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Recruiting endogenous antibodies to the surface of cancer cells using antibody-recruiting molecules has the potential to unleash innate immune effector killing mechanisms against antibody-bound cancer cells. The affinity of endogenous antibodies is relatively low, and many currently explored antibody-recruiting strategies rely on targeting over-expressed receptors, which have not yet been identified in most solid tumors. Here, both challenges are addressed by functionalizing poly(propyleneimine) (PPI) dendrimers with both multiple dinitrophenyl (DNP) motifs, as anti-hapten antibody-recruiting motifs, and myristoyl motifs, as universal phospholipid cell membrane anchoring motifs, to recruit anti-hapten antibodies to cell surfaces. By exploiting the multivalency of the ligand exposure on the dendrimer scaffold, it is demonstrated that dendrimers featuring ten myristoyl and six DNP motifs exhibit the highest antibody-recruiting capacity in vitro. Furthermore, it is shown that treating cancer cells with these dendrimers in vitro marks them for phagocytosis by macrophages in the presence of anti-hapten antibodies. As a proof-of-concept, it is shown that intratumoral injection of these dendrimers in vivo in tumor-bearing mice results in the recruitment of anti-DNP antibodies to the cell surface in the tumor microenvironment. These findings highlight the potential of dendrimers as a promising class of novel antibody-recruiting molecules for use in cancer immunotherapy., (© 2023 Wiley-VCH GmbH.)

We have synthesized B-antigen-displaying dendrimers (16-mers) with different sizes and evaluated their affinity to their IgM antibody in order to investigate which design features lead to effective multivalency. Unexpectedly, the smallest dendrimer, which cannot chelate the multiple binding sites of IgM, clearly exhibited multivalency, together with an affinity similar to or higher than those of the larger dendrimers. These results indicate that the statistical rebinding model, which involves the rapid exchange of clustered glycans, significantly contributes to the multivalency of glycodendrimers. Namely, in the design of glycodendrimers, high-density glycan presentation to enhance statistical rebinding should be considered in addition to the ability to chelate multiple binding sites. This notion stands in contrast to the currently prevailing scientific consensus, which prioritizes the chelation model. This study thus provides new and important guidelines for molecular design of glycodendrimers., (© 2022 Wiley-VCH GmbH.)

Nanomedicine is an emerging area that largely influences the efficacy of various therapies through the rational design of new materials exhibiting more targeted behavior. The synthetic effort, the amount of used material, and the cost are critical parameters to bear in mind if the production of the designed material is intended to be scaled for their widespread use. Even though materials science offers diverse options for different types of therapies, it is a difficult task to meet all the parameters mentioned above. The dendronization appears as an insightful approach to incorporate all the known benefits of the dendritic architecture by the attachment of dendrons to therapeutic agents, but in a much more affordable manner in terms of synthetic effort, amount of material, and cost. As will be presented, the most common dendrons used for biomedical applications are polyamide, polyester, carbosilane, polyether, and glycol-type, which are bonded to biological active molecules (BAMs), or molecular nanoplatforms (MPs) by hydrolysable bonds. Also relevant is the fact that the incorporation of dendrons not larger than third generation (G3) is sufficient to improve essential properties of these molecular systems, such as aqueous solubility, stability, and cellular internalization, among others. The type of dendron and its location on the BAMs or MPs, similar to placing a Lego piece on a model, will be decisive for obtaining the desired properties., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Biofilm formation by bacterial pathogens is a hallmark of chronic infections and is associated to increased antibiotic tolerance that makes pathogens difficult to eradicate with conventional antibiotic therapies. Infections caused by Pseudomonas aeruginosa are of great concern, especially for immunocompromised and cystic fibrosis patients. P. aeruginosa lectins LecA and LecB are virulence factors and play a key role in establishing biofilm; therefore, inhibition of the function of these proteins has potential in dismantling the bacterium from the protective biofilm environment and in restoring the activity of antibiotics. Here, we report the NMR characterization of the binding of a galactose-based dendrimer (Gal18) to LecA. Moreover, we demonstrate the activity of the Gal18 molecule in inhibiting P. aeruginosa biofilm formation in vitro., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Alzheimer's disease is one of the most common chronic neurodegenerative disorders. Despite several in vivo and clinical studies, the cause of the disease is poorly understood. Currently, amyloid β (Aβ) peptide and its tendency to assemble into soluble oligomers are known as a main pathogenic event leading to the interruption of synapses and brain degeneration. Targeting neurotoxic Aβ oligomers can help recognize the disease at an early stage or it can be a potential therapeutic approach. Unnatural β-peptidic foldamers are successfully used against many different protein targets due to their favorable structural and pharmacokinetic properties compared to small molecule or protein-like drug candidates. We have previously reported a tetravalent foldamer-dendrimer conjugate which can selectively bind Aβ oligomers. Taking advantage of multivalency and foldamers, we synthesized different multivalent foldamer-based conjugates to optimize the geometry of the ligand. Isothermal titration calorimetry (ITC) was used to measure binding affinity to Aβ, thereafter 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) based tissue viability assay and impedance-based viability assay on SH-SY5Y cells were applied to monitor Aβ toxicity and protective effects of the compounds. Important factors for high binding affinity were determined and a good correlation was found between influencing the valence and the capability of the conjugates for Aβ binding.

