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

• generally low affinity between sugars and receptors and possibly also by the high flexibility of the polymeric mannose linkers [9]. High molecular flexibility causes a high degree of conformational entropy that negatively affects complex formation between ligands and receptors [23]. Also the design of 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

• diverse glycans could be iteratively introduced on amino acid linkers. Inspired by Shoda’s activation [40] which provides facile access to complex glycosyl azides from native carbohydrates, we subsequently applied reiterative CuAAC conjugation of glycans on propargyl glycine residues within a peptide [41

• instructions. To this end a pilot library of fourteen PNA-tagged glycoconjugates that included mannose disaccharides joined by linkers of different lengths were paired through hybridization, varying the ligand combinations and interligand distances. Measuring the affinity of 32 different assemblies against

• between the glycan units and the distinct spatial arrangement conferred by the different linkers. This library represents the largest array of heteroglycan conjugates reported to date. Based on the results obtained with the screen for LecA, a lectin intimately involved in the pathogenicity of P

First principle investigation of the linker length effects on the thermodynamics of divalent pseudorotaxanes

• Andreas J. Achazi,
• Doreen Mollenhauer and
• Beate Paulus

Beilstein J. Org. Chem. 2015, 11, 687–692, doi:10.3762/bjoc.11.78

• energies of association (Gibbs free (binding) energies) for divalent crown-8/ammonium pseudorotaxanes are determined by investigating the influence of different linkers onto the binding. Calculations are performed with density functional theory including dispersion corrections. The translational

• linker shows an enhanced binding strength due to electronic effects, namely the dispersion interaction between the linkers from the guest and the host. For the longer linkers this ideal packing is not possible due to steric hindrance. Keywords: density functional theory (DFT); dispersion correction

• different linkers. The shortest linker shows a much larger chelate cooperativity than the longer linkers due to non-innocent linkers that contribute to the binding. To analyze the individual contributions to the binding, we perform first principle calculations of the model system shown in Figure 1, which is

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

• per DNJ unit) [11][12]. In the following years, an impressive ever-growing number of multivalent iminosugars based on various scaffolds, ligands and linkers have been synthesized to further investigate the impact of multivalency on glycosidase inhibition [9][10][11][12][13][14][15][16][17][18][19][20

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

• able to compare aminopyran 1 with aminopolyol 2 two divalent amides were synthesized from compound 16 using the same carboxylic acid dichlorides 7 and 8 as linkers affording the desired compounds 18 and 19 in excellent yields (Table 2, entries 1 and 2). Moreover, another divalent amide 20 with a longer

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

• demonstrated that the choice of linker is an important parameter in order to fully access both cavities [12][13]. Specifically, it was demonstrated that long and/or hydrophobic linkers may induce an inversion process, resulting in self-inclusion of the linker in one of the cavities, thereby limiting

C-5’-Triazolyl-2’-oxa-3’-aza-4’a-carbanucleosides: Synthesis and biological evaluation

• Roberto Romeo,
• Caterina Carnovale,
• Salvatore V. Giofrè,
• Maria A. Chiacchio,
• Adriana Garozzo,
• Emanuele Amata,
• Giovanni Romeo and
• Ugo Chiacchio

Beilstein J. Org. Chem. 2015, 11, 328–334, doi:10.3762/bjoc.11.38

• can interact with intracellular targets to induce cytotoxicity [28][29][30][31][32]. Several functionalities have been inserted as linkers on the 2’-oxa-3’-aza-4’a-carbanucleoside skeleton in order to confer novel mechanisms of action for nucleoside mimics: in this context, the 1,2,3-triazole unit

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

• phenanthridine moiety – many ethidium bromide-based dimers were prepared and reviewed in the last two decades of the 20th century, thus here will be presented results from 2000 on. Systematic variation of steric and/or electrostatic effects by means of type, number, length and flexibility of linkers connecting

• intercalator able to differentiate between A–U(T) and G–C base pairs by sign of opposite fluorimetric response. An introduction of the permanent positive charge by methylation of the heterocyclic nitrogen changed the binding mode of the conjugates with shorter linkers from minor groove binding to intercalation

• RNA dyes. Another large series of phenanthridinium-homodimers was constructed by linking two ethidium bromide subunits by peptide-like linkers of variable flexibility and rich in hydrogen-bonding possibilities within the DNA grooves (Figure 5). The resulting bis-intercalators (in comparison to the

