Covalent functionalization of solid cellulose by divergent synthesis of chemically active dendrons

Covalent surface modification of solid cellulose with well‐defined and chemically reactive dendrons is introduced as a platform for cellulose grafting with functional materials. Surface functionalization with a first generation dendron is achieved by esterification employing bifunctional molecules based on 2,2‐bis(hydroxymethyl) propionic acid (bis‐MPA) under mild conditions and short reaction times. The activated cellulose surface displays hydrophobic properties and contains two reactive alkene end‐groups per graft, which are used for covalent binding to active agents, as demonstrated by selective functionalization of the modified cellulose with fluorescent dye via photopatterning. The number of active end‐groups on the surface of cellulose is multiplied by divergent solid‐state synthesis of second and third generation dendrons having four and eight reactive sites per dendron, respectively. The dendrons are assembled in only few hours by a sequence of thiol‐ene/esterification reactions. The ability to accurately control the number of binding sites on the surface of cellulose allows fine tuning of the surface properties, as shown by the attachment of hydrophobic small molecules to the dendronized cellulose. The first, second and third generation dendrons allow preparing surfaces with increasing hydrophobicities; second and third generation dendrons functionalized with small perfluoroalkyl molecule display superhydrophobic properties. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 2103–2114     

Quantifying the Effect of Surface Ligands on Dendron–DNA Interactions: Insights into Multivalency through a Combined Experimental and Theoretical Approach

We report the synthesis, DNA binding ability and preliminary gene delivery profiles of dendrons with different amine surface groups, 1,3‐diaminopropane (DAP), N,N‐di‐(3‐aminopropyl)‐N‐(methyl)amine (DAPMA) and spermine (SPM). By using a combination of ethidium bromide displacement, gel electrophoresis and transfection assays, it is shown that the dendrons with SPM groups are the most effective DNA binders, while the DAPMA‐functionalised dendrons were the most effective systems for gene delivery (although the gene delivery profiles were still modest). In order to provide deeper insight into the experimental data, we performed a molecular dynamics simulation of the interactions between the dendrons and DNA. The results of these simulations demonstrated that, in general terms, the enthalpic contribution to binding was roughly proportional to the dendron surface charge, but that dendrons with DAP (and DAPMA) surface amines had significant entropic costs of binding to DNA. In the case of DAP, this is a consequence of the fact that the entire dendron structure has to be organised in order for each individual monoamine charge to make effective contact with DNA. For SPM, however, each surface ligand is already a multivalent triamine, therefore, each individual charge has a much lower entropic cost of binding. For DAPMA, we observed that strong binding of the hindered tertiary amine to the DNA double helix led to ligand back‐folding and significant geometric distortion of DNA. Although this weakens the overall binding, we suggest that this distortion might be an explanation for the experimentally observed enhanced gene delivery, in which DNA compaction is an important step. Overall, this paper demonstrates how structure–activity relationships can be developed for multivalent dendritic ligands and provides insights into the thermodynamics of multivalent interactions.     

Synthesis of nanoparticle-cored dendrimers by convergent dendritic functionalization of monolayer-protected nanoparticles

This article presents a synthesis method for nanoparticle-cored dendrimers (NCDs), which have dendritic architectures around a monolayer-protected gold nanoparticle. The synthesis method is based on a strategy in which the synthesis of monolayer-protected nanoparticles is followed by adding dendrons on functionalized nanoparticles by a single coupling reaction. NMR spectroscopy, IR spectroscopy, and thermogravimetric analysis (TGA) characterizations confirmed the successful coupling reaction between dendrons with different generations ([G1], [G2], and [G3]) and COOH-functionalized nanoparticles ( approximately Au201L71). The dendrimer wedge density also could be controlled by reacting nanoparticles having different loading of COOH groups ( approximately 60 and approximately 10% COOH of the 71 ligands per gold nanoparticle) with functionalized dendrons. Transmission electron microscope results showed that this synthesis strategy maintains the average size of the nanoparticle core during dendron coupling reactions. This control over the composition and core size makes the systematic study of NCDs with different generations possible. The chemical stability of NCDs was found to be affected by dendron generation around the nanoparticle core. The current-potential response of NCD films on microelectrode arrays exhibited better electrical conductivity for NCDs with lower dendron generation.     