Chondroitin sulfate (CS) is a member of the glycosaminoglycan (GAG) family, a class of polysaccharides implicated in relevant biological functions. The structural complexity of these carbohydrates demands the development of simple glycomimetics as useful tools to study the biological processes in which GAGs are involved. In this work we described the synthesis of the disaccharide unit of the CS-E (GlcA-GalNAc(4,6-di-OSO 3 )), in a multivalent presentation. Using a fluorescence polarization competition assay we have demonstrated that a hexavalent dendrimer of this disaccharide interact with midkine, in the low micromolar range. This result highlights the potency of these disaccharide-displaying multivalent systems as interesting mimetics of longer and synthetically more complex GAG oligosaccharides., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Nearly all the cationic molecules tested so far have been shown to reversibly block K⁺ current through the cation-selective PA 63 channels of anthrax toxin in a wide nM-mM range of effective concentrations. A significant increase in channel-blocking activity of the cationic compounds was achieved when multiple copies of positively charged ligands were covalently linked to multivalent scaffolds, such as cyclodextrins and dendrimers. Even though multivalent binding can be strong when the individual bonds are relatively weak, for drug discovery purposes we often strive to design multivalent compounds with high individual functional group affinity toward the respective binding site on a multivalent target. Keeping this requirement in mind, here we perform a single-channel/single-molecule study to investigate kinetic parameters of anthrax toxin PA 63 channel blockage by second-generation (G2) poly(amido amine) (PAMAM) dendrimers functionalized with different surface ligands, including G2-NH₂, G2-OH, G2-succinamate, and G2-COONa. We found that the previously reported difference in IC 50 values of the G2-OH/PA 63 binding was determined by both on- and off-rates of the reversible dendrimer/channel binding reaction. In 1 M KCl, we observed a decrease of about three folds in k o n and a decrease of only about ten times in t r e s with G2-OH compared to G2-NH₂. At the same time for both blockers, k o n and t r e s increased dramatically with transmembrane voltage increase. PAMAM dendrimers functionalized with negatively charged succinamate, but not carboxyl surface groups, still had some residual activity in inhibiting the anthrax toxin channels. At 100 mV, the on-rate of the G2-succinamate binding was comparable with that of G2-OH but showed weaker voltage dependence when compared to G2-OH and G2-NH₂. The residence time of G2-succinamate in the channel exhibited opposite voltage dependence compared to G2-OH and G2-NH₂, increasing with the 63 binding was determined by both on- and off-rates of the reversible dendrimer/channel binding reaction. In 1 M KCl, we observed a decrease of about three folds in k o n and a decrease of only about ten times in t r e s with G2-OH compared to G2-NH₂. At the same time for both blockers, k o n and t r e s increased dramatically with transmembrane voltage increase. PAMAM dendrimers functionalized with negatively charged succinamate, but not carboxyl surface groups, still had some residual activity in inhibiting the anthrax toxin channels. At 100 mV, the on-rate of the G2-succinamate binding was comparable with that of G2-OH but showed weaker voltage dependence when compared to G2-OH and G2-NH₂. The residence time of G2-succinamate in the channel exhibited opposite voltage dependence compared to G2-OH and G2-NH₂, increasing with the cis ion current modulation by two different types of the "imperfect" PAMAM dendrimers, the mixed-surface G2 75% OH 25% NH₂ dendrimer and G3-NH₂ dendron. At low voltages, both "imperfect" dendrimers show similar rate constants but significantly weaker voltage sensitivity when compared with the intact G2-NH₂ PAMAM dendrimer.63 ion current modulation by two different types of the "imperfect" PAMAM dendrimers, the mixed-surface G2 75% OH 25% NH₂ dendrimer and G3-NH₂ dendron. At low voltages, both "imperfect" dendrimers show similar rate constants but significantly weaker voltage sensitivity when compared with the intact G2-NH₂ PAMAM dendrimer., Competing Interests: The authors declare no conflict of interest.