Synthesis and characterization of a new photoinduced switchable β-cyclodextrin dimer

• Florian Hamon,
• Claire Blaszkiewicz,
• Marie Buchotte,
• Estelle Banaszak-Léonard,
• Hervé Bricout,
• Sébastien Tilloy,
• Eric Monflier,
• Christine Cézard,
• Laurent Bouteiller,
• Christophe Len and
• Florence Djedaini-Pilard

Beilstein J. Org. Chem. 2014, 10, 2874–2885, doi:10.3762/bjoc.10.304

• to the guest molecules [9][10]. These cyclodextrins linked by ester [11], thioether [12][13][14][15][16], urea [17][18][19], or triazole [20] moieties have been previously described. In addition, aromatic azobenzenes are excellent candidates as molecular switch linkers as they have two forms, namely

• cyclic polymers are aggregated into larger objects stabilized by hydrogen bonds between cyclodextrin moieties and by π-stacking interactions between azobenzene linkers. Finally, according to the computational data, the complexes of AZO-CDim 1 with ADAdim 4 are further stabilized by intramolecular

Synthesis of nanodiamond derivatives carrying amino functions and quantification by a modified Kaiser test

• Gerald Jarre,
• Steffen Heyer,
• Elisabeth Memmel,
• Thomas Meinhardt and
• Anke Krueger

Beilstein J. Org. Chem. 2014, 10, 2729–2737, doi:10.3762/bjoc.10.288

• with amino groups is typically not complete and the stability of amino groups directly bound to the diamond surface is limited as they are at least partially replaced by hydroxy groups under ambient conditions [4]. Therefore, in most cases linkers are used in order to establish stable bonding

• , the linkers are coupled to the diamond surface via heteroatoms. These sites are more easily cleaved compared to carbon–carbon single bonds, e.g., in a physiological environment or other aqueous conditions. It is hence of interest to develop methods that form stable bonds between the diamond surface

• ) BH3·THF, f) Δ, 1,2-dichlorobenzene, g) MCPBA, h) NH3, i) BH3·THF, j) APTMS, k) 4-aminobenzyl(N-Boc)amine, isopentyl nitrite, l) TFA. Surface loading of nanodiamond-carrying amino groups on different linkers using three independent quantification methods. Supporting Information Supporting Information

Synthesis and characterization of a hyper-branched water-soluble β-cyclodextrin polymer

• Francesco Trotta,
• Fabrizio Caldera,
• Roberta Cavalli,
• Andrea Mele,
• Carlo Punta,
• Lucio Melone,
• Franca Castiglione,
• Barbara Rossi,
• Monica Ferro,
• Vincenza Crupi,
• Domenico Majolino,
• Valentina Venuti and
• Dominique Scalarone

Beilstein J. Org. Chem. 2014, 10, 2586–2593, doi:10.3762/bjoc.10.271

• structural aspects and functional properties, and in particular pyromellitic nanosponges were found to present a critical cross-linking value [17]. In other words, the maximum number of cross-linkers per monomer was proved to be around 6 (i.e., 6 mol of pyromellitic dianhydride for each mol of β-CD). If the

Towards the sequence-specific multivalent molecular recognition of cyclodextrin oligomers

• Michael Kurlemann and
• Bart Jan Ravoo

Beilstein J. Org. Chem. 2014, 10, 2428–2440, doi:10.3762/bjoc.10.253

• for the interaction with α-CD, the EM cannot be increased that easy. Here the linkers of the guest and the host moieties have a crucial influence on the structure of the divalent molecules and the host–guest complexes before the intramolecular complexation [1]. Changes in the linkers’ structures can

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

• , long linkers that might interfere with protein binding are typically employed. The Verdine group has developed a cross-linking approach based on the easy postsynthetic introduction of cystamine or longer amino-alkylthiol linkers into ODN using a convertible nucleoside approach [39][40][41][42][43][44

• its neighboring base pairs. In contrast, the ideal geometry of saturated linkers will demand non-planar torsion angles. Coleman et al. [44] investigated this topic by performing molecular dynamic simulations for a disulfide cross-linked I6S/U4S base pair in B-DNA and showed that the compromise between

