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

• binary combinations of α-D-Man or β-D-GlcNAc, thus providing rapid access to attractive heteroglycosylated platforms for diverse biological applications. Keywords: chemoselective ligation; heteroglycocluster; multivalency; multivalent glycosystems; one-pot synthesis; Introduction Multivalent

• carbohydrate–protein interactions are complex mechanisms that play key roles in biology [1]. To decipher, exploit or inhibit these recognition processes, a large variety of synthetic multivalent glycoconjugates have been developed over the last decade [2][3][4]. For a long time, these structures have

• capitalized on the utilization of a core scaffold decorated with identical sugars which are covalently linked through various spacers. While mimicking the multivalent sugar display of biological systems, these structures poorly reflect their inherent heterogenicity which hampers progresses towards the

A promising cellulose-based polyzwitterion with pH-sensitive charges

• Thomas Elschner and
• Thomas Heinze

Beilstein J. Org. Chem. 2014, 10, 1549–1556, doi:10.3762/bjoc.10.159

• . Keywords: carbonate; cellulose; complexation; multivalent glycosystems; NMR; polyzwitterion; Introduction Ionic polymers are important naturally occurring macromolecules and various synthetic polyelectrolytes play an important role in commercial applications [1]. Naturally occurring biopolymers are for

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

• families of mannopyranoside-containing dendrimers for the purpose of studying subtle structural parameters involved in the measurements of multivalent carbohydrate–protein binding interactions. Toward this goal, two trimers 5 and 9, three 9-mers 12, 17, 21, and one 27-mer 23, varying by the number of atoms

• 9-mer 12, 17, and 21 were determined by pulsed-field-gradient-stimulated echo (PFG-STE) NMR experiments and were found to be 3.0, 2.5, and 3.4 nm, respectively. Keywords: carbohydrates; click chemistry; dendrimers; glycodendrimers; lectins; multivalent glycosystems; Introduction Multivalent

• supported by the recent findings that the sugar backbones themselves also possess a hydrophobic side that orients the sugars in appropriate aromatic amino acid rich pockets [26][27][28]. Unfortunately, due to the inherent complexity of studying multivalent binding interactions, researchers have used

Why a diaminopyrrolic tripodal receptor binds mannosides in acetonitrile but not in water?

• Diogo Vila-Viçosa,
• Oscar Francesconi and
• Miguel Machuqueiro

Beilstein J. Org. Chem. 2014, 10, 1513–1523, doi:10.3762/bjoc.10.156

• : conformational analysis; constant-pH MD; mannose; multivalent glycosystems; pH; synthetic receptor; Introduction The recognition of specific carbohydrates is an important step in several biological processes [1]. To better understand these recognition processes, several synthetic receptors have been developed

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

• quantified by means of sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and the results were discussed in terms of detection and decontamination of the deadly biological toxin in the Ricinus communis family. Keywords: fullerene; multivalent glycosystems; oligosaccharides; proteotoxins

• interest [7][8]. In particular, multivalent biomaterials carrying more than two carbohydrate ligands have been designed [9][10][11][12][13][14][15] and proven to enhance protein–carbohydrate interactions by means of glycocluster effects [16][17][18]. More recently, our research group has reported on

• multivalent protein–lactose interactions, prompted us to apply this glycolipid as a tool for the rapid detection and the decontamination of ricin and other biological toxins. By using an SDS-PAGE analysis, we successfully quantified distributions (%) of ricin in the aqueous and the solid phase. With this

Efficient routes toward the synthesis of the D-rhamno-trisaccharide related to the A-band polysaccharide of Pseudomonas aeruginosa

• Aritra Chaudhury,
• Sajal K. Maity and
• Rina Ghosh

Beilstein J. Org. Chem. 2014, 10, 1488–1494, doi:10.3762/bjoc.10.153

• -rhamno-trisaccharide; deoxygenation on thioglycoside; multivalent glycosystems; one-pot sequential glycosylation; Pseudomonas aeruginosa; Introduction With the firm establishment of the critical roles played by oligosaccharides in diverse biological processes [1][2][3][4], the field of oligosaccharide