Preparation of siloxy focal dendron-protected TiO2 nanoparticles and their photocatalysis

TiO2 nanoparticles were synthesized at approximately 0 degrees C by hydrolyzing [(CH3)2CHO]4Ti in 1-propanol solutions of poly(amido amine) dendrons with a siloxy focal point and long alkyl chain spacers. Transmission electron microscopic photographs showed that TiO2 nanoparticle was 1-5 nm in size and protected by dendrons, when prepared at a mixing ratio 1:10 of Ti ion and dendron. At higher contents of Ti ion, TiO2 nanoparticles aggregated up to a maximum size of 90 nm, depending on the dendron generation (first to third). It was confirmed from X-ray photoelectron spectroscopy that Si-O-Ti covalent bond was formed in dendron-protected TiO2 nanoparticles. The ability of dendron-protected TiO2 nanoparticles as a photocatalyst for the photodegradation of 2,4-dichlorophenoxyacetic acid was higher than that of nonprotected nanoparticle and superior at higher generation. It was suggested that the dendrons protecting TiO2 nanoparticle have enough void volume to conserve guest molecules and behave effectively as a reservoir of guest molecules.     

Carbosilane dendrons as stabilizing agents for the formation of gold nanoparticles

The synthesis and characterization of two new carbosilane dendrons functionalized in the focal point with a single thiol group is described. These molecules were used as stabilizing agents for the formation of gold nanoparticles. These materials were obtained by the reduction of hydrogen tetrachloroaurate phase-transferred into toluene in the presence of the carbosilane dendrons. The gold nanoparticle-cored dendrons (NCDs) were characterized by TEM, XPS, AFM, IR, UV, and NMR techniques. Average particle diameter ranged from 2.5 to 2.6 nm with narrow size distribution and remarkable stability; in particular, the elimination of the protecting shells to give naked gold, after NCDs deposition on a support, is more difficult using carbosilane dendrons than in the case of conventional dodecanethiol-protected gold nanoparticles.     

Liquid‐Crystalline Thiol‐ and Disulfide‐Based Dendrimers for the Functionalization of Gold Nanoparticles. Preliminary Communication

Liquid‐crystalline dendrons carrying either a thiol or disulfide function which display nematic, smectic A, columnar, or chiral nematic phases have been synthesized. Their mesomorphic properties are in agreement with the nature of the mesogenic units and structure of the dendrons. The first‐generation poly(aryl ester) dendron containing two cyanobiphenyl mesogenic units was used to functionalize gold nanoparticles. For full coverage, a smectic‐like supramolecular organization on the nanometer scale is observed, when the gold nanoparticles are spread onto carbon‐coated copper grids. This result indicates that the dendritic ligands reported here act as self‐organization promoters.     

Bulk properties of dendronized polymers with tailored end‐groups emanating from the same backbone

Dendronized polymers with a methacrylate backbone bearing pendant aliphatic polyester dendrons based on 2,2‐bis(methylol)propionic acid have been investigated by rheological measurements, differential scanning calorimetry (DSC), size exclusion chromatography (SEC), and ¹H NMR self‐diffusion techniques. The change in material properties due to the attachment of larger dendrons and/or different end‐groups to a backbone of the same length is investigated. Dendronized polymers of the second to fourth generation with hydroxyl, acetonide, or hexadecyl end‐group functionalities have been studied. DSC revealed that the glass transition temperature of the amorphous polymers increases with increasing size of the dendrons, and that the ability for the hexadecyl functional polymers to crystallize decreases with increasing size of dendrons. ¹H NMR self‐diffusion and longitudinal relaxation data are consistent with an elongated rod‐like model of the polymers in solution. Larger dendrons lead to a larger rod diameter that approximately double when increasing the generation of dendronized polymer from two to four. Rheological measurements demonstrated that the complex viscosity at low frequency increased with dendron size. Independently of the functionality, the second and third generation samples initially showed a Newtonian plateau, followed by a shear thinning region at higher frequencies. The fourth generation samples only showed shear thinning over the whole frequency region. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 4496–4504, 2005     

Iterative synthesis of 1,3,5-polyphenylene dendrons via C-H activation

An iterative synthesis of 1,3,5-polyphenylene dendrons via C-H activation/Suzuki-Miyaura coupling up to a third generation dendron is described. C-H bonds at the focal points of the dendrons are selectively borylated via iridium-catalyzed borylation, eliminating the need for reactive protecting groups. Sequential additions of low catalyst loadings efficiently borylate higher-generation dendrons, whereas higher initial catalyst loadings are less efficient.     

