Prof. Dr. Ralf Weberskirch

Organic Chemistry
TU Dortmund University

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  • Scalable and Recyclable All-Organic Colloidal Cascade Catalysts
    Chen, C. and Janoszka, N. and Wong, C.K. and Gramse, C. and Weberskirch, R. and Gröschel, A.H.
    Angewandte Chemie - International Edition 60 (2021)
    We report on the synthesis of core–shell microparticles (CSMs) with an acid catalyst in the core and a base catalyst in the shell by surfactant-free emulsion polymerization (SFEP). The organocatalytic monomers were separately copolymerized in three synthetic steps allowing the spatial separation of incompatible acid and base catalysts within the CSMs. Importantly, a protected and thermo-decomposable sulfonate monomer was used as acid source to circumvent the neutralization of the base catalyst during shell formation, which was key to obtain stable, catalytically active CSMs. The catalysts showed excellent performance in an established one-pot model cascade reaction in various solvents (including water), which involved an acid-catalyzed deacetalization followed by a base-catalyzed Knoevenagel condensation. The CSMs are easily recycled, modified, and their synthesis is scalable, making them promising candidates for organocatalytic applications. © 2020 The Authors. Published by Wiley-VCH GmbH
    view abstract10.1002/anie.202008104
  • Towards DNA-Encoded Micellar Chemistry: DNA-Micelle Association and Environment Sensitivity of Catalysis
    Klika Škopić, M. and Gramse, C. and Oliva, R. and Pospich, S. and Neukirch, L. and Manisegaran, M. and Raunser, S. and Winter, R. and Weberskirch, R. and Brunschweiger, A.
    Chemistry - A European Journal 27 (2021)
    The development of DNA-compatible reaction methodologies is a central theme to advance DNA-encoded screening library technology. Recently, we were able to show that sulfonic acid-functionalized block copolymer micelles facilitated Brønsted acid-promoted reactions such as the Povarov reaction on DNA-coupled starting materials with minimal DNA degradation. Here, the impact of polymer composition on micelle shape, and reaction conversion was investigated. A dozen sulfonic acid-functionalized block copolymers of different molar mass and composition were prepared by RAFT polymerization and were tested in the Povarov reaction, removal of the Boc protective group, and the Biginelli reaction. The results showed trends in the polymer structure-micellar catalytic activity relationship. For instance, micelles composed of block copolymers with shorter acrylate ester chains formed smaller particles and tended to provide faster reaction kinetics. Moreover, fluorescence quenching experiments as well as circular dichroism spectroscopy showed that DNA-oligomer-conjugates, although highly water-soluble, accumulated very effectively in the micellar compartments, which is a prerequisite for carrying out a DNA-encoded reaction in the presence of polymer micelles. © 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.
    view abstract10.1002/chem.202100980
  • Design of an automated reagent-dispensing system for reaction screening and validation with dna-tagged substrates
    Bobers, J. and Škopić, M.K. and Dinter, R. and Sakthithasan, P. and Neukirch, L. and Gramse, C. and Weberskirch, R. and Brunschweiger, A. and Kockmann, N.
    ACS Combinatorial Science 22 (2020)
    Laboratory automation strategies have vast potential for accelerating discovery processes. They enable higher efficiency and throughput for time-consuming screening procedures and reduce error-prone manual steps. Automating repetitive procedures can for instance support chemists in optimizing chemical reactions. Particularly, the technology of DNA-encoded libraries (DELs) may benefit from automation techniques, since translation of chemical reactions to DNA-tagged reactants often requires screening of multiple reaction parameters and evaluation of large numbers of reactants. Here, we describe a portable, automated system for reagent dispensing that was designed from open source materials. The system was validated by performing amide coupling of carboxylic acids to DNA-linked amine and a micelle-mediated Povarov reaction to DNA-tagged hexahydropyrroloquinolines. The latter reaction required accurate pipetting of multiple components including different solvents and a surface-active reagent. Analysis of reactions demonstrated that the robotic system achieved high accuracy comparable to experimentation by an experienced chemist with the potential of higher throughput. © 2020 American Chemical Society.
    view abstract10.1021/acscombsci.9b00207
  • Hydrogels Derivatized With Cationic Moieties or Functional Peptides as Efficient Supports for Neural Stem Cells
    Glotzbach, K. and Stamm, N. and Weberskirch, R. and Faissner, A.
