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A range of mono- and bis-adducts of beryllium dichloride with cyclic (alkyl)(amino)carbenes (CAAC), cyclic diamidocarbene (DAC), and carbodiphosphorane (CDP) are prepared, and their reactions with nucleophiles are studied. Salt elimination with Yamashita and Nozaki's lithium diazaborolide reagent led to the isolation of an unsymmetrical beryllium diazaborolyl complex and a base-stabilized diazaborolyl beryllium chloride. From structural and spectroscopic analyses, the Be-B bonding in these compounds was determined to be polar covalent in character. In addition, the nucleophilic addition of magnesium anthracenediyl to one of the adducts resulted in the isolation of an interesting tetracyclic beryllium-bridged molecule.

The aim of the study is to investigate the uptake by and transport through Caco-2 cells of two mixed micelle formulations (based on egg phosphatidylcholine and glycocholic acid) of vitamin K, i.e., with and without DSPE-PEG2000. The uptake of vitamin K and fluorescently labeled mixed micelles with and without PEG coating showed similar kinetics and their uptake ratio remained constant over time. Together with the fact that an inhibitor of scavenger receptor B1 (BLT-1) decreased cellular uptake of vitamin K by ∼80% compared to the uptake in the absence of this inhibitor, we conclude that both types of micelles loaded with vitamin K can be taken up intactly by Caco-2 cells via this scavenger receptor. The amount of vitamin K in chylomicrons fraction from Caco-2 cell monolayers further indicates that mixed micelles (with or without PEGylation) are likely packed into chylomicrons after internalization by Caco-2 cells. Uptake of vitamin K from PEGylated mixed micelles increased four- to five-fold at simulated gastrointestinal conditions. In conclusion, PEGylated mixed micelles are stable upon exposure to simulated gastric conditions, and as a result, they do show overall a higher cellular uptake efficiency of vitamin K as compared to mixed micelles without PEG coating.

Styrene-maleic acid (SMA) copolymers have attracted interest in membrane research because they allow the solubilization and purification of membrane-spanning proteins from biological membranes in the form of native-like nanodisks. However, our understanding of the underlying SMA-lipid interactions is hampered by the fact that SMA preparations are very polydisperse. Here, we obtained fractions of the two most commonly used SMA preparations: SMA 2:1 and SMA 3:1 (both with specified M w ∼10 kD), with different number-average molecular weight (M n ) and styrene content. The fractionation is based on the differential solubility of styrene-maleic anhydride (SMAnh) in hexane and acetone mixtures. SMAnh fractions were hydrolyzed to SMA and added to lipid self-assemblies. It was found that SMA fractions inserted in monolayers and solubilized vesicles to a different extent, with the highest efficiency being observed for low-M n SMA polymers. Electron microscopy and dynamic light scattering size analyses confirmed the presence of nanodisks independent of the M n of the SMA polymers forming the belt, and it was shown that the nanodisks all have approximately the same size. However, nanodisks bounded by high-M n SMA polymers were more stable than those bounded by low-M n polymers, as indicated by a better retention of the native lipid thermotropic properties and by slower exchange rates of lipids between nanodisks. In conclusion, we here present a simple method to separate SMAnh molecules based on their M n from commercial SMAnh blends, which allowed us to obtain insights into the importance of SMA length for polymer-lipid interactions., (Copyright © 2018 Biophysical Society. All rights reserved.)

Internet use disorder (IUD) presents a growing problem worldwide. Among others, it manifests in loss of control over Internet usage and social problems due to problematic Internet use. Although IUD currently is not an official diagnosis in DSM-5 or ICD-10, mounting evidence suggests that IUD indeed could be categorized as a behavioral addiction. On a systemic neuroscientific level, IUD is well characterized and dysfunctions in the fronto-striatal-limbic loop have been observed in persons being afflicted with IUD. On a molecular level underlying these neural dysfunctions less is known. Therefore, the present research investigates the influence of prenatal testosterone as measured via the 2D:4D marker of the hand on IUD. Testosterone represents an interesting hormonal marker, because sex differences in IUD have been observed, e.g., males show higher tendencies toward Internet gaming disorder (IGD) or females toward overusage of online social networks (both compared to the contrary sex). In N  = 217 participants associations between the 2D:4D marker of the hand and both unspecified IUD and specific forms of IUD were investigated. It appeared that more female hands (right side; characterized by higher digit ratio of the index to the ring finger, i.e., >1, meaning lower prenatal testosterone) were associated with lower IGD ( rho  = -0.17, p  = 0.01, N  = 211). This effect was driven by the facet of loss of control of Internet Gaming in the whole sample ( rho  = -0.20, p  < 0.01, N  = 211) and the female subsample ( rho  = -0.20, p  = 0.02, N(f)  = 137). Aside from this, a negative association appeared between the facet of loss of control of generalized IUD and the right digit ratio in males underlining earlier work. In sum, the present work demonstrates that the 2D:4D marker is an interesting marker for Internet addiction and can be easily included as a biomarker to understand the biological underpinnings of Internet (over-)usage.