The development of pathogenic bacteria resistant to current treatments is a major issue facing the world today. Here, the synthesis and biological activity of fourth generation poly(amidoamine) dendrimers decorated with 1-hexadecyl-azoniabicylo[2.2.2]octane (C 16 -DABCO), a quaternary ammonium compound known to have antibacterial activity, are described. This highly cationic dendrimer antibiotic was tested against several Gram positive and Gram negative strains of pathogenic bacteria and exhibited activity against both. Higher activity toward the Gram positive strains that were tested was observed. After the antimicrobial activity was assessed, E. coli and B. cereus were subjected to a resistance selection study. This study demonstrated that a multivalent approach to antimicrobial design significantly reduces the likelihood of developing bacterial resistance. Highly cationic dendrimers were also used as pretreatment of a membrane to prevent biofilm formation.

Peptide-decorated dendrimers (PDDs) are a class of spherical, regular, branched polymers that are modified by peptides covalently attached to their surface. PDDs have been used as protein mimetics, novel biomaterials, and in a wide range of biomedical applications. Since their design and development in the late eighties, poly-l-lysine has been a preferred core structure for PDDs. However, numerous recent innovations in polymer synthesis and ligation chemistry have re-energized the field and led to the emergence of well-defined peptide dendrimers with more diverse core structures and functions. This Minireview highlights the development of PDDs driven by significantly improved ligation chemistry incorporating structurally well-defined peptides and the emerging use of PDDs in imaging and drug development., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Antagonists of mannose binding lectin (MBL) have shown a protective role against brain reperfusion damage after acute ischemic stroke. Here we describe the design and streamlined synthesis of glycomimetic MBL antagonists based on a new tetravalent dendron scaffold. The dendron was developed by optimisation of a known polyester structure previously demonstrated to be very efficient for ligand presentation to MBL. Replacement of a labile succinyl ester bond with a more robust amide functionality, use of a longer and more hydrophilic linker, fast modular synthesis and orthogonal functionalisation at the focal point are the main features of the new scaffold. The glycoconjugate constructs become stable to silica gel chromatography and to water solutions at physiological pH, while preserving water solubility and activity in an SPR assay against the murine MBL-C isoform. Higher-order constructs were easily assembled, as demonstrated by the synthesis of a 16-valent dendrimer, which leads to two orders of magnitude increase in activity over the tetravalent version against MBL-C., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The use of angiotensin receptor blockers (ARBs) for treatment of ocular diseases associated with neovascularizations, such as proliferative diabetic retinopathy, shows tremendous promise but is presently limited due to short intravitreal half-life. Conjugation of ARB molecules to branched polymers could vastly augment their therapeutic efficacy. EXP3174, a potent non-peptide ARB, was conjugated to branched poly(ethylene glycol) (PEG) and poly(amido amine) (PAMAM) dendrimers: 7.8 ligand molecules were tethered to each 40 kDa PEG molecule whereas 16.7 ligand molecules were linked to each PAMAM generation 5 dendrimer. The multivalent PEG and PAMAM conjugates blocked AT1R signaling with an IC50 of 224 and 36.3 nM, respectively. The 6-fold higher affinity of the multivalent ligand-conjugated PAMAM dendrimers was due to their unique microarchitecture and ability to suppress polymer-drug interactions. Remarkably, both polymer-drug conjugates exhibited no cytotoxicity, in stark contrast to plain PAMAM dendrimers. With sufficiently long vitreous half-lives, both synthesized polymer-ARB conjugates have the potential to pave a new path for the therapy of ocular diseases accompanied by retinal neovascularizations.

This study investigates transgeden (TGD) dendrimers (polyamidoamine (PAMAM)-type dendrimers modified with rigid polyphenylenevinylene (PPV) cores) and compares their heparin-binding ability with commercially available PAMAM dendrimers. Although the peripheral ligands are near-identical between the two dendrimer families, their heparin binding is very different. At low generation (G1), TGD outperforms PAMAM, but at higher generation (G2 and G3), the PAMAMs are better. Heparin binding also depends strongly on the dendrimer/heparin ratio. We explain these effects using multiscale modelling. TGD dendrimers exhibit "shape-persistent multivalency"; the rigidity means that small clusters of surface amines are locally well optimised for target binding, but it prevents the overall nanoscale structure from rearranging to maximise its contacts with a single heparin chain. Conversely, PAMAM dendrimers exhibit "adaptive multivalency"; the flexibility means individual surface ligands are not so well optimised locally to bind heparin chains, but the nanostructure can adapt more easily and maximise its binding contacts. As such, this study exemplifies important new paradigms in multivalent biomolecular recognition., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We have synthesized B‐antigen‐displaying dendrimers (16‐mers) with different sizes and evaluated their affinity to their IgM antibody in order to investigate which design features lead to effective multivalency. Unexpectedly, the smallest dendrimer, which cannot chelate the multiple binding sites of IgM, clearly exhibited multivalency, together with an affinity similar to or higher than those of the larger dendrimers. These results indicate that the statistical rebinding model, which involves the rapid exchange of clustered glycans, significantly contributes to the multivalency of glycodendrimers. Namely, in the design of glycodendrimers, high‐density glycan presentation to enhance statistical rebinding should be considered in addition to the ability to chelate multiple binding sites. This notion stands in contrast to the currently prevailing scientific consensus, which prioritizes the chelation model. This study thus provides new and important guidelines for molecular design of glycodendrimers. [ABSTRACT FROM AUTHOR]