    Frontiers in Neuroscience 14 (2020)
    The increasing incidence of neurodegenerative diseases such as Alzheimer’s or Parkinson’s disease represents a significant burden for patients and national health systems. The conditions are primarily caused by the death of neurons and other neural cell types. One important aim of current stem cell research is to find a way to replace the lost cells. In this perspective, neural stem cells (NSCs) have been considered as a promising tool in the field of regenerative medicine. The behavior of NSCs is modulated by environmental influences, for example hormones, growth factors, cytokines, and extracellular matrix molecules or biomechanics. These factors can be studied by using well-defined hydrogels, which are polymeric networks of synthetic or natural origin with the ability to swell in water. These gels can be modified with a variety of molecules and optimized with regard to their mechanical properties to mimic the natural extracellular environment. In particular modifications applying distinct units such as functional domains and peptides can modulate the development of NSCs with regard to proliferation, differentiation and migration. One well-known peptide sequence that affects the behavior of NSCs is the integrin recognition sequence RGD that has originally been derived from fibronectin. In the present review we provide an overview concerning the applications of modified hydrogels with an emphasis on synthetic hydrogels based on poly(acrylamides), as modified with either cationic moieties or the peptide sequence RGD. This knowledge might be used in tissue engineering and regenerative medicine for the therapy of spinal cord injuries, neurodegenerative diseases and traumata. © Copyright © 2020 Glotzbach, Stamm, Weberskirch and Faissner.
    view abstract10.3389/fnins.2020.00475
  • Micellar Brønsted Acid Mediated Synthesis of DNA-Tagged Heterocycles
    Škopić, M.K. and Götte, K. and Gramse, C. and Dieter, M. and Pospich, S. and Raunser, S. and Weberskirch, R. and Brunschweiger, A.
    Journal of the American Chemical Society 141 (2019)
    The translation of well-established molecular biology methods such as genetic coding, selection, and DNA sequencing to combinatorial organic chemistry and compound identification has made extremely large compound collections, termed DNA-encoded libraries, accessible for drug screening. However, the reactivity of the DNA imposes limitations on the choice of chemical methods for encoded library synthesis. For example, strongly acidic reaction conditions must be avoided because they damage the DNA by depurination, i.e. the cleavage of purine bases from the oligomer. Application of micellar catalysis holds much promise for encoded chemistry. Aqueous micellar dispersions enabled compound synthesis under often appealingly mild conditions. Amphiphilic block copolymers covalently functionalized with sulfonic acid moieties in the lipophilic portion assemble in water and locate the Brønsted catalyst in micelles. These acid nanoreactors enabled the reaction of DNA-conjugated aldehydes to diverse substituted tetrahydroquinolines and aminoimidazopyridines by Povarov and Groebke-Blackburn-Bienaymé reactions, respectively, and the cleavage of tBoc protective groups from amines. The polymer micelle design was successfully translated to the Cu/Bipyridine/TEMPO system mediating the oxidation of DNA-coupled alcohols to the corresponding aldehydes. These results suggest a potentially broad applicability of polymer micelles for encoded chemistry. © 2019 American Chemical Society.
    view abstract10.1021/jacs.9b05696
  • The Tenascin-C-Derived Peptide VSWRAPTA Promotes Neuronal Branching Via Transcellular Activation of the Focal Adhesion Kinase (FAK) and the ERK1/2 Signaling Pathway In Vitro
    Jarocki, M. and Sallouh, O. and Weberskirch, R. and Faissner, A.
    Molecular Neurobiology 56 (2019)
    The central nervous system (CNS) of mammals has a limited regeneration capacity after traumatic events, which causes chronic functional disability. The development of biomaterials aims at providing support for the regeneration process. One strategy integrates peptides that mimic functional domains of extracellular matrix (ECM) or cell adhesion molecules with synthetic polymers designed to present growth-supporting cues to the neuronal microenvironment. Thus, small peptide sequences originating from molecules of the ECM may serve as promising bio-additives, acting as artificial matricryptins to gear cellular processes. The glycoprotein tenascin-C (Tnc) is a major constituent of the ECM of the developing brain and persists in the neurogenic regions of the adult CNS. It is a multimodular glycoprotein that comprises distinct domains with neurite growth promoting and axon growth repulsing properties. In the present study, the novel peptide motif VSWRAPTA that is encoded in the neurite growth promoting 6th fibronectin type III repeat close to the alternative splice site of Tnc was tested for its effects on neuron differentiation. When this newly synthesized biomimetic peptide was added to cultures of embryonic cortical neurons it significantly promoted the outgrowth of neurites. The neuron differentiation supporting effect was thereby associated with the trans-cellular activation of the focal adhesion kinase (FAK) and the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Cortical neurons supplemented with the Tnc peptide displayed a dose-dependent increase in neurite outgrowth that saturated at a peptide concentration of 50 μg/ml (56.4 mMol/l). The analysis of neuron morphology revealed that neurite branching rather than fiber length was stimulated by the Tnc peptide. Therefore, we predict that the analyzed peptide motif of the 6th constitutively expressed FNIII domain of the Tnc molecule might be a major contributor for neurite outgrowth and guiding events in the native CNS microenvironment. In conclusion, the Tnc-derived VSWRAPTA peptide may represent a promising tool to spike regeneration supportive microenvironments. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.
    view abstract10.1007/s12035-018-1108-7
  • 18F-Radiolabeling and in Vivo Analysis of SiFA-Derivatized Polymeric Core-Shell Nanoparticles
    Berke, S. and Kampmann, A.-L. and Wuest, M. and Bailey, J.J. and Glowacki, B. and Wuest, F. and Jurkschat, K. and Weberskirch, R. and Schirrmacher, R.