Postsynthetic functionalization of glycodendrons at the focal point

• Thisbe K. Lindhorst and
• Katharina Elsner

Beilstein J. Org. Chem. 2014, 10, 1482–1487, doi:10.3762/bjoc.10.152

• Thisbe K. Lindhorst Katharina Elsner Otto Diels Institute of Organic Chemistry, Christiana Albertina University of Kiel, Otto-Hahn-Platz 3–4, D-24098 Kiel 10.3762/bjoc.10.152 Abstract Glycodendrons are multivalent glycoconjugates bearing an orthogonal functional group at the focal point of the

• etherification, thiol-ene reaction and in particular olefin cross metathesis. Keywords: amphiphilic glycomimetics; cross metathesis; glycodendrons; multivalent glycoconjugates; multivalent glycosystems; Introduction In addition to nucleic acids and proteins, molecular life is based on a third important class

• of compounds, the carbohydrates. Carbohydrates are involved in numerous biological recognition processes, where they are often displayed in the form of multivalent conjugates such as on the surface of cells [1]. To investigate multivalency in carbohydrate recognition, multivalent glycomimetics, for

Multichromophoric sugar for fluorescence photoswitching

• Stéphane Maisonneuve,
• Rémi Métivier,
• Pei Yu,
• Keitaro Nakatani and
• Juan Xie

Beilstein J. Org. Chem. 2014, 10, 1471–1481, doi:10.3762/bjoc.10.151

• -functionalized moieties [18][19][20]. Monosaccharides can be readily functionalized with several propargyl groups to synthesize, using click chemistry, multivalent neoglycoconjugates for recognition studies with carbohydrate-binding proteins (lectins) [21][22][23][24] or to develop light-harvesting antenna

Carbohydrate PEGylation, an approach to improve pharmacological potency

• M. Eugenia Giorgi,
• Rosalía Agusti and
• Rosa M. de Lederkremer

Beilstein J. Org. Chem. 2014, 10, 1433–1444, doi:10.3762/bjoc.10.147

• -carbohydrates, in particular multiarm PEGylation, is presented. Keywords: bioavailability; carbohydrates; conjugates; glycoPEGylation; multivalent glycosystems; multivalent PEGylation; Introduction In recent years, the modification of biotherapeutics by covalent conjugation with polyethyleneglycol (PEG) known

• recognized as immunodominant epitopes in antigenic glycoconjugates [14]. Carbohydrates participate in molecular recognition events such as host–pathogen interactions, responsible for mammal infections, and are candidates for chemotherapy [15]. Moreover, synthesis of multivalent carbohydrate ligands provide

• multiarm PEGs, with the aim to increase the loading of the active sugar. Multivalent glycomolecules have proven to mediate or inhibit a variety of biological or pathological processes [17][23]. Review Polyethylene glycol (PEG) derivatives Polyethyleneglycol is an amphiphilic polymer consisting of repeating

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

• with different valency and alkyl spacer lengths by means of Cu(I)-catalysed azide–alkyne cycloadditions. Evaluation of these compounds as α-mannosidase inhibitors led to significant multivalent effects and further demonstrated the decisive influence of scaffold rigidity on binding affinity enhancements

• . Keywords: cyclopeptoids; glycosidases; iminosugars; inhibitors; multivalency; mutivalent glycosystems; Introduction Within a few years, the field of multivalent glycosidase inhibitors has witnessed tremendous advancement. Since the report in 2009 of the first quantifiable multivalent effect in glycosidase

• inhibition [1][2], the pace of progress has been breath-taking with the discovery of iminosugar clusters showing outstanding affinity enhancements of up to four orders of magnitude over the parent monovalent analogues [3][4][5][6][7]. The best results were obtained with multivalent systems based on C60 [3