[Display omitted] • Asymmetric synthesis of two enantiomeric ω-azido- C -alkyl hydroxypyrrolidines via Crabbé-Ma allenation. • Copper-free ligation on cyclooctyne–decorated cyclotriphosphazene-based dendrimers. • Nanomolar dodecavalent inhibitor of GCase. • First example of multivalent pyrrolidines acting as pharmacological chaperones of GCase in Gaucher disease fibroblasts. A concise asymmetric synthesis of clickable enantiomeric pyrrolidines was achieved using Crabbé-Ma allenation. The synthesized iminosugars were grafted by copper–free strain-promoted alkyne-azide cycloaddition onto phosphorus dendrimers. The hexavalent and dodecavalent pyrrolidines were evaluated as β–glucocerebrosidase inhibitors. The level of inhibition suggests that monofluorocyclooctatriazole group may contribute to the affinity for the protein leading to potent multivalent inhibitors. Docking studies were carried out to rationalize these results. Then, the iminosugars clusters were evaluated as pharmacological chaperones in Gaucher patients' fibroblasts. An increase in β–glucocerebrosidase activity was observed with hexavalent and dodecavalent pyrrolidines at concentrations as low as 1 µM and 0.1 µM, respectively. These iminosugar clusters constitute the first example of multivalent pyrrolidines acting as pharmacological chaperones against Gaucher disease. [ABSTRACT FROM AUTHOR]

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 chemistry approach involving the copper azide-alkyne-catalyzed cycloaddition (CuAAC) between suitable scaffolds bearing terminal alkyne moieties and an azido-functionalized piperidine as the bioactive moiety. A preliminary biological investigation is also reported towards commercially available and human glycosidases.

Galectin-3 meditates cell surface glycoprotein clustering, cross linking, and lattice formation. In cancer biology, galectin-3 has been reported to play a role in aggregation processes that lead to tumor embolization and survival. Here, we show that lactose-functionalized dendrimers interact with galectin-3 in a multivalent fashion to form aggregates. The glycodendrimer–galectin aggregates were characterized by dynamic light scattering and fluorescence microscopy methodologies and were found to be discrete particles that increased in size as the dendrimer generation was increased. These results show that nucleated aggregation of galectin-3 can be regulated by the nucleating polymer and provide insights that improve the general understanding of the binding and function of sugar-binding proteins.

Central scaffold topology and carbohydrate density are important features in determining the binding mechanism and potency of synthetic multivalent of poly- versus monodisperse carbohydrate systems against a model plant toxin ( Ricinus communis agglutinin (RCA120)). Lower densities of protein receptors favour the use of heterogeneous, polydisperse glycoconjugate presentations, as determined by surface plasmon resonance and dynamic light scattering. [ABSTRACT FROM AUTHOR]

This short review describes our work on the development of dendrimeric antagonists of DC-SIGN, a dendritic cells (DCs) receptor recognizing highly mannosylated structures and primarily involved in the recognition of viruses such as HIV. The structure of pseudo-di-mannoside and pseudo-tri-mannoside compounds was first finely modified to obtain DC-SIGN ligands that were more stable and selective than mannose. Their DC-SIGN affinity differences were amplified once presented on multivalent dendrimer-like scaffolds, including poly-alkyne terminated and phenylene-ethynylene rod-like ones. Libraries of mannosylated dendrimers were synthesized, improving their stability and maximizing their monodispersity. The effect of the dendrimers valency, structure, and size on DC-SIGN affinity and antiviral potency was investigated. Both the valency and the topology of the architectures were revealed as key parameters for activity optimization, together with the intrinsic affinity of the monovalent ligand. The stability, rigidity, and length of the scaffolds were also tuned. The design of geometrically adapted scaffolds afforded one of the most potent inhibitors of DC-SIGN mediated HIV infections to date. This monodispersed, not cytotoxic, and highly active compound was also tested with DCs; its internalization into endolysosomal compartments and its ability to induce the overexpression of signaling molecules makes it a good precursor to produce pathogen-entry inhibitors with immunomodulant properties. [ABSTRACT FROM AUTHOR]

