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

• Erythrina cristagalli lectin (ECL) to proteins Gal-1 and Gal-3 as well as Gal-0 as a negative control. The three protein samples were each immobilized on a streptavidin-coated chip. Then, ECL was passed over the chip at different concentrations to determine the relative binding affinity for the immobilized

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

• stable gradients of growth factors to regulate their bioavailability [11]. This matrix-immobilization of the factors might result in long-term binding to cell surface receptors, since the binding affinity of ECM-factors is relatively weak compared to growth factor receptor interactions [8]. Moreover, the

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

• located on apposing faces of the dimer (Figure 1). Although individual binding interactions with carbohydrates are weak [8], ligands for galectin-1 typically possess an array of carbohydrates to enhance the binding affinity [1][9][10]. Galectin-1 binding to carbohydrates cross-links adjacent

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

• events such as initial cell adhesion processes or pathogen invasion in host tissue. Nevertheless, ligand–receptor interactions are typically characterized by studying the binding affinity of freely dissolved ligands without surface anchorage. Typical assays in this context are “chip”-based methods like

• , steric shielding is not detected, which could explain the different outcome in terms of binding affinity per mannose unit in comparison to studies using inhibition/competition for binding affinity characterization [20][21][22]. Conclusion In this work, we successfully grafted three different carboxylic

• show that a high mannose concentration generally leads to increased adhesion energies. Although the mannose density was in principle sufficient to form multivalent binding with ConA receptors for all SCP systems, we did not observe an enhancement of binding affinity per mannose unit when increasing the

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

• ]. 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

• flexibility of the linker introduced by an unpaired region. The same approach was also used to identify the optimal spatial arrangement for assemblies targeting RCA120 and L-selectin with mannose, LacNAc and sialyl Lewis X–PNA conjugates [45]. The highest binding affinity to RCA120 was obtained with a

• bivalent glycan assembly (LacNAc, presented at 140 Å distance) that was 70 times better than the monovalent assembly. Notably, the enhanced binding affinity for the divalent display is consistent with a distance of ca. 130 Å between the binding sites. It was also demonstrated that DNA-templated displays

Exploring monovalent and multivalent peptides for the inhibition of FBP21-tWW

• Lisa Maria Henning,
• Sumati Bhatia,
• Miriam Bertazzon,
• Michaela Marczynke,
• Oliver Seitz,
• Rudolf Volkmer,
• Rainer Haag and
• Christian Freund

Beilstein J. Org. Chem. 2015, 11, 701–706, doi:10.3762/bjoc.11.80

• peptide ligand for the WW domains of FBP21 and were able to enhance the binding affinity by presenting it on a multivalent dendritic polyglycerol scaffold by a factor of ten in comparison to the monovalent ligand. However, given that on an average seven peptides are presented on the nanoparticle, this

• the interaction between hPG-peptide conjugate 2 and FBP21-tWW was measured by isothermal titration calorimetry (ITC) and compared to the KD of the interaction between the monovalent peptide and FBP21-tWW to analyze if multivalent display in form of the hPG-peptide conjugate 2 increases binding

• affinity. Results and Discussion Phage display In order to determine an optimal peptide sequence for a FBP21-tWW ligand, we conducted a phage display experiment for each of the two WW domains. Phages used in these experiments carried a randomized X9-peptide fused to phage coat protein VIII [16]. Enrichment

Synthesis of tripodal catecholates and their immobilization on zinc oxide nanoparticles

• Franziska Klitsche,
• Julian Ramcke,
• Julia Migenda,
• Andreas Hensel,
• Tobias Vossmeyer,
• Horst Weller,
• Silvia Gross and
• Wolfgang Maison

Beilstein J. Org. Chem. 2015, 11, 678–686, doi:10.3762/bjoc.11.77

• the corresponding TGA curve in Figure 4A and EDX (Figure 4C). Sulfonates have been described as ZnO binders before [47][48]. However, the binding affinity of 3-morpholinopropanesulfonate to ZnO NPs is low and most of the ligand is eliminated by washing following the immobilization. In contrast, TGA

