The phenyl vinyl ether–methanol complex: a model system for quantum chemistry benchmarking

• Dominic Bernhard,
• Fabian Dietrich,
• Mariyam Fatima,
• Cristóbal Pérez,
• Hannes C. Gottschalk,
• Axel Wuttke,
• Ricardo A. Mata,
• Martin A. Suhm,
• Melanie Schnell and
• Markus Gerhards

Beilstein J. Org. Chem. 2018, 14, 1642–1654, doi:10.3762/bjoc.14.140

• dispersion interactions [48]. The aim of the presented study is the unambiguous experimental identification of the preferred binding site of a first methanol solvent molecule to the multivalent hydrogen bond scaffold of phenyl vinyl ether, followed by a classification of theoretical methods in terms of

An overview of recent advances in duplex DNA recognition by small molecules

• Sayantan Bhaduri,
• Nihar Ranjan and
• Dev P. Arya

Beilstein J. Org. Chem. 2018, 14, 1051–1086, doi:10.3762/bjoc.14.93

• are reports of natural and designed molecules that display multivalency in DNA recognition by binding at more than recognition sites (minor groove, major groove or base pair insertion) [11][12][13]. In synthetic multivalent ligands, which are made to enhance DNA affinity, tether length and composition

• especially the multivalent ligands that can simultaneously recognize one or more sites on DNA leading to strong affinity for DNA. We finally shed light on new reports of DNA alkylating agents towards the end of this review. While it is impossible to absorb the vast expanse and comprehensiveness of reports on

Nanoreactors for green catalysis

• M. Teresa De Martino,
• Loai K. E. A. Abdelmohsen,
• Floris P. J. T. Rutjes and
• Jan C. M. van Hest

Beilstein J. Org. Chem. 2018, 14, 716–733, doi:10.3762/bjoc.14.61

• embedded in the bilayer. Reprinted with permission from [21]. Copyright 2007 American Chemical Society. Representation of DSN-G0. Reprinted with permission from [100]. The multivalent esterase dendrimer 5 catalyzes the hydrolysis of 8-acyloxypyrene 1,3,6-trisulfonates 6a–c. Reprinted with permission from

Carbohydrate inhibitors of cholera toxin

• Vajinder Kumar and
• W. Bruce Turnbull

Beilstein J. Org. Chem. 2018, 14, 484–498, doi:10.3762/bjoc.14.34

• . Individually, the interactions are much weaker than the CTB-GM1os interaction (Kd ca. 1 mM measured by ITC), but even these weak binding interactions can still be functionally useful once the effect of multivalent binding enhancement has been taken into consideration. Indeed, ITC experiments have also shown

• been drawn for the receptor binding to AB5 toxins; while some target on the individual binding sites, others are intended at designing multivalent ligands against the entire toxin B pentamer [6][30][31]. Monovalent receptor-binding inhibitors Bernardi and co-workers designed carbohydrate derivatives

• , these compounds, 7 and 8, did not display good inhibition, the non-glycosylated ligands offered new avenues for better CT ligand designs. Multivalent receptor-binding inhibitors The five-fold symmetry of AB5 toxins provides a strong encouragement to think about multivalent inhibitor design from (even

Recent applications of click chemistry for the functionalization of gold nanoparticles and their conversion to glyco-gold nanoparticles

• Vivek Poonthiyil,
• Thisbe K. Lindhorst,
• Vladimir B. Golovko and
• Antony J. Fairbanks

Beilstein J. Org. Chem. 2018, 14, 11–24, doi:10.3762/bjoc.14.2

• combination of a gold nanoparticle core and an outer-shell comprising multivalent presentation of carbohydrates. The combination of the distinctive physicochemical properties of the gold core and the biological function/activity of the carbohydrates makes glyco-gold nanoparticles a valuable tool in

• , oligosaccharides usually bind lectins in a multivalent cooperative fashion. This avidity is significantly greater than the sum of the individual monomeric carbohydrate–protein interactions, and is sometimes referred to as the ‘cluster glycoside’ effect [6]. In order to study biological processes that involve these

• types of carbohydrate–protein interactions, it is therefore essential to present carbohydrates in a multivalent fashion. For that purpose, different scaffolds, such as peptides, proteins, lipids, and synthetic polymers, have all been used [7]. The search for better scaffolds for the presentation of

What contributes to an effective mannose recognition domain?

