Selective Targeting of Dendritic Cell‐Specific Intercellular Adhesion Molecule‐3‐Grabbing Nonintegrin (DC‐SIGN) with Mannose‐Based Glycomimetics: Synthesis and Interaction Studies of Bis(benzylamide) Derivatives of a Pseudomannobioside

Dendritic cell‐specific intercellular adhesion molecule‐3‐grabbing nonintegrin (DC‐SIGN) and Langerin are C‐type lectins of dendritic cells (DCs) that share a specificity for mannose and are involved in pathogen recognition. HIV is known to use DC‐SIGN on DCs to facilitate transinfection of T‐cells. Langerin, on the contrary, contributes to virus elimination; therefore, the inhibition of this latter receptor is undesired. Glycomimetic molecules targeting DC‐SIGN have been reported as promising agents for the inhibition of viral infections and for the modulation of immune responses mediated by DC‐SIGN. We show here for the first time that glycomimetics based on a mannose anchor can be tuned to selectively inhibit DC‐SIGN over Langerin. Based on structural and binding studies of a mannobioside mimic previously described by us ( 2 ), a focused library of derivatives was designed. The optimized synthesis gave fast and efficient access to a group of bis(amides), decorated with an azide‐terminated tether allowing further conjugation. SPR inhibition tests showed improvements over the parent pseudomannobioside by a factor of 3–4. A dimeric, macrocyclic structure ( 11 ) was also serendipitously obtained, which afforded a 30‐fold gain over the starting compound ( 2 ). The same ligands were tested against Langerin and found to exhibit high selectivity towards DC‐SIGN. Structural studies using saturation transfer difference NMR spectroscopy (STD‐NMR) were performed to analyze the binding mode of one representative library member with DC‐SIGN. Despite the overlap of some signals, it was established that the new ligand interacts with the protein in the same fashion as the parent pseudodisaccharide. The two aromatic amide moieties showed relatively high saturation in the STD spectrum, which suggests that the improved potency of the bis(amides) over the parent dimethyl ester can be attributed to lipophilic interactions between the aromatic groups of the ligand and the binding site of DC‐SIGN.     

Triggering Activity of Catalytic Rod‐Like Supramolecular Polymers

Supramolecular polymers based on benzene‐1,3,5‐tricarboxamides (BTAs) functionalized with an L ‐ or D ‐proline moiety display high catalytic activity towards aldol reactions in water. High turnover frequencies (TOF) of up to 27×10^?4 s^?1 and excellent stereoselectivities (up to 96 % de, up to 99 % ee) were observed. In addition, the catalyst could be reused and remained active at catalyst loadings and substrate concentrations as low as 0.1 mol % and 50 mM , respectively. A temperature‐induced conformational change in the supramolecular polymer triggers the high activity of the catalyst. The supramolecular polymer’s helical sense in combination with the configuration of the proline (L ‐ or D ‐) is responsible for the observed selectivity.     

Molecular Recognition in Solutions of Rod‐Like Copolymers with Two Different Sequences

Segregation in a solution of rigid copolymeric molecules with two different sequences leading to co‐existence of two smectic mesophases has been studied. Thermodynamic characteristics of these mesophases and their equilibrium compositions were found in the frame of two discrete models. It was shown that the degree of ordering in the mesophase depends on the sequence of units in the identical molecules forming this mesophase. The concentration of “mismatched” molecules in the mesophase (the purity of mesophase) is determined both by the composition and the sequence of such molecules. It was shown, that a difference in the sequences can be sufficient to cause phase separation.

     

Synthesis and Characterization of Some Novel Glycodendrimers and N-alkyldendrimers with Amide Core and Triazole Functionality through Click Chemistry

The syntheses of various types of 1,2,3-triazole-based dendrimers 1–4 with sugar pyranosylazides and N-ethyl and N-heptylazides as a surface unit and benzene-1,3,5-tricorboxlyic amide as core unit through click chemistry approach are described.

Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.     