    Bioconjugate Chemistry 29 (2018)
    Nanoparticles represent the most widely studied drug delivery systems targeting cancer. Polymeric nanoparticles can be easily generated through a microemulsion polymerization. Herein, the synthesis, radiolabeling, and in vivo evaluation of nanoparticles (NPs) functionalized by an organosilicon fluoride acceptor (SiFA) are reported which can be radiolabeled without further chemical modifications. Four nanoparticles in the sub-100 nm range with distinct hydrodynamic diameters of 20 nm (NP1), 33 nm (NP2), 45 nm (NP3), and 72 nm (NP4), respectively, were synthesized under size-controlled conditions. The SiFA-labeling building block acted as an initiator for the polymerization of polymer P1. The nanoparticles were radiolabeled with fluorine-18 (18F) through simple isotopic exchange (IE) and analyzed in vivo in a murine mammary tumor model (EMT6). The facile 18F radiolabeling SiFA methodology, performed in ethanol under mild reaction conditions, gave radiochemical yields (RCYs) of 19-26% and specific activities (SA) of 0.2-0.3 GBq/mg. Based on preclinical PET analysis, the tumor uptake and clearance profiles were analyzed depending on particle size. The nanoparticle size of 33 nm showed the highest tumor accumulation of SUVmean 0.97 (= 4.4%ID/g) after 4 h p.i. through passive diffusion based on the Enhanced Permeability and Retention (EPR) effect. Overall, this approach exhibits a simple, robust, and reliable synthesis of 18F radiolabeled polymeric nanoparticles with a favorable in vivo evaluation profile. This approach represents a straightforward synthetically accessible alternative to produce radiolabeled nanoparticles without any further surface modification to attach a radioisotope. © 2017 American Chemical Society.
    view abstract10.1021/acs.bioconjchem.7b00630
  • Bipyridine copper functionalized polymer resins as support materials for the aerobic oxidation of alcohols
    Sand, H. and Weberskirch, R.
    Polymer International 66 (2017)
    Here, we report the first polymer resin supported Cu(I)/bipyridine/N-oxyl catalyst systems for the aerobic oxidation of alcohols at room temperature with ambient air. We chose polystyrene-poly(ethylene glycol) copolymer (TentaGel®) and Merrifield resin as support materials because of their different swelling properties in polar and nonpolar solvents. The bromo functionalized TentaGel resin TG1 or Merrifield resin MR1 were functionalized with 4,4′-dimethoxy-2,2′-bipyridine (MeObpy) to give the ligand modified polymer resin TG2/MR2 that was loaded with CuI(Br) to give the final CuI(Br)/bipyridine support TG3/MR3. These resins were characterized by Fourier transform infrared, SEM, SEM energy dispersive X-ray spectroscopy and elemental analysis. Catalytic activity and recyclability of TG3 was investigated in acetonitrile and cyclohexane and displayed high activities in acetonitrile but also high metal leaching. In cyclohexane as solvent leaching was reduced to 1% − 2%, and catalytic activity was still at 75% after the fifth run. MR3 was consequently tested in cyclohexane and toluene. In both solvents low metal leaching was observed with higher activity in toluene as solvent, showing still over 90% conversion after the seventh run with 9-azabicyclo[3.3.1]nonane N-oxyl (ABNO) and 80% with 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO). © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry
    view abstract10.1002/pi.5277
  • Chemoenzymatic one-pot reaction of noncompatible catalysts: Combining enzymatic ester hydrolysis with Cu(i)/bipyridine catalyzed oxidation in aqueous medium
    Sand, H. and Weberskirch, R.
    RSC Advances 7 (2017)
    The combination of chemical catalysts and biocatalysts in a one-pot reaction has attracted considerable interest in the past years. However, since each catalyst requires very different reaction conditions, chemoenzymatic one-pot reactions in aqueous media remain challenging and are limited today to metal-catalysts that display high activity in aqueous media. Here, we report the first combination of two incompatible catalytic systems, a lipase based ester hydrolysis with a water-sensitive Cu/bipyridine catalyzed oxidation reaction, in a one-pot reaction in aqueous medium (PBS buffer). Key to the solution was the compartmentalization of the Cu/bipyridine catalyst in a core-shell like nanoparticle. We show the synthesis and characterization of the Cu/bipyridine functionalized nanoparticles and the application in the oxidation of allylic and benzylic alcohols in aqueous media. Furthermore, the work demonstrates the implementation of a one-pot reaction process with optimized reaction conditions involving a lipase (CAL-B) to hydrolyze various acetate ester substrates in the first step, followed by oxidation of the resulting alcohols to the corresponding aldehydes under aerobic conditions in aqueous media. © 2017 The Royal Society of Chemistry.
    view abstract10.1039/c7ra05451c
  • The Synergistic Effect of Cationic Moieties and GRGDSF-Peptides in Hydrogels on Neural Stem Cell Behavior
    Sallouh, M. and Jarocki, M. and Sallouh, O. and Degen, P. and Faissner, A. and Weberskirch, R.
