Abstract Many biological functions at cell level are mediated by the glycocalyx, a dense carbohydrate-presenting layer. In this layer specific interactions between carbohydrate ligands and

• a concanavalin A (ConA) layer via poly(ethylene glycol)-(PEG)-based soft colloidal probes (SCPs). Special emphasis is on the dependence of multivalent presentation and density of carbohydrate units on specific adhesion. Consequently, we first present a synthetic strategy that allows for controlled

• type. Remarkably, the results indicated the absence of a molecular-level enhancement of mannose/ConA interaction due to chelate- or subsite-binding. The results seem to support the fact that weak carbohydrate interactions at mechanically flexible interfaces hardly undergo multivalent binding but are

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

• Alexandre Novoa Nicolas Winssinger Department of Organic Chemistry, NCCR Chemical Biology, University of Geneva 30, quai Ernest Ansermet, 1211 Geneva, Switzerland 10.3762/bjoc.11.81 Abstract Glycans (carbohydrate portion of glycoproteins and glycolipids) frequently exert their function through

• oligomeric interactions involving multiple carbohydrate units. In efforts to recapitulate the diverse spatial arrangements of the carbohydrate units, assemblies based on hybridization of nucleic acid conjugates have been used to display simplified ligands with tailored interligand distances and valences. The

• ]. The first method reported was leveraged on a nucleophilic coupling between readily available glycosyl thiol (obtained in one step by treatment of a native carbohydrate with Lawesson’s reagent [37]) and a chloroacetamide-functionalized PNA (Scheme 7) [38][39]. Using this method, we have shown that

Synthesis of carbohydrate-scaffolded thymine glycoconjugates to organize multivalency

• Anna K. Ciuk and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2015, 11, 668–674, doi:10.3762/bjoc.11.75

• Anna K. Ciuk Thisbe K. Lindhorst Christiana Albertina University of Kiel, Otto Diels Institute of Organic Chemistry, Otto-Hahn-Platz 3/4, D-24118 Kiel, Germany, Fax: +49 431 8807410 10.3762/bjoc.11.75 Abstract Multivalency effects are essential in carbohydrate recognition processes as occurring

• on the cell surface. Thus many synthetic multivalent glycoconjugates have been developed as important tools for glycobiological research. We are expanding this collection of molecules by the introduction of carbohydrate-scaffolded divalent glycothymine derivatives that can be intramolecularily

• ] photocycloaddition; carbohydrate scaffolds; multivalency; thymine glycoconjugates; Introduction Multivalency of molecular interactions is a fundamental principle in carbohydrate recognition. It influences the avidity and specificity of carbohydrate–protein interactions as well as it enables supramolecular changes

Design, synthesis and photochemical properties of the first examples of iminosugar clusters based on fluorescent cores

• Mathieu L. Lepage,
• Antoine Mirloup,
• Manon Ripoll,
• Fabien Stauffert,
• Anne Bodlenner,
• Raymond Ziessel and
• Philippe Compain

Beilstein J. Org. Chem. 2015, 11, 659–667, doi:10.3762/bjoc.11.74

• the endocyclic oxygen have been reported in the literature [1][2]. Iminosugars are mainly known to be inhibitors of a number of carbohydrate-processing enzymes with an emphasis on glycosidases [1][2]. In the early 2000’s, iminosugars were, remarkably, found to inhibit metalloproteinases [3], protein

Synthesis of multivalent carbohydrate mimetics with aminopolyol end groups and their evaluation as L-selectin inhibitors

• Joana Salta,
• Jens Dernedde and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2015, 11, 638–646, doi:10.3762/bjoc.11.72

• Platz 1, D-13353 Berlin, Germany 10.3762/bjoc.11.72 Abstract In this article a series of divalent and trivalent carbohydrate mimetics on the basis of an enantiopure aminopyran and of serinol is described. These aminopolyols are connected by amide bonds to carboxylic acid derived spacer units either by

• compounds could not be tested as L-selectin inhibitor by SPR due to their insolubility in water, nevertheless, a divalent and a trivalent amide showed surprisingly good activities with IC50 values in the low micromolar range. Keywords: aminopolyols; carbohydrate mimetics; carboxylic acid amides; inhibition