Synthesis and surface grafting of a β-cyclodextrin dimer facilitating cooperative inclusion of 2,6-ANS

• Lars W. Städe,
• Thorbjørn T. Nielsen,
• Laurent Duroux,
• Reinhard Wimmer,
• Kyoko Shimizu and
• Kim L. Larsen

Beilstein J. Org. Chem. 2015, 11, 514–523, doi:10.3762/bjoc.11.58

• initial reports [1][2][3][4] of the cooperative effects exerted by β-cyclodextrin (β-CD) dimers, they have been suggested for a wide range of applications, for example, for catalysis [5][6] and photochemistry [7][8], as synthetic enzymes [5] and in general to obtain improved binding affinity (as compared

• accessibility for inclusion-complex formation [13]. The research presented here aims to bring the cooperative effects of β-CD dimers to solid silicon dioxide surfaces. Modification of these surfaces allows the introduction of the extraordinary binding affinity and selectivity of CD dimers to silicon wafer

• exception: the resonance at 3.46 ppm, these hydrogen atoms do not overlap with H-3 and H-5). In order to determine the binding affinity and to confirm the 1:1 stoichiometry of the complex, fluorescence titration experiments were conducted. Figure 6 shows the fluorescence spectra of 50 µM 2,6-ANS in PBS

A comparative study of the interactions of cationic hetarenes with quadruplex-DNA forming oligonucleotide sequences of the insulin-linked polymorphic region (ILPR)

• Darinka Dzubiel,
• Heiko Ihmels,
• Mohamed M. A. Mahmoud and
• Laura Thomas

Beilstein J. Org. Chem. 2014, 10, 2963–2974, doi:10.3762/bjoc.10.314

• stabilize this DNA just moderately (ΔTm = ca. 3–6 °C). Although the cyanine derivatives 1d and 1e show the highest binding affinity towards ILPR-quadruplex, these ligands induce only a moderate shift of its melting temperature (Table 2). This apparent contradiction may be the result of different buffer

• with the telomeric quadruplex 22AG (Table 2). For example, the cyanine derivative 1e shows the most significant difference between the binding affinity towards ILPR and the telomeric quadruplex (a2: Kba2 = 1.7 × 107 M−1; 22AG: Kb22AG = 3.9 × 105 M−1). Although thiazole orange (6) has a relatively high

• terminal π-stacking [20], which is in agreement with the observed binding stoichiometry of 1:1 (Figure 7), the different composition of the loops in ILPR-quadruplex (ACA and TGT in ILPR versus TTA in telomeric quadruplex) may affect the binding affinity of ligands towards the ILPR-DNA. On the other hand

Come-back of phenanthridine and phenanthridinium derivatives in the 21st century

• Lidija-Marija Tumir,
• Marijana Radić Stojković and
• Ivo Piantanida

Beilstein J. Org. Chem. 2014, 10, 2930–2954, doi:10.3762/bjoc.10.312

• impact on the binding affinity toward ds-DNA. The comparison of three substituents in 6-position, 4-N,N-diethylaminophenyl, phenyl (EB) and methyl, revealed that the first one exhibits the strongest DNA binding affinity and the strongest fluorescence enhancement. That was related to the twist angle in

• monomeric analogues) revealed significantly increased DNA-binding affinity and consequently enhanced telomerase and reverse transcriptase inhibition [69]. Conjugates of phenanthridine with other DNA and RNA active moieties Another common approach to increased selectivity of DNA- and RNA-targeting small

• much more dependent on the binding mode than on the substituents attached to the chromophore. However, by the rule of thumb, if phenanthridine substituents at 3,8-positions sterically allow the intercalation into ds-DNA or ds-RNA, than a binding affinity within the micromolar range could be expected

Binding mode and free energy prediction of fisetin/β-cyclodextrin inclusion complexes

• Bodee Nutho,
• Wasinee Khuntawee,
• Chompoonut Rungnim,
• Piamsook Pongsawasdi,
• Peter Wolschann,
• Alfred Karpfen,
• Nawee Kungwan and
• Thanyada Rungrotmongkol