Label-free characterisation of oligonucleotide hybridisation using reflectometric interference spectroscopy

The potential of a label-free detection method, reflectometric interference spectroscopy (RIfS), for temperature-dependent DNA hybridisation experiments (for example in single nucleotide polymorphism (SNP) analysis) is investigated. Hybridisations of DNA, peptide nucleic acid (PNA), and locked nucleic acid (LNA) to a single stranded DNA were measured for several temperatures, and the melting curves and temperatures were calculated from the changes in optical thickness obtained. These measurements were performed by hybridising surface-immobilised single stranded oligomers with their complementary ssDNA or with ssDNA containing SNPs at different temperatures. DNA was compared to its analogue oligomers PNA and LNA due to their stability against nuclease. A comparison of melting temperatures demonstrated the higher binding affinities of the DNA analogues. Moreover, a continuous melting curve was obtained by first hybridising the functionalised surface with its complementary DNA at room temperature and then heating up in-flow. Measurement of the continuous melting curve was only possible due to the insensitivity of the RIfS method towards temperature changes. This is an advantage over other label-free detection methods, which are based on determining the refractive index.Dedicated to the memory of Wilhelm Fresenius.     

Multifunctional triazolylferrocenyl Janus dendron: Nanoparticle stabilizer,smart drug carrier and supramolecular nanoreactor

Owing to their unique broken symmetry, amphiphilic Janus dendrimers and dendons provide fascinating properties for material, biological, pharmaceutical and biomedical applications. The integration of various organometallic moieties into these macromolecules will further offer the opportunity to form complex and intelligent architectures and materials. Here, we report a novel, simple and multifunctional Janus dendron containing redox‐reversible hydrophobic ferrocene (Fc) unit, complexing‐effective 1,2,3‐triazole ligand and biocompatible hydrophilic triethylene glycol termini. Silver and gold nanoparticles were firstly successfully prepared by using the Janus dendron as the reducing agent of Au(III) and Ag(I), and the stabilizer of the corresponding nanoparticles. The redox response of the Fc moiety was then employed to trigger the release of model drug, rhodamine B, encapsulated in supramolecular micelles formed by the self‐assembly of the Janus dendron. Finally, the precise and excellent metal‐complexing ability of the triazole group in this dendron was fully utilized to stabilize a water‐soluble Cu(I) catalyst, forming supramolecular nanoreactors for the catalysis of the copper(I)‐catalyzed azide alkyne cycloaddition click reaction in only water. The multifunctional characteristics of this dendron highlight the potential for organometallic Janus dendrimers and dendrons in the fields of functional materials and nanomedicines.     

Dendritic phosphoramidite ligands in Rh-catalysed asymmetric hydrogenations

The axially chiral BICOL backbone was functionalised with two third generation carbosilane dendritic wedges and further elaborated to a phosphoramidite ligand. High enantioselectivities were obtained when these monodentate ligands were applied in the rhodium-catalysed asymmetric hydrogenation of methyl 2-acetamidocinnamate.     

Degradable self-assembling dendrons for gene delivery: experimental and theoretical insights into the barriers to cellular uptake

This paper uses a combined experimental and theoretical approach to gain unique insight into gene delivery. We report the synthesis and investigation of a new family of second-generation dendrons with four triamine surface ligands capable of binding to DNA, degradable aliphatic-ester dendritic scaffolds, and hydrophobic units at their focal points. Dendron self-assembly significantly enhances DNA binding as monitored by a range of experimental methods and confirmed by multiscale modeling. Cellular uptake studies indicate that some of these dendrons are highly effective at transporting DNA into cells (ca. 10 times better than poly(ethyleneimine), PEI). However, levels of transgene expression are relatively low (ca. 10% of PEI). This indicates that these dendrons cannot navigate all of the intracellular barriers to gene delivery. The addition of chloroquine indicates that endosomal escape is not the limiting factor in this case, and it is shown, both experimentally and theoretically, that gene delivery can be correlated with the ability of the dendron assemblies to release DNA. Mass spectrometric assays demonstrate that the dendrons, as intended, do degrade under biologically relevant conditions over a period of hours. Multiscale modeling of degraded dendron structures suggests that complete dendron degradation would be required for DNA release. Importantly, in the presence of the lower pH associated with endosomes, or when bound to DNA, complete degradation of these dendrons becomes ineffective on the transfection time scale-we propose this explains the poor transfection performance of these dendrons. As such, this paper demonstrates that taking this kind of multidisciplinary approach can yield a fundamental insight into the way in which dendrons can navigate barriers to cellular uptake. Lessons learned from this work will inform future dendron design for enhanced gene delivery.     