    Macromolecular Bioscience 17 (2017)
    This article reports the behavior of embryonic neural stem cells on a hydrogel that combines cationic, non-specific cell adhesion motifs with glycine-arginine-glycine-aspartic acid-serine-phenylalanine (GRGDSF)-peptides as specific cell adhesion moieties. Therefore, three hydrogels are prepared by free radical polymerization that contains either a GRGDSF-peptide residue (P1), amino ethylmethacrylate as a cationic residue (P2), or a combination of both motifs (P3). For each gel, cross linker concentrations of 8 mol% is used to have a comparable gel stiffness of 8–9 kPa. The cell experiments indicate a synergistic effect of the non-specific, cationic residues, and the specific GRGDSF-peptides on embryonic neural stem cell behavior that is especially pronounced in the cell adhesion experiments by more than doubling the number of cells after 72 h when comparing P3 with P2 and is less pronounced in the proliferation and differentiation experiments. (Figure presented.). © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
    view abstract10.1002/mabi.201600178
  • Efficient synthesis of polyoxazoline-silica hybrid nanoparticles by using the "grafting-onto" approach
    Bissadi, G. and Weberskirch, R.
    Polymer Chemistry 7 (2016)
    Well-defined silica poly(2-methyl-2-oxazoline) nanoparticles were prepared via the "grafting to" method employing either click chemistry or silane coupling using different reaction conditions. In the first approach, alkyne-functionalized poly(2-methyl-2-oxazoline), P1, was prepared by ring opening cationic polymerization and clicked on azide-functionalized silica nanoparticles (SNPs), which led to the fabrication of hybrid nanoparticles. In the second approach, trimethoxysilane-functionalized poly(2-methyl-2-oxazoline), P2, was prepared similar to P1 and grafted on the surface of SNPs using coupling reactions between trimethoxysilane and hydroxyl groups of the silica nanoparticle. Hybrid particles were characterized by Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), transmission electron microscopy (TEM), and elemental analysis (EA). The grafting density ranged from 0.183 chains per nm2 for the click chemistry approach up to 0.45 chains per nm2 when using trimethoxysilane-functionalized P2 in acetonitrile at 80 °C. The water-in-oil microemulsion approach resulted still in a relatively high grafting density of 0.353 chains per nm2 and has the advantage of a one-step process and mild reaction conditions. © The Royal Society of Chemistry 2016.
    view abstract10.1039/c5py01775k
  • Facile formation of hydrogels by using functional precursor polymers and the chemoselective Staudinger coupling
    Sallouh, O. and Weberskirch, R.
    Polymer (United Kingdom) 86 (2016)
    Hydrogel formation based on chemoselective crosslinking methods has become an important topic in biomedicine. Although the Staudinger ligation has been utilized in protein modification for many years only one example based on polysaccharides has been published to apply this reaction also for hydrogel formation. Therefore, methacrylate monomers with azide Az-MA or triphenylphosphine TPP-MA functional groups were synthesized and used to prepare two water-soluble precursor copolymers P1 (with Az-MA) and P2 (with TPP-MA) by free radical polymerization. The molecular weight and the composition of the copolymers were analyzed by SEC, 1H NMR, FTIR and UV/Vis spectroscopy. Mixing of the water-soluble copolymers P1 and P2 in aqueous media led to the irreversible and easy formation of covalently crosslinked polymers. The kinetics of gelation, swelling and mechanical properties of the hydrogels in aqueous PBS buffer can be tuned by the total polymer concentration and the stoichiometric ratio of the complementary functional groups. © 2016 Elsevier Ltd. All rights reserved.
    view abstract10.1016/j.polymer.2016.01.066
  • Formation of polyoxazoline-silica nanoparticles: Via the surface-initiated cationic polymerization of 2-methyl-2-oxazoline
    Bissadi, G. and Weberskirch, R.
    Polymer Chemistry 7 (2016)
    Well-defined polyoxazoline-silica hybrid nanoparticles were prepared by coating silica nanoparticles (SNPs) with poly(2-methyl-2-oxazoline) using a surface-initiated cationic ring-opening polymerization process. First, reverse microemulsion was used to synthesize monodisperse SNPs followed by immobilizing (chloromethyl)phenylethyl)trimethoxysilane on the surface of the nanoparticles acting as an initiator. The grafting density of the polymeric shell was controlled by varying the polymerization time, PSNPs-A, and the monomer/initiator ratio concentration, PSNPs-B. Hybrid nanoparticles were characterized by Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and transmission electron microscopy (TEM). The molecular weight and polydispersity indices of the polymer chains were determined by size exclusion chromatography (SEC) after etching the silica core. The hybrid nanoparticles were further functionalized with fluorescein isothiocyanate (FITC) and folic acid (FA) as a fluorescence imaging molecule and a cancer-targeting ligand, respectively. Moreover, hybrid nanoparticles with Rubpy as a fluorophore encapsulated in the silica core and the poly(2-methyl-2-oxazoline) shell were prepared. © 2016 The Royal Society of Chemistry.
    view abstract10.1039/c6py01034b
  • Formation of Well-Defined Polymer Particles in the Sub-100 nm Size Range by Using Amphiphilic Block Copolymer Surfactants and a Microemulsion Approach
    Kampmann, A.-L. and Luksin, M. and Pretzer, I. and Weberskirch, R.