Metallogels Self‐Assembled from Linear Rod‐Like Platinum Complexes: Influence of the Linkage

Two linear rod‐like platinum complexes, which only differed in the linkage, were prepared. They both self‐assemble into metallogels in nonpolar solvents; however, a very big contrast was observed. Unexpectedly, a much weaker gel was acquired upon replacing the ester linkage by an amide group. The intermolecular hydrogen bonding offered by the amide motif leads to a different stacking fashion and mechanism. The results demonstrated herein contribute to the rational design of metallogels as well as other functional supramolecular materials.     

Amphiphilic Comb‐Like Poly(oxyethylene) and Its Complexes with LiClO4: Synthesis and Mesomorphic Behavior

Summary: We prepared an amphiphilic, comb‐like poly(oxyethylene) containing decyl‐tri(oxyethylene) amphiphiles in the side chain using a polymer analogous reaction to obtain a novel nonionic amphiphilic polymeric system with high molecular weight. The amphiphilic comb‐like poly(oxyethylene) itself only showed a side‐chain crystalline phase below its melting temperature of −31 °C. When the polymer was mixed with lithium perchlorate, a smectic liquid‐crystalline phase appeared. The ordered phases of the polymer and the polymer mixture were studied by differential scanning calorimetry, polarized optical microscopy, and X‐ray diffraction.

POM image (200 X) of D3OTP1 at room temperature.     

Mimicking Biological Membranes with Programmable Glycan Ligands Self‐Assembled from Amphiphilic Janus Glycodendrimers

An accelerated modular synthesis produced 18 amphiphilic Janus glycodendrimers with three different topologies formed from either two or one carbohydrate head groups or a mixed constellation with a noncarbohydrate hydrophilic arm. By simple injection of their THF solutions into water or buffer, all of the Janus compounds self‐assembled into uniform, stable, and soft unilamellar vesicles, denoted glycodendrimersomes. The mixed constellation topology glycodendrimersomes were demonstrated to be most efficient in binding plant, bacterial, and human lectins. This evidence with biomedically relevant receptors offers a promising perspective for the application of such glycodendrimersomes in targeted drug delivery, vaccines, and other areas of nanomedicine.     

Comb‐Like Amphiphilic Polycarbonates with Different Lengths of Cationic Branches for Enhanced siRNA Delivery

Owing to the biodegradability and good biocompatibility polycarbonates show the versatile class of applications in biomedical fields. While their poor functional ability seriously limited the development of functional polycarbonates. Herein, a new Br‐containing cyclic carbonate (MTC‐Br) and a polycarbonate atom transfer radical polymerization (ATRP) macro‐initiator (PEG‐PMTC‐Br) is synthesized. Then, by initiating the side‐chain ATRP of 2‐(dimethyl amino)ethyl methacrylate (DMAEMA) on PEG‐PMTC‐Br, a series of comb‐like amphiphilic cationic polycarbonates, PEG‐b‐(PMTC‐g‐PDMAEMA) (GMDMs), with different lengths of cationic branches are successfully prepared. All these poly(ethylene glycol)‐b‐(poly((5‐methyl‐2‐oxo‐1,3‐dioxane‐5‐yl) methyl 2‐bromo‐2‐methylpropanoate/1,3‐dioxane‐2‐one)‐g‐poly(2‐dimethyl aminoethyl methacrylate) (GMDMs) self‐assembled nanoparticles (NPs) (≈180 nm, +40 mV) can well bind siRNA to form GMDM/siRNA NPs. The gene silence efficiency of GMDM/siRNA high to 80%, which is even higher than the commercial transfection reagent lipo2000 (76%). But GMDM/siRNA shows lower cell uptake than lipo2000. So, the high gene silence ability of GMDM/siRNA NPs can be attributed to the strong intracellular siRNA trafficking capacity. Therefore, GMDM NPs are potential siRNA vectors and the successful preparation of comb‐like polycarbonates also provides a facile way for diverse side‐chain functional polycarbonates, expanding the application of polycarbonates.     

Aqueous Networks and Toroids of Amphiphilic Block Copolymer with Non‐ionic Surfactants

Network formation: Comicellization of polystyrene‐block‐polyethylene oxide (PS–PEO) with non‐ionic surfactants leads to the formation of networks and chains of spheres. The aqueous network solutions are responsive to dilution, undergoing morphological transformations to cylinders with Y junctions and both two‐ and three‐dimensional toroids (see figure).