Synthesis and Characterization of Gold‐Nanoparticle‐Cored Dendrimers Stabilized by Metal–Carbon Bonds

Synthesis and characterization of gold‐nanoparticle‐cored dendrimers (NCDs), in which the dendrons are attached to the gold core through gold–carbon bonds, are described. Synthesis of these materials involved the simultaneous reduction of HAuCl₄ and a Fréchet‐type dendron with a diazonium group at the focal point, all in an organic solvent such as toluene. These materials possess a nanometer‐sized gold core surrounded by a shell of polyaryl ether dendrons, which are connected radially to the core. The NCDs were characterized by TEM, thermogravimetric analysis (TGA), and IR, UV, and NMR spectroscopic techniques. Average particle diameter of the NCDs ranged from 4.7 to 5.5 nm for the different generations. All NCDs exhibit the characteristic plasmon absorption of gold nanoparticles at 520 nm. Average numbers of dendrons per NCD in AuG_n were calculated using results from TGA and TEM studies. Multiple layering of the dendrons is proposed as a possible reason for the high dendron/NCD value.     

Synthesis and energy-transfer properties of poly(amidoamine) dendrons modified with naphthyl and dansyl groups

Poly(amidoamine) dendrons of 1-3 generations with naphthyl groups at the periphery and a dansyl group at the focal point were synthesized and carefully characterized. Intramolecular energy-transfer properties of these flexible aliphatic-scaffold light-harvesting dendrons were investigated by UV-vis absorption and fluorescence spectroscopy. Efficient energy transfer from the naphthyl groups to the dansyl group occurred for both the first and the second generation dendrons (the energy-transfer efficiency was 94.3% and 76.9%, respectively), whereas the third generation dendron exhibited a low energy-transfer efficiency of 17.8%. The average donor-acceptor distances between the naphthyl and dansyl groups were calculated for different generation dendrons. Different degrees of the backfolding of dendritic branches were used to interpret the different donor-acceptor distances.     

Amphiphilic Polyphenylene Dendron Conjugates for Surface Remodeling of Adenovirus 5

Amphiphilic surface groups play an important role in many biological processes. The synthesis of amphiphilic polyphenylene dendrimer branches (dendrons), providing alternating hydrophilic and lipophilic surface groups and one reactive ethynyl group at the core is reported. The amphiphilic surface groups serve as biorecognition units that bind to the surface of adenovirus 5 (Ad5), which is a common vector in gene therapy. The Ad5/dendron complexes showed high gene transduction efficiencies in coxsackie‐adenovirus receptor (CAR)‐negative cells. Moreover, the dendrons offer incorporation of new functions at the dendron core by in situ post‐modifications, even when bound to the Ad5 surface. Surfaces coated with these dendrons were analyzed for their blood‐protein binding capacity, which is essential to predict their performance in the blood stream. A new platform for introducing bioactive groups to the Ad5 surface without chemically modifying the virus particles is provided.     

Electrochemical oxidation of underivatized-nucleic acids at highly boron-doped diamond electrodes