• Christoph P. Sager,
• Deniz Eriş,
• Martin Smieško,
• Rachel Hevey and
• Beat Ernst

Beilstein J. Org. Chem. 2017, 13, 2584–2595, doi:10.3762/bjoc.13.255

• carbohydrate ligand and/or a multivalent display of the ligand [13][14][15]. This accumulation of individual binding events increases the overall binding strength either by avidity or local concentration effects [16][17]. However, other approaches, such as the reduction of desolvation costs or ligand and

• Brewer reviewed the role of density and number of glycan epitopes involved in multivalent carbohydrate interactions for legume lectins as well as for lectins of the innate immune system [74]. As an example, HIV-1 establishes multivalent contacts to DC-SIGN (E)-decorated dendritic cells in order to bypass

• host immune attack. Thus, DC-SIGN plays a key role in the dissemination of HIV-1 by capturing of HIV-1 at entry sites of infection and subsequent transport of the virus to CD4+ T cells in lymphoid tissues. The weak monovalent binding affinity of DC-SIGN (E) is compensated for by a multivalent display

Glycoscience@Synchrotron: Synchrotron radiation applied to structural glycoscience

• Serge Pérez and
• Daniele de Sanctis

Beilstein J. Org. Chem. 2017, 13, 1145–1167, doi:10.3762/bjoc.13.114

Glyco-gold nanoparticles: synthesis and applications

• Federica Compostella,
• Olimpia Pitirollo,
• Alessandro Silvestri and
• Laura Polito

Beilstein J. Org. Chem. 2017, 13, 1008–1021, doi:10.3762/bjoc.13.100

• , Nanotechnology Lab., Via G. Fantoli 16/15, 20138 Milan, Italy 10.3762/bjoc.13.100 Abstract Glyco-gold nanoparticles combine in a single entity the peculiar properties of gold nanoparticles with the biological activity of carbohydrates. The result is an exciting nanosystem, able to mimic the natural multivalent

• interaction is ever lower than those measured when a glyco-multivalent presentation is exploited [2]. Following nature’s design, carbohydrate multivalent systems are, at the present time, the most common strategy used to study weak carbohydrate–carbohydrate or carbohydrate–protein interactions and the

• for the multivalent carbohydrate presentation [51][52][53]. In fact, a denser ligand packing can be obtained when NP dimensions are bigger and the curvature radius is reduced. This observation was already highlighted by Lin et al., during their studies on the interactions among Shiga toxins and

Interactions between shape-persistent macromolecules as probed by AFM

• Johanna Blass,
• Jessica Brunke,
• Franziska Emmerich,
• Cédric Przybylski,
• Vasil M. Garamus,
• Artem Feoktystov,
• Roland Bennewitz,
• Gerhard Wenz and
• Marcel Albrecht

Beilstein J. Org. Chem. 2017, 13, 938–951, doi:10.3762/bjoc.13.95

• hydrophobic guest molecules are of special interest, since CDs are readily available bio-based materials and interactions take place under physiological conditions [17]. CDs are ideal candidates for the investigation of multivalent interactions as they combine high affinities with a versatile integrability in

• macromolecular systems [18]. CDs have already been employed for the construction of supramolecular polymers [19][20][21], supramolecular hydrogels [22][23], molecular printboards [24][25] or multivalent interfaces [26][27][28] with tunable chemical and physical properties. Herein, for the first time, we present

• studies concerning the synthesis of shape-persistent CD polymers to investigate multivalent binding with ditopic guest molecules on the molecular level (Figure 1). The ditopic guest (shown in red colour) should act as a connector between opposing CD moieties. Only a few examples of shape-persistent CD

Robust C–C bonded porous networks with chemically designed functionalities for improved CO₂ capture from flue gas

• Damien Thirion,
• Joo S. Lee,
• Ercan Özdemir and
• Cafer T. Yavuz

Beilstein J. Org. Chem. 2016, 12, 2274–2279, doi:10.3762/bjoc.12.220

• ; Findings Porous polymers are network polymers that are made from multivalent monomers and form permanent pores through the net formation [1]. They differ slightly from cross-linked polymers with more certainty in the location of branching and the type and quantity of functionalities. Also, the rigidity of