Chondroitin sulfate (CS) is a member of the glycosaminoglycan (GAG) family, a class of polysaccharides implicated in relevant biological functions. The structural complexity of these carbohydrates demands the development of simple glycomimetics as useful tools to study the biological processes in which GAGs are involved. In this work we described the synthesis of the disaccharide unit of the CS-E (GlcA-GalNAc(4,6-di-OSO3)), in a multivalent presentation. Using a fluorescence polarization competition assay we have demonstrated that a hexavalent dendrimer of this disaccharide interact with midkine, in the low micromolar range. This result highlights the potency of these disaccharide-displaying multivalent systems as interesting mimetics of longer and synthetically more complex GAG oligosaccharides. [ABSTRACT FROM AUTHOR]

Over the past decade cyclodextrin vesicles were established as a versatile model for biological membranes since they can be easily modified with functional groups due to the spontaneous formation of host-guest complexes. In this article we report the interaction of phenylboronic acid functionalized polyamidoamine (PAMAM) dendrimers and cyclodextrin vesicles decorated with a catechol-adamantane conjugate to investigate dynamic multivalent recognition processes on membrane surfaces. The orthogonality and the multivalency in the ternary system of host vesicle, guest catechol conjugate and functionalized dendrimers were studied by isothermal titration calorimetry (ITC), dynamic light scattering (DLS) and time-depended measurements of optical density at 400 nm (OD400). It was shown that the aggregation of vesicles is highly dependent on the concentration of boronic acids as well as the generation, i.e. valency, of the dendrimers. [ABSTRACT FROM AUTHOR]

Chronic colonization of lungs by opportunist bacteria is the major cause of mortality for cystic fibrosis patients. Among these pathogens, Burkholderia cenocepacia is responsible for cepacia syndrome, a deadly exacerbation of infection that is the main cause of poor outcomes of lung transplantation. This bacterium contains three soluble carbohydrate-binding proteins, including the B. cenocepacia lectin A (BC2L-A), which is proposed to bind to oligomannose-type N-glycan structures to adhere to host tissues. In this work, several mannosylated glycoclusters and glycodendrimers with valencies ranging from four to 24 were prepared and their interactions with BC2L-A were thermodynamically characterized by isothermal titration calorimetry. The results show that a 24-valent structure binds to BC2L-A at nanomolar concentration, which makes this compound the highest affinity monodisperse ligand for this lectin. [ABSTRACT FROM AUTHOR]

The preparation of low-generation dendrimers based on a simple calix[4]arene scaffold by insertion of the iminosugar-analogue C2-symmetric 3,4-dihydroxypyrrolidine is described. This methodology allows a rapid incorporation of a considerable number of iminosugar-like moieties in a reduced volume and in a well-defined geometry. The inclusion of alkali-metal ions (sodium and potassium) in the polar cavity defined by the acetamide moieties at the lower rim of the calixarene was demonstrated, which allows also the 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 with more complex and/or biologically relevant iminosugars.

Peptide-decorated dendrimers (PDDs) are a class of spherical, regular, branched polymers that are modified by peptides covalently attached to their surface. PDDs have been used as protein mimetics, novel biomaterials, and in a wide range of biomedical applications. Since their design and development in the late eighties, poly- l-lysine has been a preferred core structure for PDDs. However, numerous recent innovations in polymer synthesis and ligation chemistry have re-energized the field and led to the emergence of well-defined peptide dendrimers with more diverse core structures and functions. This Minireview highlights the development of PDDs driven by significantly improved ligation chemistry incorporating structurally well-defined peptides and the emerging use of PDDs in imaging and drug development. [ABSTRACT FROM AUTHOR]

The monitoring of diabetes mellitus, as it develops and becomes clinically evident, remains a major challenge for diagnostic imaging in clinical practice. Here we present a novel approach to beta-cell imaging by targeting the sulphonylurea receptor subtype 1 (SUR1), using multivalent derivatives of the anti-diabetic drug glibenclamide. Since glibenclamide has a high affinity for SUR1 but does not contain a suitable functional group to be linked to an imaging probe, we have synthesized 11 glibenclamide derivatives and evaluated their affinity to SUR1 in MIN6 cells. The most promising compound has been used to obtain multivalent glibenclamide-polyamidoamine (PAMAM) derivatives, containing up to 15 sulphonylurea moieties per dendrimer. The remaining functional groups on the dendrimers can consecutively be used for labeling with reporter groups for different imaging modalities, thus allowing for multifunctional imaging, and for the modification of pharmacokinetic properties. We synthesized fluorochrome-labeled multivalent probes, that demonstrate in cellular assays affinities to SUR1 in the nanomolar range, superior to native glibenclamide. The probes specifically label MIN6 cells, but not HeLa or PANC-1 cells which do not express SUR1. A very low cytotoxicity of the multivalent probes is demonstrated by the persistent release of insulin from MIN6 cells exposed to high glucose concentrations. Furthermore, the probes display positive labeling of beta-cells of primary mouse and human islet-cells ex vivo and of islets of Langerhans in vivo . The data document that multivalent probes based on glibenclamide derivatives provide a suitable platform for further developments of cell-specific probes, and can be adapted for multiple imaging modalities, including those that are now used in the clinics. [ABSTRACT FROM AUTHOR]