     

Solvent‐Responsive Behavior of Polymer‐Brush‐Modified Amphiphilic Gold Nanoparticles

Amphiphilic polymer brushes grafted onto gold nanoparticles impart distinct solvent‐responsive behavior via the change to particle size and surface chemistry and, therefore, wide application prospects can be expected. Coarse‐grained simulations are performed for block and/or mixed polystyrene (PS)/poly(ethylene oxide) (PEO)‐modified amphiphilic gold nanoparticles (AuNP) to investigate their responsive behavior in five different solvents by analyzing their morphology, distribution density profiles, and gyration radii. Typical core–shell, Janus‐type, buckle‐like, ring‐like, jellyfish‐like, and octopus‐like morphologies are formed. Influence of block sequence, mixing mode, and several other effects are discussed. Responsive particle size and surface hydrophilicity can be successfully reproduced by altering solvents.

     

Synthesis of Novel Rod‐Coil Amphiphilic Block Copolymers PAA‐b‐DPS with Fréchet‐Type Dendronized Polystyrene and Poly(acrylic acid)

A series of well‐defined rod‐coil PAA‐b‐DPS block copolymers, containing Fréchet‐type dendronized polystyrene (DPS) with different generation as a rod‐like hydrophobic block and poly(acrylic acid) (PAA) as a hydrophilic coil were synthesized. The procedure included the following steps: the precursor PMA‐b‐DPS copolymer was prepared through ATRP of Fréchet‐type dendritic styrene macromonomer bearing the first to the third generation (G1–G3), respectively, initiated by poly(methyl acrylate) (PMA‐Br). Then, by converting PMA into PAA by subsequent hydrolysis, the targeted amphiphilic copolymers were obtained. Moreover, by using the rod‐coil amphiphiles as building blocks, large compound micelles and vesicles were formed in a binary solvent mixture of DMF/H₂O. Morphological changes in self‐assembly showed dependence on the length of the dendronized block.

     

Preparation of Nanostructured Polyaniline and its Super‐Amphiphilic Behavior

PANI nanofibers are prepared electrochemically by template‐free method on a stainless steel electrode. Both the hydrophilicity and the lipophilicity of the modified SS surface are enhanced by the nanostructured PANI, and a super‐amphiphilic surface is obtained in this way. The influence of polymerization conditions, such as polymerization potentials, polymerization time, the acidity, and the dopants on the super‐amphiphilic property, has been systematically investigated. In addition, the mechanisms of obtaining a super‐amphiphilic surface are briefly discussed.

     

Self‐Assembly of Rod–Coil Polyethylenimine–Poly(ethylene glycol)–α‐Cyclodextrin Inclusion Complexes into Hollow Spheres and Rod‐Like Particles

This paper describes the self‐assembly of rod–coil inclusion complexes, polyethylenimine–poly(ethylene glycol)–α‐cyclodextrin (PEI–PEG–α‐CD). It is demonstrated that α‐CDs should exclusively thread on the PEG block in PEI–PEG copolymers and the resulting complexes have both rigid block (PEG–α‐CD) and coil block (protonated PEI). By varying the rigid block fraction, aggregates with hollow spheres or rod‐like particles could be formed simply by self‐assembly in aqueous solution.     

Polyglycidol Based Amphiphilic Double‐Comb Copolymers and Their Self‐Association in Aqueous Solution

Herein, we report synthesis and self‐association properties of amphiphilic double‐comb polymers with polyglycidol backbones. First, a bifunctional polyglycidol precursor is synthesized via monomer activated anionic polymerization. Next, two efficient and orthogonal polymer analogous reactions are carried out for grafting hydrophilic oligoethylene glycol side chains and hydrophobic linear aliphatic side‐chains. The polymers are analyzed by means of NMR, GPC, and DSC. From the DSC analysis of the bulk samples it is evident that aliphatic side chains segregate from the polar backbone and thus crystallize. Furthermore, in aqueous media the double‐comb polymers spontaneously self‐assemble to form a multilayer structure. The present results pave a way to tailor and design amphiphilic polymers based on glycidols. Major advantages are spontaneous self‐assembly in water and the possibility to form onion polymersomes relevant to encapsulation.