    Macromolecular Chemistry and Physics 217 (2016)
    Here, the formation of nanoparticles based on a microemulsion approach and the use of polymer surfactants are described. Therefore, two amphiphilic poly(2-oxazoline) block copolymers P1 and P2 with alkyne groups in their hydrophobic block have been synthesized by ring-opening, cationic polymerization. The polymers P1 and P2 are employed in a microemulsion process to stabilize the particle core by core cross-linking of 1,6-hexanediol diacrylate (HDDA) using either AIBN as azo-initiator or 2-propanethiol as a photo-initiator for the polymerization reaction. The results show that particle size can be controlled by sonication time, the hydrophilic–hydrophobic balance of the polymer surfactant, and the ratio of polymer surfactant versus HDDA giving access to water-soluble nanoparticles in a size range of 10–70 nm. (Figure presented.). © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
    view abstract10.1002/macp.201600108
  • Sustainable Micellar Gold Catalysis - Poly(2-oxazolines) as Versatile Amphiphiles
    Lempke, L. and Ernst, A. and Kahl, F. and Weberskirch, R. and Krause, N.
    Advanced Synthesis and Catalysis 358 (2016)
    The application of five polymer amphiphiles in the gold-catalyzed allene cycloisomerizations under aqueous micellar conditions is described. The polymers were prepared by ring-opening cationic polymerization based on poly(2-methyl-2-oxazoline) as hydrophilic segment and different hydrocarbon- or fluorocarbon-based hydrophobic segments. The catalytic activity in the gold-catalyzed allene cyclization is strongly dependent on the type of gold precursor, the salt concentration in the bulk aqueous medium, and the concentration of the polymeric amphiphile. Best results were obtained with 2 mol% of gold(III) bromide, 1 mM of amphiphile and 5 M sodium chloride, affording over 80% yield for different heterocyclic products. The catalyst system is also suitable for the dehydrative cyclization of acetylenic diols to furans. Moreover, successful catalyst recycling was demonstrated in three consecutive runs when using optimized extraction conditions. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    view abstract10.1002/adsc.201600139
  • Synthesis of well-defined core-shell nanoparticles based on bifunctional poly(2-oxazoline) macromonomer surfactants and a microemulsion polymerization process
    Kampmann, A.-L. and Grabe, T. and Jaworski, C. and Weberskirch, R.
    RSC Advances 6 (2016)
    Particles in the sub-100 nm range have attracted widespread attention in the past few years due to their application in drug delivery and diagnostics. Here we describe the synthesis of two bifunctional, amphiphilic poly(2-oxazoline) macromonomers with multiple acrylate groups in their hydrophobic block and azide or primary amino end groups. The amphiphilic macromonomers were applied in a microemulsion polymerization to form well-defined core-crosslinked nanoparticles with surface functional azide or amine groups. Therefore, an amphiphilic poly(2-oxazoline) was prepared by cationic ring-opening polymerization of 2-methyl-2-oxazoline to form the hydrophilic block and a mixture of 2-heptyl-2-oxazoline and 2-(5-pentyl-[(1,2,3-triazol)-4-yl-methacrylat)]-oxazoline to form the hydrophobic block and was terminated with an azide moiety as end group. The introduction of multiple methacrylate groups into the poly(2-oxazoline) macromonomers serve as a stabilizer in the microemulsion process to covalently link the polymer to the particle core. Variable particle sizes of 20-75 nm have been prepared by encapsulating different amounts of 1,6-hexanedioldimethacrylate (HDDMA) to swell the micellar core before subsequent crosslinking takes place. Finally, particle surface functionalization was achieved by converting the terminal azide group via Staudinger-reaction to a primary amine group. Nanoparticles with surface primary amine groups were functionalized with folic acid (FA), a GRGDS-peptide derivative and fluorescein isothiocyanate (FITC) by simple amidation reaction (FA, RGD-peptide) or thiourea formation (FITC). © 2016 Royal Society of Chemistry.
    view abstract10.1039/c6ra22896h
  • 1H HR-MAS NMR spectroscopy as a simple tool to characterize peptide - Functionalized hydrogels as a function of cross linker density
    Sallouh, M. and Degen, P. and Hiller, W. and Weberskirch, R.
    Polymer (United Kingdom) 56 (2015)
    High resolution magic angle spinning (1H HR-MAS) NMR spectroscopy has been used to analyze the composition of a set of bioactive hydrogels. Therefore, a set of six hydrogels with different cross linker densities ranging from 1 to 12 mol% were prepared by free radical polymerization. The disulfide based cross linkers of the hydrogels were reduced with dithiothreitol (DTT) to generate free sulfhydryl groups giving access to soluble copolymers. Comparison of the 1H NMR results of the soluble copolymers with those obtained from 1H HR-MAS experiments revealed that for lower cross linker densities of 1-2 mol%, HR-MAS spectroscopy of the hydrogels matches quantitatively the peptide content of the soluble copolymer. With increasing cross linker densities up to 12 mol% the signal intensity of the aromatic unit is linearly reduced to 62% compared to the results obtained by 1H NMR spectroscopy. © 2014 Elsevier Ltd. All rights reserved.
    view abstract10.1016/j.polymer.2014.11.045
  • Bipyridine-functionalized amphiphilic block copolymers as support materials for the aerobic oxidation of primary alcohols in aqueous media
    Sand, H. and Weberskirch, R.