• ; multivalency; selectins; sulfation; Introduction In a series of publications [1][2][3][4][5][6] our group reported on the syntheses of carbohydrate mimetics [7][8][9][10][11] that are based on aminopyrans, aminooxepanes or other aminopolyols. These compounds and their conjugates were prepared to be examined

Automated solid-phase synthesis of oligosaccharides containing sialic acids

• Chian-Hui Lai,
• Heung Sik Hahm,
• Chien-Fu Liang and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2015, 11, 617–621, doi:10.3762/bjoc.11.69

• carbohydrate antigens (TACAs) such as the sialyl-Tn antigen (sTn) [2]. Neu5Ac is often the terminal residue and is usually linked via an α-(2,3) or α-(2,6) linkage to galactose (Gal) (Figure 1) [3]. Automated glycan assembly enables rapid access to structurally defined oligosaccharides [4][5] including

• synthesis in the future as well. The tumor associated sTn carbohydrate antigen (Neu5Ac-α(2,6)GalNAc-α(1,1)linker) disaccharide 17, that resembles the sTn antigen glycan framework (Neu5Ac-α(2,6)GalNAc-α(1,1)Ser/Thr) was synthesized. In order to install the cis-glycoside formed by the union of the

Synthesis of 1,2-cis-2-C-branched aryl-C-glucosides via desulfurization of carbohydrate based hemithioacetals

• Henok H. Kinfe,
• Fanuel M. Mebrahtu,
• Mandlenkosi M. Manana,
• Kagiso Madumo and
• Mokela S. Sokamisa

Beilstein J. Org. Chem. 2015, 11, 583–588, doi:10.3762/bjoc.11.64

• biologically important compounds. Although the synthesis of such carbohydrate derivatives is extensively studied, the synthesis of 1,2-cis-2-C-branched C-, S-, and N-glycosides is less explored. In this article a synthetic strategy for the synthesis of 1,2-cis-2-C-branched-aryl-C-glucosides is reported via a

• hydrogenolytic desulfurization of suitably orientated carbohydrate based hemithioacetals. 1,2-cis-2-Hydroxymethyl and 2-carbaldehyde of aryl-C-glucosides have been synthesized using the current strategy in very good yields. The 2-carbaldehyde-aryl-C-glucosides have been identified as suitable substrates for the

• stereospecific preparation of 2,3-unsaturated-aryl-C-glycosides (Ferrier products). Keywords: aryl-C-glucoside; desulfurization; Ferrier product; hemithioacetal; Introduction 1-C (C-glycosides) and 2-C-branched carbohydrates are important carbohydrate analogues which have found wide application in

Synthesis and biological evaluation of a novel MUC1 glycopeptide conjugate vaccine candidate comprising a 4’-deoxy-4’-fluoro-Thomsen–Friedenreich epitope

• Manuel Johannes,
• Maximilian Reindl,
• Bastian Gerlitzki,
• Edgar Schmitt and
• Anja Hoffmann-Röder

Beilstein J. Org. Chem. 2015, 11, 155–161, doi:10.3762/bjoc.11.15

• cells from healthy ones by means of tumor-associated antigens (TACA), e.g., partial structures of the mucin glycoprotein MUC1 [6][7]. Cancer-associated MUC1 is characterized by the presence of specifically altered carbohydrate side chains in its extracellular tandem-repeat domain due to fundamental

• , which becomes accessible to the immune system and can be used as an additional immunogenic determinant for carbohydrate-based cancer vaccines [13]. Despite encouraging results with two- and three-component MUC1 conjugate vaccines in mice models [14][15][16][17][18][19][20][21][22][23][24][25], immune

• tolerance to carbohydrate antigens remains a major obstacle in initiating an effective and long-lasting immune protection against malignancies. One strategy to enhance the immunogenicity of carbohydrate antigens relies upon modification of the glycan hapten [26][27], which renders it more foreign to the