Synthetic polymers play a critical role in pharmaceutical discovery and development. Current research and applications of pharmaceutical polymers are mainly focused on their functions as excipients and inert carriers of other pharmacologically active agents. This review article surveys recent advances in alternative pharmaceutical use of polymers as pharmacologically active agents known as polymeric drugs. Emphasis is placed on the benefits of polymeric drugs that are associated with their macromolecular character and their ability to explore biologically relevant multivalency processes. We discuss the main therapeutic uses of polymeric drugs as sequestrants, antimicrobials, antivirals, and anticancer and anti-inflammatory agents. [ABSTRACT FROM AUTHOR]

A number of new polyhydroxy-dendritic structures have been constructed from a few basic modules. The cores were derived from N - tert (butyloxycarbonyl)tris[(propargyloxy)methyl]aminomethane, N,N ′-bis-1,3-(tris-(propargyloxymethyl)methyl)-5-(hydroxymethyl)isophthalamide, and N,N ′, N ″-tris-1,3,5-(tris-(propargyloxymethyl)methyl)-1,3,5-benzene tricarboxamide while the terminal groups were derived from β -azido-galactose and β -azido-lactose leading to six new glycodendrimeric compounds with up to 63 hydroxyl groups on the periphery. The binding ability of the new compounds to peanut agglutinin (PNA), a galactose recognizing lectin from Arachis hypogaea , was investigated by nano-Isothermal Titration Calorimetry and nano-Differential Scanning Calorimetry. We found that the compounds had stronger stabilising effect on the macromolecules compared to the corresponding sugars. The interaction between lectin and the glycodendrimeric unit is entropically driven with only a low enthalpic contribution. A trend was found with increasing number of carbohydrates that is strongly influenced by the steric constraints of the ligands. Our results indicate the significance of multivalency and size control in the successful design of lectin inhibitors. [ABSTRACT FROM AUTHOR]

Galectins are evolutionarily conserved and ubiquitously present animal lectins with a high affinity for β-galactose-containing oligosaccharides. To date, 15 mammalian galectins have been identified. Their involvement in cell-cell and cell-matrix interactions has highlighted their importance in signal transduction and other intracellular processes. Human galectin-7 (hGal-7) is a 15 kDa proto type galectin that forms a dimer in solution and its involvement in the stimulation and development of tumour growth has been reported. Previously, we reported the crystal structure of hGal-7 and its complex with galactose and lactose which provided insight into its molecular recognition and detailed interactions. Here, we present newly obtained high-resolution structural data on carbohydrate-based dendrons in complex with hGal-7. Our crystallographic data reveal how multivalent ligands interact with and form cross-links with these galectin molecules. Understanding how these dendrimeric compounds interact with hGal-7 would help in the design of new tools to investigate the recognition of carbohydrates by lectins. Database The atomic coordinates and structure factors for hGal-7-D1 (code ), hGal7-D2 (codes , ) and hGal-7-D3 (code ) complexes have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ, USA (). [ABSTRACT FROM AUTHOR]

This study investigates transgeden (TGD) dendrimers (polyamidoamine (PAMAM)-type dendrimers modified with rigid polyphenylenevinylene (PPV) cores) and compares their heparin-binding ability with commercially available PAMAM dendrimers. Although the peripheral ligands are near-identical between the two dendrimer families, their heparin binding is very different. At low generation (G1), TGD outperforms PAMAM, but at higher generation (G2 and G3), the PAMAMs are better. Heparin binding also depends strongly on the dendrimer/heparin ratio. We explain these effects using multiscale modelling. TGD dendrimers exhibit 'shape-persistent multivalency'; the rigidity means that small clusters of surface amines are locally well optimised for target binding, but it prevents the overall nanoscale structure from rearranging to maximise its contacts with a single heparin chain. Conversely, PAMAM dendrimers exhibit 'adaptive multivalency'; the flexibility means individual surface ligands are not so well optimised locally to bind heparin chains, but the nanostructure can adapt more easily and maximise its binding contacts. As such, this study exemplifies important new paradigms in multivalent biomolecular recognition. [ABSTRACT FROM AUTHOR]