Beilstein J. Org. Chem. 2014, 10, 2789–2799, doi:10.3762/bjoc.10.296

• inclusion complex. The ligand binding mode and water accessibility, host–guest interaction, and binding free energy of the inclusion complex were analyzed. The MM-PBSA/GBSA and M06-2X/6-31G(d,p)//MM-PBSA/GBSA approaches were used to predict the binding affinity of fisetin/β-CD complexes. The M06-2X/6-31G(d

Reversibly locked thionucleobase pairs in DNA to study base flipping enzymes

• Christine Beuck and
• Elmar Weinhold

Beilstein J. Org. Chem. 2014, 10, 2293–2306, doi:10.3762/bjoc.10.239

• of base flipping to the overall binding affinity of the DNA adenine-N6 MTase from Thermus aquaticus (M.TaqI) as an example. Results Selective cross-linking of thionucleobase pairs in DNA by bis-alkylation with 1,2-diiodoethane Thionucleobases are excellent soft nucleophiles, and chemoselective

• association equilibrium with the dissociation constant KD,init, followed by flipping of the target base with the equilibrium constant Kflip (Figure 6a) [55][56][69]. The binding affinity of base-flipping enzymes is often determined using DNA with the fluorescent base analog 2-aminopurine (2AP) at the target

• (Kflip) to the overall observed binding affinity cannot be extracted from these data because the non-flipped and flipped enzyme complexes A and B (Figure 6) cannot be distinguished in a single binding experiment. Therefore the overall dissociation constant is given by (see Supporting Information File 1

Molecular recognition of AT-DNA sequences by the induced CD pattern of dibenzotetraaza[14]annulene (DBTAA)–adenine derivatives

• Marijana Radić Stojković,
• Marko Škugor,
• Łukasz Dudek,
• Jarosław Grolik,
• Julita Eilmes and
• Ivo Piantanida

Beilstein J. Org. Chem. 2014, 10, 2175–2185, doi:10.3762/bjoc.10.225

• many groove binding molecules. The inability of the entire AP series to stabilize ds-DNA/RNA (Table 1), in combination with a considerable binding affinity (Table 2) gives rise to the question of the AP series binding mode. To shed more light on the unusual binding process of the AP dyes, it was

The effect of permodified cyclodextrins encapsulation on the photophysical properties of a polyfluorene with randomly distributed electron-donor and rotaxane electron-acceptor units

• Aurica Farcas,
• Ana-Maria Resmerita,
• Pierre-Henri Aubert,
• Flavian Farcas,
• Iuliana Stoica and
• Anton Airinei

Beilstein J. Org. Chem. 2014, 10, 2145–2156, doi:10.3762/bjoc.10.222

• –guest complexation stoichiometry. Thus, the Ks in CHCl3 was determined to be approximately 205 and 150 (±30) M−1, respectively (see the determined Ks of 1b in Figure 2). Concerning the binding affinity of molecule 1 to the TMS-β-CD and TMS-γ-CD cavities, it should be mentioned that the values toward

Synthesis of trifluoromethyl-substituted pyrazolo[4,3-c]pyridines – sequential versus multicomponent reaction approach

• Barbara Palka,
• Angela Di Capua,
• Maurizio Anzini,
• Gyté Vilkauskaité,
• Algirdas Šačkus and
• Wolfgang Holzer

Beilstein J. Org. Chem. 2014, 10, 1759–1764, doi:10.3762/bjoc.10.183

• lipophilicity [1][2]. Moreover, incorporation of fluorine often results in an increase of the binding affinity of drug molecules to the target protein [1][2]. As a consequence, a considerable amount – approximately 20% – of all the pharmaceuticals being currently on the market contain at least one fluorine

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

• the sensograms (Figure 3) showed a weak affinity of all calixarenes for Gal-3. However, the three synthetic molecules showed a very similar trend of Gal-3 binding affinity in three independent measurements (experiments A, B and C in Figure 4a). In particular, glycocalixarene 3 (cone structure, four

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

• highly interesting to also modulate the binding affinity of a single molecule through a structural change as a response to an external stimulus, for example light. In order to gain such control over the binding affinity of glycooligomers towards specific lectins, a few studies have recently been