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

• stacked dimers within the DNA minor groove similar to the crystal structure of close analogue (Figure 4, right). Conversely, the AP5 and AP6 aliphatic linkers are long enough to allow self-folding and easy intramolecular π–π stacking of adenine with DBTAA (Figure 4, upper right). During the binding event

Macrocyclic bis(ureas) as ligands for anion complexation

• Claudia Kretschmer,
• Gertrud Dittmann and
• Johannes Beck

Beilstein J. Org. Chem. 2014, 10, 1834–1839, doi:10.3762/bjoc.10.193

• ring with two ethynylene groups as linkers and 2 the larger ring with two butadiynylene groups. On thermal treatment to 130 °C molecule 1 splits up into two dihydroindoloquinolinone (3) molecules. Both compounds 1 and 2 form adducts with polar molecules such as dimethyl sulfoxide (DMSO) and

• planar ligand, as was shown by indole-based macrocycles [9]. This ligand system represents a stiff ring of two bis(indole) units connected via two ethynylene groups as linkers. As proven by a crystal structure determination, a chloride ion fits into the cavity bound via four N−H∙∙∙Cl bonds and strong

• butadiynylene groups as spacers turned out as a suitable receptor for small anions with high binding constants. The molecule is flexible. In the complex with a bromide ion embedded in the ring cavity, the cyclic ligand is strongly tilted. The smaller cycle with ethynylene groups as linkers is a much weaker

Influence of perylenediimide–pyrene supramolecular interactions on the stability of DNA-based hybrids: Importance of electrostatic complementarity

• Christian B. Winiger,
• Simon M. Langenegger,
• Oleg Khorev and
• Robert Häner

Beilstein J. Org. Chem. 2014, 10, 1589–1595, doi:10.3762/bjoc.10.164

• (Table 1, hybrids 1*2 and 7*6) than hybrids containing both types of aromatic compounds. Although the actual stability of such duplexes strongly depends on several parameters like, e.g., the geometry of the building blocks and the flexibility of the linkers, a general trend can be deduced from the

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

• moieties and an aromatic central core but the introduction of distinct functionalized linkers may change the overall hydrophobic/hydrophilic balances of the structures. As such, they could engage supplementary intramolecular hydrogen bonding or hydrophobic interactions that could mediate their three

• ranging from 1.51 to 1.33 × 10−10 m2s−1 for protons in the core or the periphery. Interestingly, calculation of the extended conformation (MM2, Chem3D) of the linkers in 12, 17, and 21 showed lengths of 14.8, 17.1, and 21.8 Å, respectively. Conclusion The syntheses of three related families of

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

• protonable amines into neutral amide or carbamate linkers. Even though PEGylation of chitosan via the amino group is the most commonly used method a number of examples of polysaccharide derivatisation on the hydroxy groups have been reported. Chitosan-O-poly(ethylene glycol) graft copolymers were synthesized

Automated solid-phase peptide synthesis to obtain therapeutic peptides

• Veronika Mäde,
• Sylvia Els-Heindl and
• Annette G. Beck-Sickinger

Beilstein J. Org. Chem. 2014, 10, 1197–1212, doi:10.3762/bjoc.10.118

• ) group [43]). For a precise overview, the review of Isidro-Llobet 2009 and detailed manuals of major companies are recommended [44][45][46]. Optimal resins and linkers for peptide synthesis: The solid phase has to meet a number of requirements to be suitable for peptide synthesis. It has to be insoluble

• . recently published a collection of commonly used resins, together with their individual swelling and loading (is defined by the equivalents of amino acid in mmol/g, which can be attached to the resin) properties [50]. With respect to PEG-functionalized linkers, peptide synthesis yields can be improved by

• -terminus can be modified as hydrazide, alcohol, aldehyde, thioester and many more [22][50]. Furthermore, there are linkers that enable the synthesis of partially and fully protected peptides such as the 2-chlorotrityl resin [51] or the Sieber amide resin [52]. Consequently, the choice of resin and linker

N-Alkylated dinitrones from isosorbide as cross-linkers for unsaturated bio-based polyesters

• Oliver Goerz and
• Helmut Ritter

Beilstein J. Org. Chem. 2014, 10, 902–909, doi:10.3762/bjoc.10.88

• ) were used as model systems and reacted with dimethyl itaconate to further characterize the 1,3-dipolaric cycloaddition. Keywords: bio-based polyesters; cross-linkers; dinitrones; 1,3-dipolar cycloaddition; isosorbide; Introduction Nitrones represent a class of compounds with a versatile use as