Noncovalent dendrimer-dendrimer complexes were successfully ionized by electrospray ionization of partly protonated amino-terminated polypropylene amine (POPAM) and POPAM dendrimers fully functionalized with benzo[21]crown-7 on all branches. Hydrogen/deuterium exchange (HDX) experiments conducted on dendrimer-dendrimer complexes in the high vacuum of a mass spectrometer give rise to a complete exchange of all labile NH hydrogen atoms. As crown ethers represent noncovalent protective groups against HDX reactions on the ammonium group to which they are coordinated, this result provides evidence for a very dynamic binding situation: each crown is mobile enough to move from one ammonium binding site to another. Schematically, one might compare this motion with two rock 'n' roll dancers that swirl around each other without completely losing all contact at any time. Although the multivalent attachment certainly increases the overall affinity, the 'microdynamics' of individual site binding and dissociation remains fast. [ABSTRACT FROM AUTHOR]

Due to its rigid cage structure, adamantane has received considerable interest as a scaffold with a defined tetrahedral geom-etry. In this paper we describe orthogonally functionalized tetrasub-stituted adamantane derivatives. These compounds may be conjugated to other functional molecules by standard techniques such as amide formation or click chemistry and are thus useful (3 + 1) scaffolds for medicinal and material chemistry. [ABSTRACT FROM AUTHOR]

We have developed a straightforward strategy to multimerize an apoptogenic peptide that mimics the natural tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by using adamantane-based dendrons as multivalent scaffolds. The selective binding affinity of the ligands to TRAIL receptor 2 (TR2) was studied by surface plasmon resonance, thus demonstrating that the trimeric and hexameric forms of the peptide exert an increased affinity of about 1500- and 20 000-fold, respectively, relative to the monomer. Moreover, only the trimeric and hexameric ligands were able to induce cell death in TR2 expressing cells (BJAB), thus confirming that a multivalent form of the peptide is necessary to trigger a substantial TR2-dependent apoptotic response in vitro. These results provide interesting insight into the multivalency effect on biological ligand/receptor interactions for future therapeutic applications. [ABSTRACT FROM AUTHOR]

Abstract: Dendrimers are ideal platforms to study multivalent effects due to the presence of uniform end groups at their peripheries. This report concerns with a study of multivalent dendritic catalysts, both within and across dendrimer generations, and their effects to mediate C–C bond forming reactions on multivalent substrates that have two and three acrylate reactive sites. As many as fourteen multivalent dendritic catalysts were prepared using 0–3 generations of poly(propyl ether imine) dendrimers, incorporated with Pd(II) catalytic sites, both within and across the dendrimer generations. C–C Bond forming reactions of these substrates with iodobenzene, mediated by uniform concentration of the metal across all catalysts, showed formation of partially and fully functionalized cinnamates in varying ratios, depending on the extent of clustering of catalytic moieties at the peripheries of dendrimers within a dendrimer generation. In a given generation, higher clustering of catalytic moieties greatly assisted multiple C–C bond formations than presenting the same in lesser number. The studies demonstrate true benefits of clustering catalytic moieties within a dendrimer generation and the beneficial effects applicable to catalysis of substrates presenting more than one reactive center. [Copyright &y& Elsevier]

Abstract: The development of methodology that is designed to allow a significant increase in the patterning and in the functionalization of the dendrimer is the ultimate goal of the research described here. Glycoside clusters based on TRIS were formed using click chemistry and were attached to PAMAM dendrimers. A series of dendrimers bearing tris-mannoside and an ethoxyethanol group was synthesized, and the binding interactions of these dendrimers with Concanavalin A were evaluated using inhibition ELISAs. The results of the inhibition ELISAs suggest that tris-mannoside clusters can replace individual sugars on the dendrimer without loss of function. Since tris-mannoside clustering allows for a redistribution of the dendrimers’ surface functionalities, from this chemistry one can envision patterned dendrimers that incorporate multiple groups to increase the function and utility of the dendrimer. [Copyright &y& Elsevier]

The synthesis of a glycodendrimer by incorporating repetitive mannoside units onto a glucoside core was carried out to multivalently probe fundamental carbohydrate-protein interactions. The dendritic structure was constructed by a modified procedure that utilized multiple glycosylations between a thioether glycosyl donor and five elongated spacer arms of a glycosyl acceptor. The completed dendrimer bears a full carbohydrate structure, and thus should find its potential application in the study of mannose-lectin interactions. [ABSTRACT FROM AUTHOR]