Biantennary oligoglycines and glyco-oligoglycines self-associating in aqueous medium

• Svetlana V. Tsygankova,
• Alexander A. Chinarev,
• Alexander B. Tuzikov,
• Nikolai Severin,
• Alexey A. Kalachev,
• Juergen P. Rabe,
• Alexandra S. Gambaryan and
• Nicolai V. Bovin

Beilstein J. Org. Chem. 2014, 10, 1372–1382, doi:10.3762/bjoc.10.140

• assembling glycopeptides demonstrated an antiviral potency which was up to 50 times higher than the activity of peptide-free glycans. Keywords: glycopeptides; influenza virus; multivalent glycosystems; oligoglycine; polyglycine II; self-assembling; tectomers; Introduction Recently, we have synthesized and

• blocker (inhibitor) is the design of multivalent receptor analogs such as the oligoglycine-based tectomers described above. A first success for an application in this regard was achieved by inhibiting the influenza virus by sialo derivatives of the associating tetraantennary peptides, which demonstrated

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

• agglutinin. It was found that the printed carbohydrates retain their characteristic selectivity towards the synthetic and natural lectins and that the recognition of synthetic and natural lectins is strictly orthogonal. Keywords: carbohydrates; lectins; molecular recognition; microarrays; multivalent

Glycosystems in nanotechnology: Gold glyconanoparticles as carrier for anti-HIV prodrugs

• Fabrizio Chiodo,
• Marco Marradi,
• Javier Calvo,
• Eloisa Yuste and
• Soledad Penadés

Beilstein J. Org. Chem. 2014, 10, 1339–1346, doi:10.3762/bjoc.10.136

• glyconanoparticles as a new multifunctional drug-delivery system in the therapy against HIV. Keywords: drug-delivery system; gold glyconanoparticles; HAART; HIV; multivalent glycosystems; reverse transcriptase inhibitors; Introduction Acquired immune deficiency syndrome (AIDS), caused by human immunodeficiency

• have been explored in biomedicine as multivalent and multifunctional scaffolds [12][13]. Thanks to their relative inertness and low toxicity gold nanoparticles have been widely explored to conjugate biomolecules on their surface, because the chemistry of their surface is easy to control [12]. The

• addition glucose-coated gold nanoparticles did not elicit any immune response in animal models [27][28]. We thus decided to use them as a scaffold to insert antiretroviral drugs to construct new multivalent anti-HIV systems. Here we describe the preparation of anti-HIV prodrug candidates and their assembly

Design and synthesis of multivalent neoglycoconjugates by click conjugations

• Feiqing Ding,
• Li Ji,
• Ronny William,
• Hua Chai and
• Xue-Wei Liu

Beilstein J. Org. Chem. 2014, 10, 1325–1332, doi:10.3762/bjoc.10.134

• hydroamination/glycosylation on glycal scaffolds has been developed to form propargyl 3-tosylamino-2,3-dideoxysugars in a one-pot manner. Subsequent construction of multivalent 3-tosylamino-2,3-dideoxyneoglycoconjugates with potential biochemical applications was presented herein involving click conjugations as

• the key reaction step. The copper-catalyzed regioselective click reaction was tremendously accelerated with assistance of microwave irradiation. Keywords: click conjugations; copper-catalyzed; microwave irradiation; multivalent glycosystems; neoglycoconjugates; one-pot; Introduction Oligosaccharides

• approach to multivalent 3-tosylamino-2,3-dideoxyneoglyco conjugates 4 with potential biochemical applications involving click conjugations as the key reaction step (Figure 3). Results and Discussion Primarily, we successfully synthesized propargyl 3-p-toluenesulfonamido-4,6-di-O-acetyl-2,3-dideoxy-α-D

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

• strategies based on dendritic cells (DCs) armed with specific tumor antigens have been widely exploited due the properties of these immune cells in coordinating an innate and adaptive response. Here, we describe the convergent synthesis of the bifunctional multivalent glycodendron 5, which contains nine