• synthesis of polymers bearing nitrones as photosensitive material [7][8] was also described. We focused on the preparation of polynitrones as efficient cross-linkers for unsaturated polyesters based on fumaric und maleic acid [9]. In the light of the growing interest in polymers from renewable resources the

• synthesis of bio-based nitrones as novel cross-linkers for unsaturated bio-polyesters [10] offers an interesting access to biocompatible materials. This paper presents the synthesis of bio-based N-alkylated dinitrones based on isosorbide and the subsequent use of these dinitrones as cross-linkers in a 1,3

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

• couplings [16][23], the classical formation of ester [12][17], amide [25][26] or imide [27] bonds between CDs or amino CDs and acid- or anhydride-linkers, and finally urea/thiourea bonds [28][29]. However, the obvious advantages of the Staudinger ligation (high reaction rates, absence of a catalyst, aqueous

•  1, Figure S1). Compound 3 showed a single methoxy group in the 1H NMR spectrum (3.57 ppm) and a single carbonyl signal in the 13C NMR spectrum (166.8 ppm), reflecting the compound’s high molecular symmetry. Both linkers were stored under argon at −20 °C to minimize oxidation, although best results

• studied the mechanism of the Staudinger ligation of arylphosphine ester linkers such as 2 with various alkyl azide substrates [7]. They have shown that the ligation is a second order process: polar protic solvents and electron-donating substituents on the aryphosphine accelerate the reaction, while the

Preparation of new alkyne-modified ansamitocins by mutasynthesis

• Kirsten Harmrolfs,
• Lena Mancuso,
• Binia Drung,
• Florenz Sasse and
• Andreas Kirschning

Beilstein J. Org. Chem. 2014, 10, 535–543, doi:10.3762/bjoc.10.49

• that a release mechanism of the cytotoxin is part of the molecular architecture of the conjugate [31]. Disulfide linkers have shown to be well suited when utilizing the reducing power between extra- and intracellular milieus which results in cleavage and liberation of the drug. Mitomycin conjugates [32

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

• ligands with a furanylmethyl substituent (Figure 3), we decided to use a short linker. As an alternative approach, bivalent ligands with much longer linkers can bind simultaneously to both protomers in a receptor dimer, allowing selective targeting of specific receptor oligomers [21]. We also sought to

• provide a suitable attachment point for such linkers based on our previous studies of C-2 alkoxymethyl ethers [22][23], which have higher tolerance to alkyl chain extension [24] than other derivatives of 1 [1]. Results Synthesis Initial attempts to form the 16-dimethylaminomethyl derivative 2 by treatment

• is thus not a promising attachment point. At the opposite extreme, the C-2 alkoxymethyl ether series is highly tolerant to alkyl chain extension. Compound 6 and the synthetic route used may prove useful for the attachment of very long linkers, as used with other scaffolds to bridge receptor dimers

Synthesis of nucleotide–amino acid conjugates designed for photo-CIDNP experiments by a phosphotriester approach

• Tatyana V. Abramova,
• Olga B. Morozova,
• Vladimir N. Silnikov and
• Alexandra V. Yurkovskaya

Beilstein J. Org. Chem. 2013, 9, 2898–2909, doi:10.3762/bjoc.9.326

• conjugates consisting of amino acid, nucleotide, and dye residues including linkers of different lengths (Figure 1). Target compounds 1–8 have been synthesized by the phosphotriester block liquid phase synthesis (LPS). Results and Discussion Design of model compounds Our previous studies revealed a great

Gold(I)-catalyzed hydroarylation reaction of aryl (3-iodoprop-2-yn-1-yl) ethers: synthesis of 3-iodo-2H-chromene derivatives

• Pablo Morán-Poladura,
• Eduardo Rubio and
• José M. González

Beilstein J. Org. Chem. 2013, 9, 2120–2128, doi:10.3762/bjoc.9.249

• , two facts are of mechanistic significance. First, the 2:3 ratio for a given R substituent (Scheme 4A, R = 4-Cl) can be compared for the two linkers. For the nitrogen-containing tether (X = NTs, Scheme 4A), almost exclusive formation of 2 was noticed (reaction in 1,2-dichloroethane, at rt for 24 h, [43