A carbohydrate approach for the formal total synthesis of (−)-aspergillide C

• Pabbaraja Srihari,
• Namballa Hari Krishna,
• Ydhyam Sridhar and
• Ahmed Kamal

Beilstein J. Org. Chem. 2014, 10, 3122–3126, doi:10.3762/bjoc.10.329

Synthesis and characterization of pH responsive D-glucosamine based molecular gelators

• Navneet Goyal,
• Hari P. R. Mangunuru,
• Bargav Parikh,
• Sonu Shrestha and
• Guijun Wang

Beilstein J. Org. Chem. 2014, 10, 3111–3121, doi:10.3762/bjoc.10.328

• ]. Several pH responsive small molecular gelators have been designed and synthesized and have shown a variety of potential applications [29][30][31][32][33][34]. Among the different classes of LMWGs, carbohydrate-based systems are especially interesting due to their potential applications in biomedical

A general metal-free approach for the stereoselective synthesis of C-glycals from unactivated alkynes

• Shekaraiah Devari,
• Manjeet Kumar,
• Ramesh Deshidi,
• Masood Rizvi and
• Bhahwal Ali Shah

Beilstein J. Org. Chem. 2014, 10, 2649–2653, doi:10.3762/bjoc.10.277

• single step from a variety of acetylenes , i.e., arylacetylenes and most importantly aliphatic alkynes. Keywords: α-selective; C-alkynylation; glycal; metal free; TMSOTf; Introduction C-Glycosides represent an important class of carbohydrate mimics, owing to their presence in a large number of

• particular interest as it is amenable to further modifications into chiral molecules, carbohydrate analogues, and natural products, such as tautomycin [17][18] and ciguatoxin [19][20][21]. In recent past, significant efforts have been directed toward the C-alkynylation of glycals [9][22][23]. However, all

Formal total syntheses of classic natural product target molecules via palladium-catalyzed enantioselective alkylation

• Yiyang Liu,
• Marc Liniger,
• Ryan M. McFadden,
• Jenny L. Roizen,
• Jacquie Malette,
• Corey M. Reeves,
• Douglas C. Behenna,
• Masaki Seto,
• Jimin Kim,
• Justin T. Mohr,
• Scott C. Virgil and
• Brian M. Stoltz

Beilstein J. Org. Chem. 2014, 10, 2501–2512, doi:10.3762/bjoc.10.261

• . This publication highlights recent methods for setting quaternary and tetrasubstituted tertiary carbon stereocenters to address the synthetic hurdles encountered over many decades across multiple compound classes spanning carbohydrate derivatives, terpenes, and alkaloids. These enantioselective methods

Synthesis of aromatic glycoconjugates. Building blocks for the construction of combinatorial glycopeptide libraries

• Markus Nörrlinger and
• Thomas Ziegler

Beilstein J. Org. Chem. 2014, 10, 2453–2460, doi:10.3762/bjoc.10.256

• difficult despite the great achievements in this field during the past decades. Therefore, the application of oligosaccharide mimetics which may be synthesized more easily in larger amounts appears to be a useful tool to investigate, for instance, specific carbohydrate–protein or carbohydrate–carbohydrate

• interactions. Recently our group has prepared a series of trifunctional glycopeptide building blocks with aliphatic backbones, which allow for the automated construction of combinatorial libraries of highly divers glycopeptides suitable for studying carbohydrate–protein interactions [5][6][7][8]. Hitherto, our

A versatile δ-aminolevulinic acid (ΑLA)-cyclodextrin bimodal conjugate-prodrug for PDT applications with the help of intracellular chemistry

• Chrysie Aggelidou,
• Theodossis A. Theodossiou,
• Antonio Ricardo Gonçalves,
• Mariza Lampropoulou and
• Konstantina Yannakopoulou

Beilstein J. Org. Chem. 2014, 10, 2414–2420, doi:10.3762/bjoc.10.251

• hydrophobic cavity [7]. The cyclodextrins (CDs) are a notable family of semi-natural carbohydrate molecules approved as pharmaceutical excipients that improve the solubility and bioavailability of drugs through molecular encapsulation. We demonstrated [6] the conjugate’s (PpIX-CD) bimodal action of