Boron-doped diamond (BDD) electrodes have been examined for the electrochemical oxidation of underivatized-nucleic acids in terms of single stranded and double stranded DNA. Cyclic voltammetry and square wave voltammetry have been used to study the oxidation reactions and to detect DNA without derivatization or hydrolysis steps. At the diamond electrode, at least two well-defined voltammetric peaks were observed for both single stranded and double stranded DNA. Diamond electrode is the first material to show a well-defined voltammetric peaks for adenine group oxidation directly in the helix structure of nucleic acid due to its wide potential window. For single stranded DNA, a third peak, related to the pyrimidine group oxidation was also observed. As-deposited diamond film with predominantly hydrogen-terminated surface exhibited superior performance over oxygen-terminated diamond in terms of sensitivity. However, by optimizing the ionic strength, sensitivity of O-terminated films could be improved. Linear calibration results have shown linearity of current with concentration in the range 0.1-8 microg mL(-1) for both guanine and adenine residues at as-deposited BDD. Detection limits (S/N = 3) of 3.7 and 10 ng mL(-1) for adenine and guanine residue in single stranded DNA, respectively, and 5.2 and 10 ng mL(-1) for adenine and guanine residue in double stranded DNA, respectively, were observed. This work shows the promising use of diamond as an electrochemical detector for direct detection of nucleic acids. The results also show the possibility of using the oxidation peak current of adenine group that is more sensitive for the direct detection of nucleicacids.     

Dendronized Anionic Gold Nanoparticles: Synthesis,Characterization, and Antiviral Activity

Anionic carbosilane dendrons decorated with sulfonate functions and one thiol moiety at the focal point have been used to synthesize water‐soluble gold nanoparticles (AuNPs) through the direct reaction of dendrons, gold precursor, and reducing agent in water, and also through a place‐exchange reaction. These nanoparticles have been characterized by NMR spectroscopy, TEM, thermogravimetric analysis, X‐ray photoelectron spectroscopy (XPS), UV/Vis spectroscopy, elemental analysis, and zeta‐potential measurements. The interacting ability of the anionic sulfonate functions was investigated by EPR spectroscopy with copper(II) as a probe. Different structures and conformations of the AuNPs modulate the availability of sulfonate and thiol groups for complexation by copper(II). Toxicity assays of AuNPs showed that those produced through direct reaction were less toxic than those obtained by ligand exchange. Inhibition of HIV‐1 infection was higher in the case of dendronized AuNPs than in dendrons.     

Dendronized polymers via Diels–Alder “click” reaction

A modular approach toward the synthesis of polymers containing dendron groups as side chains is developed using the Diels–Alder “click” reaction. For this purpose, a styrene‐based polymer appended with anthracene groups as reactive side chains was synthesized. First through third‐generation polyester dendrons containing furan‐protected maleimide groups at their focal point were synthesized. Facile, reagent‐free, thermal Diels–Alder cycloaddition between the anthracene‐containing polymer and latent‐reactive dendrons leads to quantitative functionalization of the polymer chains to afford dendronized polymers. The efficiency of this functionalization step was monitored using ¹H and ¹³C NMR spectroscopy and FTIR and UV–vis spectrometry. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 410–416, 2010     

On the Synthesis and Selective Deprotection of Low‐Generation Dendrons with Orthogonally Protected Peripheral Amine Groups and a Possible Impact of the Deprotection Conditions on the Stability of Dendronized Polymers' Skeletons

The synthesis of first‐ and second‐generation dendrons with defined ratios of orthogonally protected amine groups in the periphery ((benzyloxy)carbonyl (Cbz) and (tert‐butoxy)carbonyl (Boc) protection) and the degree to which they can be selectively removed are described. The reaction conditions required for these deprotections were applied to methacrylic acid (= 2‐methylprop‐2‐enoic acid) based dendronized polymers carrying the same peripheral protecting groups to investigate whether they have any detrimental interference with the polymer skeleton. Specifically it was explored whether dendrons attached to the backbone could possibly be cleaved off as a whole (de‐dendronization). Finally it was investigated how de‐dendronizations can be used for quantifying both the dendron‐structure perfection and the polymer‐backbone configurations.     

Design and synthesis of new cationic water‐soluble pyrene containing dendrons for DNA sensory applications

A series of new water‐soluble cationic pyrene‐dendron derivatives, G1 , G2 , and G3, was successfully synthesized and characterized. These new dendrons were designed with the quaternized amino moieties at the periphery of the dendrons for DNA detection and functionalized with pyrene as a fluorescent probe. The electrostatic interactions between the plasmid DNA (pDNA) and cationic charged dendrons in an aqueous solution resulted in a change in the photophysical properties of pyrene, which could be shown in the UV‐vis and fluorescence spectra. Pyrene dendrons showed a high and rapid fluorescence response upon the addition of pDNA, which was strongly dependent on the size and hydrophobicity of the dendrons. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012