• expression and MHCII. Furthermore, DCs activated by the glycodendron 5 stimulate T lymphocytes to proliferate in a mixed lymphocytes reaction (MLR). Keywords: cancer immunotherapy; DC-SIGN; DC targeting; glycodendron; GM3-lactone mimetic; multivalent glycosystems; multivalent interactions; Introduction

• (Figure 1) was able to elicit in vivo antimelanoma antibodies [32]. More recently [33], we established that the multivalent presentation of this synthetic mimetic positively interferes with human melanoma cell (A375) adhesion, migration and resistance to apoptosis, showing a clear amplification of the

Synthesis of a sucrose dimer with enone tether; a study on its functionalization

• Zbigniew Pakulski,
• Norbert Gajda,
• Magdalena Jawiczuk,
• Jadwiga Frelek,
• Piotr Cmoch and
• Sławomir Jarosz

Beilstein J. Org. Chem. 2014, 10, 1246–1254, doi:10.3762/bjoc.10.124

• oxidized with osmium tetroxide to a diol. Absolute configurations of the allylic alcohol as well as the diol were determined by circular dichroism (CD) spectroscopy using the in situ dimolybdenum methodology. Keywords: CD-spectroscopy; Cotton effect; multivalent glycosystems; osmylation; stereoselective

Towards allosteric receptors – synthesis of β-cyclodextrin-functionalised 2,2’-bipyridines and their metal complexes

• Christopher Kremer,
• Gregor Schnakenburg and
• Arne Lützen

Beilstein J. Org. Chem. 2014, 10, 814–824, doi:10.3762/bjoc.10.77

• processes. Multivalent [1][2] and cooperative binding [3][4][5] are two of the major concepts to ensure and control the efficiency in those events and the associated complex biochemical cascades following. In order to regulate several of their metabolical functions, a process named “allosteric regulation

Staudinger ligation towards cyclodextrin dimers in aqueous/organic media. Synthesis, conformations and guest-encapsulation ability

• Malamatenia D. Manouilidou,
• Yannis G. Lazarou,
• Irene M. Mavridis and
• Konstantina Yannakopoulou

Beilstein J. Org. Chem. 2014, 10, 774–783, doi:10.3762/bjoc.10.73

• shown recently [30] that depending on the linker connecting the CD moieties, self-inclusion occurs in water, frequently associated with inversion of one glucopyranose unit, that may totally incapacitate the cavity and annihilate the prospective utility of the oligomer as a multivalent host. These

Synthesis of new enantiopure poly(hydroxy)aminooxepanes as building blocks for multivalent carbohydrate mimetics

• Léa Bouché,
• Maja Kandziora and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2014, 10, 213–223, doi:10.3762/bjoc.10.17

• resulting multivalent conjugates showed extremely high binding to P- and L-selectine [33][34]. For the planned biological testing of the corresponding aminooxepanes as components of multivalent conjugates, we required the fully deprotected compounds. Moreover, it was desirable to have additional derivatives

• mimetics, also in a multivalent fashion. Conclusion In summary, the presented route employs the following key steps: Dondoni protocol for nitrone synthesis, [3 + 3]-cyclization with lithiated TMSE-protected allene, Lewis acid-induced rearrangement and reductive processes including a final hydrogenolysis

• such as alkynyl or azido substituents at the bicyclic skeleton will also allow further transformations such as click reactions or palladium-catalyzed couplings. We expect that the newly prepared aminooxepanes or their multivalent conjugates will have interesting properties and possibly biological

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

• the straightforward synthesis of multivalent glycoligands with full control over monomer sequence and functionalization pattern. We demonstrate the potential of this building-block approach by synthesizing oligomers with different numbers and spacing of carbohydrates and also show the feasibility of