Synthesis and immunological evaluation of protein conjugates of Neisseria meningitidis X capsular polysaccharide fragments

• Laura Morelli,
• Damiano Cancogni,
• Marta Tontini,
• Alberto Nilo,
• Sara Filippini,
• Paolo Costantino,
• Maria Rosaria Romano,
• Francesco Berti,
• Roberto Adamo and
• Luigi Lay

Beilstein J. Org. Chem. 2014, 10, 2367–2376, doi:10.3762/bjoc.10.247

• infections is still unknown. Over the recent years, advances in the synthesis of complex glycans are rendering accessible a variety of carbohydrate antigens with well-defined chemical structure and devoid of bacterial contaminations which could derive from purification of biological materials [21][22][23][24

• excess of unconjugated carbohydrate by precipitation with ammonium sulfate and reconstitution in 10 mM NaPi pH 7.2. The occurrence of conjugation was assessed by SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis) and MALDI–TOF mass spectrometry (see Supporting Information File 1). The

• same conjugation chemistry and different carbohydrate structures [26][27]. However, it needs to be taken in consideration that this loading is comparable to that achieved in the preparation of anti-meningococcal vaccines commercially available [37]. Furthermore, a number of 2.5 and 1.7–4.1 sugar

Multivalent glycosystems for nanoscience

• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2014, 10, 2345–2347, doi:10.3762/bjoc.10.244

• this field of research. Now, a third “sweet” Thematic Series is presented in which the borderline between Alice’s Wonderland and real-life applications of carbohydrates has been deliberately crossed. The structural world of natural sugars has been extended towards artificial carbohydrate architectures

Expanding the scope of cyclopropene reporters for the detection of metabolically engineered glycoproteins by Diels–Alder reactions

• Anne-Katrin Späte,
• Verena F. Schart,
• Julia Häfner,
• Andrea Niederwieser,
• Thomas U. Mayer and
• Valentin Wittmann

Beilstein J. Org. Chem. 2014, 10, 2235–2242, doi:10.3762/bjoc.10.232

• found application in MOE, and several dienophiles, such as terminal alkenes [19], isonitriles [20][21], and cyclopropenes [22][23][24], have been incorporated in carbohydrate derivatives and detected by reaction with 1,2,4,5-tetrazines [25] (Scheme 1). An important advantage of the DAinv reaction is the

Indium-mediated allylation in carbohydrate synthesis: A short and efficient approach towards higher 2-acetamido-2-deoxy sugars

• Christopher Albler,
• Ralph Hollaus,
• Hanspeter Kählig and
• Walther Schmid

Beilstein J. Org. Chem. 2014, 10, 2230–2234, doi:10.3762/bjoc.10.231

• Christopher Albler Ralph Hollaus Hanspeter Kahlig Walther Schmid Department of Organic Chemistry, University of Vienna, Währingerstrasse 38, 1090 Vienna, Austria 10.3762/bjoc.10.231 Abstract Higher aminosugars are interesting targets in carbohydrate synthesis since these compounds play important

De novo macrolide–glycolipid macrolactone hybrids: Synthesis, structure and antibiotic activity of carbohydrate-fused macrocycles

• Richard T. Desmond,
• Anniefer N. Magpusao,
• Chris Lorenc,
• Jeremy B. Alverson,
• Nigel Priestley and
• Mark W. Peczuh

Beilstein J. Org. Chem. 2014, 10, 2215–2221, doi:10.3762/bjoc.10.229

• . Glycosylation of an available hydroxy group on the macrocycle gave a hybrid macrolide with features common to erythromycin and sophorlipid macrolactone. Weak antibiotic activity (MICs <100 μg/mL) was observed for several of the compounds. Keywords: antibiotic; carbohydrate; exo-anomeric effect; macrolide

• ; structure; synthesis; Introduction In contemporary usage, “macrolide” describes any large ring lactone [1]. It was originally coined, however, with reference to a narrower set of compounds: antimicrobial natural products containing a macrolactone ring adorned with deoxygenated carbohydrate residues [2