    RSC Advances 5 (2015)
    Amphiphilic block copolymers with 4-methoxy-4′-alkoxybipyridine ligands in the hydrophobic block were synthesized by cationic ring-opening polymerization. The bipyridine moiety was either introduced directly as a 2-oxazoline monomer (P1) or by polymer-analogous coupling to a precursor poly(2-oxazoline) with chloropentyl side chains (PP2-PP7) to prepare the polymer ligands (P2-P7). The polymers were characterized by NMR and SEC measurements to determine polymer composition, molar masses and polydispersities. In water, these polymers form micelles with cmc values ranging from 1.8 to 22 μmol l-1. SAXS and DLS measurements exhibited spherical particles with particle sizes of 8 to 21 nm. Polymers P1-P7 were finally utilized to carry out the aerobic oxidation of primary alcohols, including allylic, benzylic, and aliphatic derivatives at room temperature (T = 20°C) and ambient air in aqueous media indicating higher activities for P2-P7 compared to P1 as a consequence of the different preparation methods. Moreover, product isolation and catalyst recycling can be easily accomplished by solvent extraction five times without significant loss of activity. © The Royal Society of Chemistry 2015.
    view abstract10.1039/c5ra05715a
  • Extracellular Matrix Glycoprotein-Derived Synthetic Peptides Differentially Modulate Glioma and Sarcoma Cell Migration
    Brösicke, N. and Sallouh, M. and Prior, L.-M. and Job, A. and Weberskirch, R. and Faissner, A.
    Cellular and Molecular Neurobiology 35 (2015)
    Glycoproteins of the extracellular matrix (ECM) regulate proliferation, migration, and differentiation in numerous cell lineages. ECM functions are initiated by small peptide sequences embedded in large constituents that are recognized by specific cellular receptors. In this study, we have investigated the biological effects of peptides derived from collagen type IV and tenascin-C compared to the well-known RGD peptide originally discovered in fibronectin. The influence of glycoproteins and corresponding peptides on the migration of the glioma cell lines U-251-MG and U-373-MG and the sarcoma line S-117 was studied. When the cell lines were tested in a modified Boyden chamber assay on filters coated with the ECM glycoproteins, glioma cells showed a strong migration response on tenascin-C and the basal lamina constituent collagen IV, in contrast to S-117 cells. In order to identify relevant stimulatory motifs, peptides derived from fibronectin (6NHX-GRGDSF), tenascin-C (TN-C, VSWRAPTA), and collagen type IV (MNYYSNS) were compared, either applied in solution in combination with ECM glycoprotein substrates, in solution in the presence of untreated membranes, or coated on the filters of the Boyden chambers. Using this strategy, we could identify the novel tenascin-C-derived peptide motif VSWRAPTA as a migration stimulus for glioma cells. Furthermore, while kin peptides generally blocked the effects of the respective homologous ECM proteins, unexpected effects were observed in heterologous situations. There, in several cases, addition of soluble peptides strongly boosted the response to the coated ECM proteins. We propose that peptides may synergize or antagonize each other by stimulating different signaling pathways. © 2015, Springer Science+Business Media New York.
    view abstract10.1007/s10571-015-0170-1
  • Micellization and Mobility of Amphiphilic Poly(2-oxazoline) Based Block Copolymers Characterized by 1H NMR Spectroscopy
    Hiller, W. and Engelhardt, N. and Kampmann, A.-L. and Degen, P. and Weberskirch, R.
    Macromolecules 48 (2015)
    Three amphiphilic diblock poly(2-oxazoline) copolymers composed of the hydrophilic poly(2-methyl-2-oxazoline) and hydrophobic poly(2-alkyl-2-oxazoline) with alkyl = pentyl (P1), heptyl (P2), and nonyl side chain (P3) lengths of the hydrophobic block were synthesized by ring-opening cationic polymerization. These polymers form micelles in water above their critical micelle concentration. The temperature-dependent stability of the micellar aggregates was analyzed by DLS and turbidity measurements as well as pyrene solubilization between 20 and 80 °C in water. Moreover, the chemical composition of the block copolymers was determined by 1H NMR spectroscopy. In particular, it was possible to quantify the degree of aggregations of the individual groups of both blocks by including the chemical composition into the derived equations. It could be shown by varying the temperature that both the chemical composition and the degree of micellization depend on the number of bonds of the considered structural groups of the side chain with respect to the backbone of the hydrophobic block as well as the length of the side chain. In addition, temperature-dependent T<inf>1</inf> and T<inf>2</inf> measurements were performed to determine the dynamics of the structural groups of the hydrophilic and hydrophobic blocks. Correlation times and activation energies were determined of the individual structural groups confirming the different mobilities. © 2015 American Chemical Society.
    view abstract10.1021/acs.macromol.5b00149
  • Blocked isocyanates: An efficient tool for post-polymerization modification of polymers
    Bode, S. and Enke, M. and Görls, H. and Hoeppener, S. and Weberskirch, R. and Hager, M.D. and Schubert, U.S.