     

2,6‐Diaminopyridine and Acrylamide‐Based Copolymers with Upper Critical Solution Temperature‐type Behavior in Aqueous Solution

A novel copolymer based on supramolecular motif 2,6‐diaminopyridine and water‐soluble acrylamide, poly[N‐(6‐acetamidopyridin‐2‐yl) acrylamide‐co‐acrylamide], was synthesized via reversible addition–fragmentation chain transfer (RAFT) polymerization with various monomer compositions. The thermoresponsive behavior of the copolymers was studied by turbidimetry and dynamic light scattering (DLS). The obtained copolymers showed an upper critical solution temperature (UCST)‐type phase transition behavior in water and electrolyte solution. The phase transition temperature was found to increase with decreasing amount of acrylamide in the copolymer and increasing concentration of the solution. Furthermore, the phase transition temperature varied in aqueous solutions of electrolytes according to the nature and concentration of the electrolyte in accordance with the Hoffmeister series. A dramatic solvent isotope effect on the transition temperature was observed in this study, as the transition temperature was almost 10–12 °C higher in D₂O than in H₂O at the same concentration and acrylamide composition. The size of the aggregates below the transition temperature was larger in D₂O compared to that in H₂O that can be explained by deuterium isotope effect. The thermoresponsive behavior of the copolymers was also investigated in different cell medium and found to be exhibited UCST‐type phase transition behavior in different cell medium. Such behavior of the copolymers can be useful in many applications including biomedical, microfluidics, optical materials, and in drug delivery. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 2064–2073     

Assembly of a Nanoreactor System with Confined Magnetite Core and Shell for Enhanced Fenton‐Like Catalysis

Conventional solid catalysts for heterogeneous Fenton‐like reactions in bulk solution usually suffer from aggregation and vulnerability, which greatly lower the catalytic efficiency and hamper their practical application. Herein, we demonstrate a promising yolk–shell nanostructure with both the core and the shell composed of magnetite (designated as yolk‐like Fe₃O₄@Fe₃O₄/C) as a nanoreactor capable of accommodating the Fenton‐like reaction into its void space. Benefiting from the mesoporous shell and perfect interior cavity of this composite, reactants can access and be abundantly confined within the microenvironment where Fe₃O₄ sites are dispersed on the entire cavity surfaces, thus leading to a higher catalytic efficiency compared with the conventional solid catalysts in bulk solution. The chosen model reaction of chlorophenols degradation in the presence of the as‐prepared materials as well as hydrogen peroxide (H₂O₂) confirms this assumption. Under the optimal reaction conditions, more than 97 % 4‐chlorophenol (4‐CP) can be degraded in the Fe₃O₄@Fe₃O₄/C nanoreactor, whereas only 28 % can be achieved by using bare Fe₃O₄ particles within 60 min. Furthermore, owing to the existence of the outermost carbon layer and high‐magnetization properties, the nanoreactor can be re‐used for several runs. The synthesized nanoreactor displays superior catalytic activity toward the Fenton‐like reaction compared with the bare solid catalysts, and thereby holds significant potential for practical application in environmental remediation.     

Chain Architecture Dependent 3‐Dimensional Supramolecular Assembly of Rod‐Coil Molecules with a Conjugated Hexa‐p‐phenylene Rod

Summary: We have prepared hexa‐p‐phenylene based rod‐coil molecules with identical coil volume fractions, but different poly(propylene oxide) (PPO) coil architectures (linear versus dibranched), and investigated their self‐assembling behavior in the solid state by small angle X‐ray scattering (SAXS) and transmission electron microscopy (TEM) techniques. Rod‐coil molecules with a linear PPO coil showed a honeycomb‐like lamellar assembly of rod segments with hexagonally arrayed PPO coil perforations. In contrast, the rod‐coil molecules with dibranched PPO coils self‐organized into rod bundles with a body centered tetragonal symmetry surrounded by a PPO coil matrix. These results demonstrate that the steric hindrance at the rod/coil interface arising from coil architectural variation is a dominant parameter governing supramolecular rod assembly in the rod‐coil system.

TEM images and schematic illustrations of the self‐assembled structures of rod‐coil molecules with linear (left) and dibranched (right) PPO coils, respectively.