• ], have investigated compounds that blend features of macrolides and glycolipid lactones. These natural product-like compounds fuse the carbohydrate ring to the macrocycle rather than connecting them through a glycosidic linkage. Compounds 3 and 4 in Figure 1 illustrate one approach that has been reported

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

• 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

• bioactivity of these lectins in host recognition and adhesion in biofilm formation represents an attractive antibacterial strategy, as multivalent carbohydrate motifs on cell surfaces are known to mediate a broad range of cellular and tissue adhesion processes. Carbohydrate recognition in biological systems

• high density of proximate carbohydrate epitopes with limited degrees of freedom onto a sulfurated heteroaromatic scaffold as novel glycosylated asterisk ligands [30]. We have thus designed a simple, yet effective new family of multivalent glycosylated architectures built around a trithiotriazine core

Reaction of selected carbohydrate aldehydes with benzylmagnesium halides: benzyl versus o-tolyl rearrangement

• Maroš Bella,
• Bohumil Steiner,
• Vratislav Langer and
• Miroslav Koóš

Beilstein J. Org. Chem. 2014, 10, 1942–1950, doi:10.3762/bjoc.10.202

• possible mechanism for the Grignard reaction leading to the benzyl→o-tolyl rearrangement is also proposed. Keywords: aldehyde; benzyl versus o-tolyl; carbohydrate; Grignard reaction; rearrangement; X-ray crystallography; Introduction One of the most popular synthetic routes leading to the formation of

• possible the preparation of a series of useful carbohydrate derivatives [1][2][3][4][5][6][7][8]. Despite the demonstrable advantages of the Grignard reaction, there remain, in addition to the recognised drawbacks, some new unexpected impediments limiting its application in the synthesis of branched

• more detailed inspection. Results and Discussion Although 1 and 2 have frequently been used for the introduction of the benzyl group into a carbohydrate molecule [12][13][14][15][16][17][18], the benzyl→o-tolyl rearrangement has, to the best of our knowledge, only been reported once. In this regard

Synthesis of rigid p-terphenyl-linked carbohydrate mimetics

• Maja Kandziora and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2014, 10, 1749–1758, doi:10.3762/bjoc.10.182

• Maja Kandziora Hans-Ulrich Reissig Freie Universität Berlin, Institut für Chemie und Biochemie, Takustraße 3, D-14195 Berlin, Germany 10.3762/bjoc.10.182 Abstract An approach to β-D-2-aminotalose- and β-D-2-aminoidose-configured carbohydrate mimetics bearing a phenyl substituent is described

• -couplings to form biphenyl aminopyran or p-terphenyl-linked dimers. Hydrogenolysis afforded new unnatural aminosugar mimetics. Zinc in the presence of acid or samarium diiodide were examined for the N–O bond cleavage in order to obtain the rigid p-terphenyl-linked C-glycosyl dimers. Keywords: carbohydrate

• -glycosides which possess structural and functional aspects of the corresponding carbohydrates, these disadvantages can be overcome, resulting in an improved bioavailability, higher affinities and improved selectivities [8][9][10][11][12][13]. Recent results indicate that divalent rigid carbohydrate

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

• carbohydrate building block was coupled to the self-adjuvanting lipidic moiety (three lipidated Fmoc-lysines) on solid support. Four copies of a group A streptococcal B cell epitope (J8) were then conjugated to the glyco-lipopeptide using a copper-catalyzed cycloaddition reaction. The approach was elaborated

• severe GAS related problems are post-streptococcal rheumatic fever and rheumatic heart disease, which are responsible for over half a million deaths annually [14]. Previously, we developed methodologies for the synthesis of carbohydrate building blocks as scaffold carriers of multiple B cell epitopes

• derived from GAS. The vaccine constructs consisted of the LCP adjuvanting moiety, and a carbohydrate core bearing four copies of a GAS B cell epitope [11][15][16][17][18]. When administered to B10.BR (H-2k) mice, the carbohydrate-based LCP vaccines elicited high serum IgG antibody titres [11]. One of the