    Polymer Chemistry 5 (2014)
    The utilization of blocked isocyanates for efficient post-polymerization functionalization of different polymers is presented. For this purpose, well-defined polymers obtained by the RAFT polymerization procedure are modified by conversion of the end groups to blocked isocyanates. Furthermore, α,ω-carboxy-terminated polystyrene and poly(phenylene ethynylene) are functionalized with blocked isocyanates. The utilization of these end groups could be shown by functionalization with anthracene moieties. The blocked isocyanates offer improved stability of functional polymers compared to isocyanate functionalized polymers. Their handling is much easier and it is possible to precipitate these polymers in methanol. On the other hand, an efficient reaction with an amine or an alcohol at 130 °C could be demonstrated. Thus, the versatility of this approach is shown, which offers a wide range of possibilities for potential applications, e.g., as soft segments in polyurethanes or for further functionalization towards tailor-made polymers. © 2014 The Royal Society of Chemistry.
    view abstract10.1039/c3py01360j
  • Synthesis of α,ω-isocyanate telechelic polymethacrylate soft segments with activated ester side functionalities and their use for polyurethane synthesis
    Eschweiler, N. and Keul, H. and Millaruelo, M. and Weberskirch, R. and Moeller, M.
    Polymer International 63 (2014)
    Isocyanate homo telechelic poly(methyl methacrylate-co-acryloxy succinimide) and poly(methyl methacrylate-co-acrylamidohexanoic succinimide) were prepared and used as soft segments for polyurethanes. Polymer structures are characterized by SEC, Raman, and 1H NMR spectroscopy. The synthetic route for the preparation of α,ω-isocyanate-telechelic poly(methyl methacrylate-co-acryloxysuccinimide) and α,ω- isocyanate-telechelic poly(methyl methacrylate-co-acrylamidohexanoic succinimide) soft segments is presented. The strategy includes reversible addition fragmentation chain transfer (RAFT) copolymerization and two post polymerization modification steps. The RAFT polymerizations result in copolymers with an activated ester proportion within the polymer chains of 8% N-acryloxysuccinimide and 5% 6-acrylamidohexanoic succinimide. The reactivity ratios of the monomer pairs were determined. In a first post polymerization reaction carboxylic acid homo telechelic polymers were prepared by reacting the ω-dithiobenzoate end-group with an excess of azobis(cyanovaleric acid). In a second modification step the α- and ω-carboxylic acid end-groups were reacted with hexamethylene diisocyanate and 100% isocyanate telechelic copolymers were obtained. Finally segmented polyurethanes were prepared by coupling hexamethylene diisocyanate (HDI) end capped soft segments with hard segments composed of 1,4-butanediol and HDI. © 2013 Society of Chemical Industry.
    view abstract10.1002/pi.4535
  • "grafting-from" Polymerization of PMMA from stainless steel surfaces by a raft-mediated polymerization process
    Zammarelli, N. and Luksin, M. and Raschke, H. and Hergenröder, R. and Weberskirch, R.
    Langmuir 29 (2013)
    The synthesis of grafted PMMA homopolymer films is reported using a surface-initiated reversible addition-fragmentation chain transfer (SI-RAFT) polymerization from a RAFT-agent immobilized on a silanized stainless steel surface. Therefore, stainless steel surfaces were hydroxylated with piranha solution followed by silanization with 3-aminopropylsilane (APS). The pendant primary amino groups of the cross-linked polysiloxane layer were reacted with 4-cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanoic acid N-hydroxysuccinimide ester to produce a surface with covalently immobilized RAFT agents. PMMA homopolymers of different molecular weights between 13 060 and 45 000 g/mol were then prepared by a surface-initiated RAFT polymerization. Molecular weight (MW) and polydispersity index (PDI) were determined from sacrificial polymerization in solution. The different steps of stainless steel surface modification and the ultrathin films were investigated using atomic force microscopy (AFM), static, X-ray photoelectron spectroscopy (XPS), attenuated total reflectance infrared spectroscopy (ATR-IR), and ellipsometry. © 2013 American Chemical Society.
    view abstract10.1021/la402870p
  • Synthesis and characterization of surface functional polymer nanoparticles by a bottom-up approach from tailor-made amphiphilic block copolymers
    Engelhardt, N. and Ernst, A. and Kampmann, A.-L. and Weberskirch, R.