• –receptor binding and thus the resulting binding affinity. In order to determine the binding affinity of the precision glycooligomers to PA-IL, surface plasmon resonance (SPR) experiments were performed. At first, an inhibition/competition assay was carried out. The SPR chip was modified with a β-D

• could previously also show for glycooligomers binding to Concanavalin A (Con A) lectin receptor [7][10][11]. All multivalent glycooligomers show a decrease in IC50, i.e., an increase in binding affinity in comparison to the monovalent β-methyl galactoside. Overall, IC50 values are in the µM range, with

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

• formation as previously postulated [18][31][36]. Ongoing studies on the aggregate stoichiometry should provide valuable insight on this matter. Overall, the results presented here indicate that clustering and aggregation events should be considered in addition to carbohydrate binding affinity for galectin-3

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

• incapacity to form sufficient hydrogen bonds with the mannoside. Probably, the high propensity to form hydrogen bonds with water and the high flexibility of the arms of the receptor, are the main reasons that explain its low binding affinity in aqueous solvent. This work also presents a new application of

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

• cyclopeptoid-based iminosugar clusters and their evaluation as α-mannosidase inhibitors. Modest but significant inhibitory multivalent effects were observed for most of the compounds evaluated. This study further highlights the decisive impact of the scaffold rigidity on binding affinity enhancements. In

Molecular recognition of isomeric protonated amino acid esters monitored by ESI-mass spectrometry

• Andrea Liesenfeld and
• Arne Lützen

Beilstein J. Org. Chem. 2014, 10, 825–831, doi:10.3762/bjoc.10.78

• trace amounts of material, and can be used to explore competitive experiments that are difficult to perform using UV–vis or NMR spectroscopy. Results and Discussion Design and synthesis of the concave templates Ammonium ions exhibit strong binding affinity towards crown ether moieties. Hence, we decided

• interact via those interactions is weaker [33][34][35]. This observation perfectly agrees with the conclusion that the ester group gets into close contact with the non-polar parts of the templates, and thereby, contribute to the binding affinity by attractive dispersive interactions. Hence, we can conclude

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

• have the drawbacks of carbohydrates such as low binding affinity or instability [4][5]. Many carbohydrates and their mimetics contain pyran rings, however, the corresponding ring-expanded compounds, oxepanes, have been investigated only in a limited number of studies. Several oxepane units can be found

Studies toward bivalent κ opioids derived from salvinorin A: heteromethylation of the furan ring reduces affinity

• Thomas A. Munro,
• Wei Xu,
• Douglas M. Ho,
• Lee-Yuan Liu-Chen and
• Bruce M. Cohen

Beilstein J. Org. Chem. 2013, 9, 2916–2924, doi:10.3762/bjoc.9.328

• ]GTPγS assay. No compound caused detectable antagonism at 3 μM. Syntheses of heteromethylated derivatives of 1. b.r.s.m. = based on recovered starting material. Synthesis of (2-hydroxyethoxy)methyl ether 6. Binding affinity, potency and maximal response at κ-OR. Supporting Information Supporting

Stereoselectively fluorinated N-heterocycles: a brief survey

• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2013, 9, 2696–2708, doi:10.3762/bjoc.9.306

• basicity of the secondary amine was thereby reduced by nearly two orders of magnitude, and this led to a marked improvement in bioavailability. Incidentally, it is also worthy of note that the bioavailability (and 5-HT2A binding affinity) could be further improved by the introduction of a second fluorine

Biosynthesis of rare hexoses using microorganisms and related enzymes

• Zijie Li,
• Yahui Gao,
• Hideki Nakanishi,
• Xiaodong Gao and
• Li Cai

Beilstein J. Org. Chem. 2013, 9, 2434–2445, doi:10.3762/bjoc.9.281

• may lead to low to moderate yields and difficulties in product purification. Advancements in genomics and bioengineering can potentially solve this problem by improving the properties (activity, thermostability, or substrate-binding affinity) of existing enzymes or discovering new systems and robust