Abstract: Collagen is an attractive marker for tissue remodeling in a variety of common disease processes. Here we report the preparation of protein dendrimers as multivalent collagen targeting ligands by native chemical ligation of the collagen binding protein CNA35 to cysteine-functionalized dendritic divalent (AB2) and tetravalent (AB4) wedges. The binding of these multivalent protein constructs was studied on collagen-immobilized chip surfaces as well as to native collagen in rat intestinal tissues. To understand the importance of target density we also created collagen-mimicking surfaces by immobilizing synthetic collagen triple helical peptides at various densities on a chip surface. Multivalent display of a weak-binding variant (CNA35-Y175K) resulted in a large increase in collagen affinity, effectively restoring the collagen imaging capacities for the AB4 system. In addition, dissociation of these multivalent CNA35 dendrimers from collagen surfaces was found to be strongly attenuated. [Copyright &y& Elsevier]

Abstract: Understanding protein/carbohydrate interactions is essential for elucidating biological pathways and cellular mechanisms but is often difficult due to the prevalence of multivalent interactions. Here, we evaluate the multivalent glycodendrimer framework as a means to describe the inhibition potency of multivalent mannose-functionalized dendrimers using surface plasmon resonance (SPR). Using highly robust, mannose-functionalized dithiol self-assembled monolayers on gold surfaces, we found that glycodendrimers were efficient inhibitors of protein/carbohydrate interactions. IC50 values ranging from 260nM to 13nM were obtained for mannose-functionalized dendrimers with Concanavalin A. [Copyright &y& Elsevier]

Abstract: DOTA (1,4,7,10-tetraazacyclodocecane-N,N′,N″,N‴-tetraacetic acid), which forms extremely stable complexes with a large number of metal ions, is one of the most important and most commonly used chelators for in vivo applications such as cancer diagnosis and therapy. However, many of the published synthesis protocols for DOTA derivatives are complicated and give the products in low yields. Here we report improved synthesis routes for tris-tBu-DOTA, tris-benzyl-DOTA, and thiol-DOTA, and also describe the synthesis of the novel compound tris-4-nitro-benzyl-DOTA. In addition, we determined the applicability of the DOTA derivatives tris-tBu-DOTA, thiol-DOTA, tris-benzyl-DOTA, tris-4-nitrobenzyl-DOTA, tris-allyl-DOTA, DOTA-PFP-ester, and DOTA-PNP-ester for multimerization reactions using amino functionalized PAMAM dendrimers of different sizes. Thiol-DOTA was found to be the best compound for efficient reactions with dendritic scaffolds generating highly homogeneous DOTA-multimers. This DOTA derivative could be quantitatively conjugated to a 128-mer dendrimer. [Copyright &y& Elsevier]

Solid-phase synthesis is an ideal tool for reactions that require high concentrations and excess reagents and forcing chemical conditions. One such chemistry is that required for dendrimer construction. In this paper the synthesis of a series of symmetrical AB3 isocyanate-type monomers is reported and used for the preparation of tri-branched dendrimers on the solid-phase. This method not only allows isolable dendrimer but can generate high-loading supports and devices for multivalent presentation. [Copyright &y& Elsevier]

Glycodendrimers are receiving considerable attention to mimic a number of imperative features of cell surface glycoconjugate and acquired excellent relevance to a wide domain of investigations including medicine, pharmaceutics, catalysis, nanotechnology, carbohydrate-protein interaction, and moreover in drug delivery systems. Toward this end, an expeditious, modular, and regioselective triazole-forming CuAAC click approach along with double stage convergent synthetic method was chosen to develop a variety of novel chlorine-containing cyclen cored glycodendrimers of high sugar tethers at low generation of promising therapeutic potential. We developed a novel chlorine-containing hypercore unit with 12 alkynyl functionality originated from cyclen scaffold which was confirmed by its single crystal X-ray data analysis. Further, the modular CuAAC technique was utilized to produce a variety of novel 12–sugar coated (G 0) glycodendrimers 12-15 adorn with β -Glc-, β -Man-, β -Gal-, β -Lac, along with 36-galactose coated (G 1) glycodendrimer 18 in good-to-high yield. The structures of the developed glycodendrimer architectures have been well elucidated by extensive spectral analysis including NMR (1H &13CNMR), HRMS, MALDI-TOF MS, UV–Vis, IR, and SEC (Size Exclusion Chromatogram) data. [Display omitted] • A series of Cyclen Cored Glycodendrimer has been achieved with high Sugar Tethers at Low Generation by using modular CuAAC 'Click Chemistry'. • A double stage convergent protocol was explored to facilitate generation of 36-galactose coated (G 1) glycodendrimer. • The developed sugar coated (G 0) glycodendrimers have been characterized by its NMR, MALDI-TOF, UV–Vis, IR, and SEC analysis. • The high functional group density at the low generation of glycodendrimer may open a new area for the carbohydrate-protein interaction. [ABSTRACT FROM AUTHOR]