    Macromolecular Chemistry and Physics 214 (2013)
    Core-crosslinked nanoparticles presenting secondary amine functional groups in the hydrophilic shell are synthesized by a bottom-up approach. The route utilizes polymerization of 2-oxazolines to prepare tailor-made block copolymers with a primary or secondary amine end group in the hydrophilic block and alkynyl moieties in the hydrophobic part of the polymer. Upon solubilization in the aqueous media, these block copolymers form micelles that are photocrosslinked by a radical polymerization process to afford two types of core-crosslinked nanoparticles, either with secondary amines, NP1, or primary amines, NP2, on the surface. The dimensions and stability of the core-crosslinked nanoparticles are characterized by dynamic light scattering and fluorescence spectroscopy. The availability and reactivity of the amine groups in the hydrophilic shell are demonstrated by reaction with different aromatic model compounds resulting in a degree of surface functionalization of 4-47% for NP1 nanoparticles with secondary amino groups and a 20-95% degree of surface functionalization for NP2 with primary amine groups, as determined by UV-vis spectroscopy. Core-crosslinked nanoparticles with surface functional groups are interesting materials for medical applications. Micelle formation of amphiphilic block copolymers with two orthogonal chemical groups is used to prepare core-crosslinked nanoparticles by UV-irradiation of the alkynyl moieties in the hydrophobic block. Further surface functionalization is achieved via primary or secondary amine end groups in the hydrophilic shell. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    view abstract10.1002/macp.201300573
  • Synthesis of α,ω-isocyanate-telechelic poly(methyl methacrylate-co-allyl methacrylate) soft segments
    Greving, N. and Keul, H. and Millaruelo, M. and Weberskirch, R. and Moeller, M.
    European Polymer Journal 49 (2013)
    Isocyanate homo telechelic poly(methyl methacrylate-co-allyl methacrylate)s were prepared and used as soft segments for thermoplastic polyurethanes. Copolymerization of allyl methacrylate and methyl methacrylate by RAFT leads to selective conversion of the methacrylate C,C double bonds, leaving the allyl groups in the polymer side chain intact. A hetero telechelic MMA/AMA copolymer (Het-PMMA/AMA, molar ratio of MMA/AMA = 10/1) with a carboxylic acid and a dithiobenzoate terminus was obtained using 4,4-azobis(4-cyano pentanoic acid) as initiator and 4-cyano pentanoic acid dithiobenzoate as chain transfer agent. In a second reaction step the dithiobenzoate terminus is converted to carboxylic acid groups by a radical exchange reaction. The carboxylic acid homo telechelic statistical copolymer (Ca-Hot-PMMA/AMA) is converted quantitatively by reaction with hexamethylene diisocyanate in order to form isocyanate homo telechelic copolymer (Is-Hot-PMMA/AMA). Last the obtained soft segments were used for polyurethane synthesis. The well-defined polymer structures are characterized by SEC, Raman, and 1H NMR spectroscopy.© 2012 Elsevier Ltd. All rights reserved.
    view abstract10.1016/j.eurpolymj.2012.09.018
  • Synthesis of α,ω-Isocyanate-Telechelic Poly(methyl methacrylate)
    Greving, N. and Keul, H. and Millaruelo, M. and Weberskirch, R. and Moeller, M.
    Macromolecular Chemistry and Physics 213 (2012)
    The preparation of α,ω-isocyanate-telechelic poly(methyl methacrylate) using RAFT polymerization and two postpolymerization modification steps is presented. The synthetic strategy includes the RAFT polymerization of methyl methacrylate, which results in a hetero telechelic polymer. In the first modification step by radical exchange, a carboxylic acid homo telechelic PMMA was successfully prepared. Second, the carboxylic acid end groups are reacted with hexamethylene diisocyanate in excess and magnesium chloride as a catalyst. Under mild reaction conditions (80 °C, 4 h), the isocyanate homo telechelic PMMA is obtained. A conversion of 86% of the carboxylic acid end groups was achieved. The synthesis of α,ω-isocyanate-telechelic poly(methyl methacrylate) is described as follows: (i) RAFT polymerization, (ii) synthesis of a carboxylic acid homo telechelic polymer by radical exchange at the ω-terminus, and (iii) a catalyzed coupling of the carboxylic acid end groups with a diisocyanate. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    view abstract10.1002/macp.201200034
  • Scaleup of lipase-catalyzed polyester synthesis
    Korupp, C. and Weberskirch, R. and Müller, J.J. and Liese, A. and Hilterhaus, L.
    Organic Process Research and Development 14 (2010)
    One of the critical steps for the commercialization of new enzyme-based products is the successful scaleup of the catalyzed reaction. In the study presented here, we achieved a scaleup for the enzymatic production of glycerol adipate on a 500 g scale in a heated, solvent-free system. The influence of various reaction conditions (i.e., temperature, pressure, enzyme concentration, reactants ratio, stirrer type, stirring rate, and reaction time) on the substrate conversion and molecular weight of the product was investigated. Conversions were higher than 0.9, and molecular weights were in the desired range of 2000-3000 Da. Space time yields of 370 g d-1 L-1 could be achieved. Maximal polymer yield was achieved at 60 °C, < 20 mbar, 3 wt % Novozym 435, glycerol:adipic acid ratio 1.1:1, < 48 h while stirring at 100 rpm. © 2010 American Chemical Society.
    view abstract10.1021/op1000868
  • block copolymers

  • nanoparticles

  • polymers

  • ring opening polymerization

  • stem cell research

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