• heteromultivalent glycosylation patterns by combining building blocks presenting different mono- and disaccharides. Keywords: continuous flow; flow chemistry: flow synthesis; glycoligands; multivalency; photochemistry; solid-phase synthesis; thiol–ene; thioglycosides; Introduction Multivalent carbohydrate ligand

• ]. Since single carbohydrate ligand–protein interactions are usually weak [4], several sugar ligands have to be introduced in order to achieve the desired biological effect [4]. This multivalent presentation of ligands then results in an increased binding affinity to the targeted protein receptors [4]. It

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

• interactions, it is now well known that making a system multivalent increases the binding or inhibitory potency of ligands, whose monovalent counterparts would otherwise be too weak to have biological relevance [19][20][21][22]. The spacer is an important factor in the design of an effective multivalent ligand

• 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

Multivalent display of the antimicrobial peptides BP100 and BP143

• Imma Güell,
• Rafael Ferre,
• Kasper K. Sørensen,
• Esther Badosa,
• Iteng Ng-Choi,
• Emilio Montesinos,
• Eduard Bardají,
• Lidia Feliu,
• Knud J. Jensen and
• Marta Planas

Beilstein J. Org. Chem. 2012, 8, 2106–2117, doi:10.3762/bjoc.8.237

• synthesis involved the preparation of the corresponding peptide aldehyde followed by coupling to an aminooxy-functionalized carbohydrate template. After purification, the multivalent display systems were obtained in high purities (90–98%) and in good yields (42–64%). These compounds were tested against

• prenucleating a number of appropriately spaced and oriented antimicrobial peptide monomers in order to reduce the threshold concentration required for their activity. The interaction of these multivalent species should a priori make the interaction with the microbial membrane strongly and entropically more

• favorable. Representative studies include multimeric derivatives of alamethicin [16] and the dimeric antimicrobial peptide A3-APO [17]. Moreover, studies of multivalent antimicrobial peptides are of growing importance because they could represent an interesting tool to provide insights into the modes of

Synthesis of trifunctional cyclo-β-tripeptide templates

• Frank Stein,
• Tahir Mehmood,
• Tilman Plass,
• Javid H. Zaidi and
• Ulf Diederichsen

Beilstein J. Org. Chem. 2012, 8, 1576–1583, doi:10.3762/bjoc.8.180

• enzymatic degradation, and their ability to form intermolecular staples by backbone hydrogen bonding. This might be of special advantage to target or imitate multivalent and/or cooperative processes. As an initial effort, we equipped the cyclic β-tripeptide with a fluorophore and a protected cell

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

• 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

• role of oligosaccharides on cell surfaces is the fact that human blood types (A, B, AB and 0) are solely determined by minor changes in the composition of the erythrocyte glycocalyx. Additionally, many biological mechanisms are mediated by multivalent recognition of carbohydrates. For example, lectins

Low-generation dendrimers with a calixarene core and based on a chiral C₂-symmetric pyrrolidine as iminosugar mimics

• Marco Marradi,
• Stefano Cicchi,
• Francesco Sansone,
• Alessandro Casnati and
• Andrea Goti

Beilstein J. Org. Chem. 2012, 8, 951–957, doi:10.3762/bjoc.8.107

• rigidification of the dendrimer structure and the iminosugar presentation in the clusters. The combination of the supramolecular properties of calixarenes with the advantage of a dendrimeric presentation of repetitive units opens up the possibility of generating well-defined multivalent and multifaceted systems

• occasionally, and their properties as multivalent enzyme inhibitors gave contrasting results. Early findings indicated in fact that poor multivalent phenomena take place [4][5][6], but more recently moderate [7] to remarkable [8][9] effects have been reported on glycosidases. Unlike lectin-mediated

• interactions [10], the effect of iminosugar-based multivalent inhibitors on enzyme activity is difficult to rationalise. However, the introduction of several copies of an N-alkyl analogue of iminosugar 1-deoxynojirimycin onto a fullerene ball [8] or onto β-cyclodextrin [9] afforded the first pieces of evidence