Organic chemistry meets polymers, nanoscience, therapeutics and diagnostics

• Vincent M. Rotello

Beilstein J. Org. Chem. 2016, 12, 1638–1646, doi:10.3762/bjoc.12.161

• demonstrate that we could use non-covalent sidechain modification between multivalent polymers and monovalent guests to generate "plug and play polymers" (Figure 2) [17]. We also showed that we could self-assemble a polymer around an electroactive guest, effectively encapsulating and isolating it [18]. The

• research really became interesting when we started mixing multivalent complementary polymers together. When we mixed together diaminopyridine and uracil polymers together in chloroform we generated a turbid solution. Under the microscope we found that the turbidity surprisingly arose from vesicular

Enabling technologies and green processes in cyclodextrin chemistry

• Giancarlo Cravotto,
• Marina Caporaso,
• Laszlo Jicsinszky and
• Katia Martina

Beilstein J. Org. Chem. 2016, 12, 278–294, doi:10.3762/bjoc.12.30

• isocyanates and isothiocyanate gave ureido and thioureido persubstituted β-CD derivatives in a MW oven at 85 °C for 4 h (see Scheme 9). A multivalent azido-scaffold such as persubstituted 6-azido-6-deoxy-α-, β- or γ-CD with conformational constraints can be efficiently perfunctionalized in a MW- and ligand

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

• , Universidad de Sevilla, c/ Prof. García González 1, E-41012, Sevilla, Spain 10.3762/bjoc.11.282 Abstract The synthesis of new multivalent architectures based on a trihydroxypiperidine α-fucosidase inhibitor is reported herein. Tetravalent and nonavalent dendrimers were obtained by means of the click

• (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

• terms of inhibition and therefore were not encouraging [4][5][6]. However, following the first promising affinity enhancements reported towards jack-bean α-mannosidase for a trivalent derivative of 1-deoxynojirimycin [7], over the past six years the multivalent effect in glycosidase inhibition has

Smart molecules for imaging, sensing and health (SMITH)

• Bradley D. Smith

Beilstein J. Org. Chem. 2015, 11, 2540–2548, doi:10.3762/bjoc.11.274

• and there is coplanar stacking of the squaraine aromatic surfaces with the anthracene sidewalls of the macrocycle. We are beginning to use Synthavidin technology as a self-assembly platform to rapidly fabricate libraries of targeted multivalent probes for fluorescence imaging of over-expressed

Size-controlled and redox-responsive supramolecular nanoparticles

• Raquel Mejia-Ariza,
• Gavin A. Kronig and
• Jurriaan Huskens

Beilstein J. Org. Chem. 2015, 11, 2388–2399, doi:10.3762/bjoc.11.260

• steric repulsion is important for achieving SNP stability. SNPs of controlled particle size and good stability (up to seven days) were prepared by fine-tuning the ratio of multivalent and monovalent interactions. Finally, reversibility of the SNPs was confirmed by oxidizing the Fc guest moieties in the

• these SNPs using host–guest interactions between CD and Ad. Tseng et al. studied the formation of SNPs that are assembled solely by host–guest interactions [11][12]. Here, the core is composed of multivalent interactions between positively charged CD-grafted polymers and positively charged poly

• (amidoamine) (PAMAM) dendrimers, and a monovalent neutral Ad-PEG stopper is introduced at the surface for stabilization. The SNP size was increased by increasing the amount of multivalent guest molecules in the core, while keeping the host and stopper concentration constant and having an excess of stopper to

Multivalency as a chemical organization and action principle

• Rainer Haag

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

• Rainer Haag Institute for Chemistry and Biochemistry, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany 10.3762/bjoc.11.94 Keywords: glycoarchitectures; supramolecular chemistry; multivalency; multivalent protein inhibitors; pathogen binding; Multivalency is a key principle in nature

• to establish strong, but also reversible chemical interactions between two units, e.g., a receptor and a ligand, viruses and host cells, or between two cell surfaces. Multivalent binding is based on multiple simultaneous molecular recognition processes and plays an important role in the self

• -organization of matter, in biological recognition processes as well as in signal transduction in biological systems. The targeted development of multivalent molecules is not only used for the strong inhibition of proteins and prevention of pathogen infections, but also allows for the selective production of

Peptide–polymer ligands for a tandem WW-domain, an adaptive multivalent protein–protein interaction: lessons on the thermodynamic fitness of flexible ligands

• Katharina Koschek,
• Vedat Durmaz,
• Oxana Krylova,
• Marek Wieczorek,
• Shilpi Gupta,
• Martin Richter,
• Alexander Bujotzek,
• Christina Fischer,
• Rainer Haag,
• Christian Freund,
• Marcus Weber and
• Jörg Rademann

Beilstein J. Org. Chem. 2015, 11, 837–847, doi:10.3762/bjoc.11.93

• Informationstechnik Berlin, Numerical Analysis and Modelling, Takustr. 7, 14195 Berlin, Germany 10.3762/bjoc.11.93 Abstract Three polymers, poly(N-(2-hydroxypropyl)methacrylamide) (pHPMA), hyperbranched polyglycerol (hPG), and dextran were investigated as carriers for multivalent ligands targeting the adaptive

• determine the binding affinity, the enthalpic and entropic contributions to free binding energy, and the stoichiometry of binding for all peptide–polymer conjugates. Binding affinities of all multivalent ligands were in the µM range, strongly amplified compared to the monovalent ligand P1 with a KD > 1 mM

• superior to induce multivalent binding and to increase affinity, while the more flexible and dendritic polymers, pHPMA and hPG are suitable to induce crosslinking upon binding. Keywords: inhibitors of protein–protein interactions; isothermal titration calorimetry; multivalency; peptide–polymer conjugates

Adsorption mechanism and valency of catechol-functionalized hyperbranched polyglycerols

• Stefanie Krysiak,
• Qiang Wei,
• Klaus Rischka,
• Andreas Hartwig,
• Rainer Haag and
• Thorsten Hugel

Beilstein J. Org. Chem. 2015, 11, 828–836, doi:10.3762/bjoc.11.92

• forces above 700 pN and another had a second high force peak at 1 nN. This is due to the interaction of two catechol groups, either multivalent by two catechols on one molecule or polyvalent by two molecules each with one catechol, as discussed below. The measurement showed that adding more catechol end

• is probably due to the required molecular rearrangement of the hPG in order to properly position the catechol groups for the interaction with the surface. The double peaks in the measurement could be multivalent, as illustrated in Figure 3A, or polyvalent, as in Figure 3B. In a multivalent

• . Multivalent binding of two catechols in a single hPG also occurred, but more rarely. In the case of the 10 s dwell measurements there was even a triple interaction involving both poly- and multivalent anchoring. In addition, increasing the surface contact time leads to higher interaction forces for a single

Mechanical stability of bivalent transition metal complexes analyzed by single-molecule force spectroscopy

• Manuel Gensler,
• Christian Eidamshaus,
• Maurice Taszarek,
• Hans-Ulrich Reissig and
• Jürgen P. Rabe

Beilstein J. Org. Chem. 2015, 11, 817–827, doi:10.3762/bjoc.11.91

• 10.3762/bjoc.11.91 Abstract Multivalent biomolecular interactions allow for a balanced interplay of mechanical stability and malleability, and nature makes widely use of it. For instance, systems of similar thermal stability may have very different rupture forces. Thus it is of paramount interest to study

• and understand the mechanical properties of multivalent systems through well-characterized model systems. We analyzed the rupture behavior of three different bivalent pyridine coordination complexes with Cu2+ in aqueous environment by single-molecule force spectroscopy. Those complexes share the same

• rupture forces for the stiffer backbones. Interestingly, the medium-flexible connection has the highest rupture forces, whereas the ligands with highest and lowest rigidity seem to be prone to consecutive bond rupture. The presented approach allows separating bond and backbone effects in multivalent model

Influence of length and flexibility of spacers on the binding affinity of divalent ligands

• Susanne Liese and
• Roland R. Netz

Beilstein J. Org. Chem. 2015, 11, 804–816, doi:10.3762/bjoc.11.90

• ]. Also in drug design, the synthesis of artificial multivalent ligands is a promising route to increase the binding affinity or to reduce the amount of substance required for treatment [4][5][6][7]. The term multivalency is used for systems that consist of several identical binding partners. Thereby, the

• larger binding partner, for example a protein, is commonly denoted as receptor, whereas the smaller binding partner, for instance an enzyme or a single molecule, is denoted as ligand. The binding strength of a multivalent structure significantly depends on details of the presentation of ligands and

• receptors [1]. Each multivalent ligand consists of several monovalent ligands that are connected via a scaffold. The binding affinity of such a multivalent ligand is determined by the interplay between gain in binding energy and loss of entropy associated with conformational degrees of freedom. The more

Impact of multivalent charge presentation on peptide–nanoparticle aggregation

• Daniel Schöne,
• Boris Schade,
• Christoph Böttcher and
• Beate Koksch

Beilstein J. Org. Chem. 2015, 11, 792–803, doi:10.3762/bjoc.11.89

• nanoparticles. As the assembly of charged gold nanoparticles depends on the local charge of the coiled-coil in a multivalent fashion, we wanted to study different aspects of nanoparticle–peptide interactions such as the aggregation tendency of the peptide and the morphology of the obtained peptide–nanoparticle

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

• Berlin, Institut für Organische und Bioorganische Chemie, Institut für Chemie, Brook-Taylor-Str. 2, 12489 Berlin, Germany 10.3762/bjoc.11.88 Abstract To add new tools to the repertoire of protein-based multivalent scaffold design, we have developed a novel dual-labeling strategy for proteins that

• the generation of nanostructured scaffolds with precisely defined dimensions and configurations [7][8][9][10][11][12]. We have recently contributed to this field using globular proteins as multivalent scaffolds for the structurally-defined presentation of ligands. In a proof-of-principle study to

• engineer multivalent glycoprotein conjugates, we have used the incorporation of non-canonical amino acids (NCAA) [13] by supplementation based incorporation (SPI) [14][15][16][17] in auxotroph expression systems followed by the chemoselective Cu-catalyzed azide–alkyne cycloaddition (CuAAC) to attach

Regulation of integrin and growth factor signaling in biomaterials for osteodifferentiation

• Qiang Wei,
• Theresa L. M. Pohl,
• Anja Seckinger,
• Joachim P. Spatz and
• Elisabetta A. Cavalcanti-Adam

Beilstein J. Org. Chem. 2015, 11, 773–783, doi:10.3762/bjoc.11.87

• factors to induce osteogenic differentiation of stem cells, and discuss the signaling pathways that are initiated by both individual and cooperative parameters. The joint effect of integrin ligands and growth factors is highlighted as the multivalent interactions for bone therapy. Keywords: biomaterials

Multivalent dendritic polyglycerolamine with arginine and histidine end groups for efficient siRNA transfection

• Fatemeh Sheikhi Mehrabadi,
• Hanxiang Zeng,
• Mark Johnson,
• Cathleen Schlesener,
• Zhibin Guan and
• Rainer Haag

Beilstein J. Org. Chem. 2015, 11, 763–772, doi:10.3762/bjoc.11.86

• residues (His) are important for safe and efficient siRNA transfection, this study indicates that AAdPGs containing higher degrees of His display lower cytotoxicity and more efficient endosomal escape. Keywords: arginine; dendritic polyglycerolamine; histidine; multivalent vector; siRNA delivery

• with low dispersity. Moreover, the tree-like structure of such polymers provides multivalent positions for functionalization and interaction with DNA/siRNA. Dendritic polyglycerol (dPG) can be synthesized on a kilogram scale by a one-step, ring-opening polymerization of glycidol with controllable sizes

• cytotoxicity increases at higher concentrations which limits its further application. Here, we compare the potential of multivalent amino acid functionalized dPGs (AAdPGs), for siRNA transfection with dPG-NH2 90%. The initial in vitro results indicated that AAdPGs were capable of mediating efficient siRNA

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

• 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

• glycocalyx interacts also with surface anchored membrane receptors. Thus, the interactions between these surfaces are again multivalent interactions, just on a larger scale between two surfaces. Such carbohydrate based multivalent surface–surface interactions represent a large range of crucial biological