Convenient solution-phase syntheses of tetrahalodiboranes(4) B 2 F 4 , B 2 Cl 4 and B 2 I 4 are presented herein from common precursor B 2 Br 4 . In addition, the dimethylsulfide adducts B 2 Cl 4 (SMe 2 ) 2 and B 2 Br 4 (SMe 2 ) 2 are conveniently prepared in one-step gram and multigram scale syntheses from the commercially-available starting material B 2 (NMe 2 ) 4 . The results provide simple access to the full range of tetrahalodiboranes(4) for the exploration of their untapped synthetic potential.

Herein are reported the first π-complexes of compounds with boron-boron triple bonds with transition metals, in this case Cu I . Three different compounds were isolated that differ in the number of copper atoms bound to the BB unit. Metalation of the B-B triple bonds causes lengthening of the B-B and B-C NHC bonds, as well as large upfield shifts of the 11 B NMR signals, suggesting greater orbital interactions between the boron and transition metal atoms than those observed with recently published diboryne/alkali metal cation complexes. In contrast to previously reported fluorescent copper(I) π-complexes of boron-boron double bonds, the Cu n -π-diboryne compounds (n = 2, 3) show intense phosphorescence in the red to near-IR region from their triplet excited states, according to their microsecond lifetimes, with quantum yields of up to 58%. While the Cu diborene bond is dominated by electrostatic interactions, giving rise to S 1 and T 1 states of pure IL(π-π*) nature, DFT studies show that the Cu I π-complexes of diborynes reported herein exhibit enhanced metal d orbital contributions to HOMO and HOMO-1, which results in S 1 and T 1 having significant MLCT character, enabling strong spin-orbit coupling for highly efficient intersystem-crossing S 1 → T n and phosphorescence T 1 → S 0 .

Extensive efforts and numerous methodologies have been explored to develop safe and efficient gene carriers that are capable of overcoming multiple extra- and intracellular barriers during the transfection process. However, it is a great challenge to fabricate a gene carrier system containing multiple functional components. In this work, we propose a facile modular approach to design targeted multifunctional gene delivery systems, which are based on building blocks with pre-defined functions to tackle specific barriers. These building blocks can be rationally combined and self-assemble into an integrated gene delivery system via host-guest interactions. As a proof of concept, three adamantyl-terminated targeting guest modules, adamantyl terminated RGD peptide (Ad-RGD), folate and lactobionic acid terminated PEGs (FA-PEG-Ad and LA-PEG-Ad), were synthesized, characterized, and utilized for post-functionalizing of adamantyl decorated cationic PEI based supramolecular polyplexes (PEI-Ad 4 /PCD/DNA) through the free CD units of the poly(β-cyclodextran) (PCD) host module. These multifunctional targeting supramolecular polyplexes exhibited enhanced cellular uptake and excellent transfection activity in receptor-positive cells. By modulating the functional components of the supramolecular platform, we can customize the gene carriers for further research on different tissues or cells in vitro or in vivo.

The metals of the s block of the periodic table are well known to be exceptional electron donors, and the vast majority of their molecular complexes therefore contain these metals in their fully oxidized form. Low-valent main-group compounds have recently become desirable synthetic targets owing to their interesting reactivities, sometimes on a par with those of transition-metal complexes. In this work, we used stabilizing cyclic (alkyl)(amino)carbene ligands to isolate and characterize the first neutral compounds that contain a zero-valent s-block metal, beryllium. These brightly coloured complexes display very short beryllium-carbon bond lengths and linear beryllium coordination geometries, indicative of strong multiple Be-C bonding. Structural, spectroscopic and theoretical results show that the complexes adopt a closed-shell singlet configuration with a Be(0) metal centre. The surprising stability of the molecule can be ascribed to an unusually strong three-centre two-electron π bond across the C-Be-C unit.

We report the synthesis of the first 1,1'-bis(boratabenzene) species by tetrabromodiborane(4)-induced ring-expansion reactions of cobaltocene. Six equivalents of cobaltocene are required as the species plays the dual role of reagent and reductant to yield [{(η(5) -C5 H5 )Co}2 {μ:η(6) ,η(6) -(BC5 H5 )2 }]. The formally dianionic bis(boratabenzene) moiety with a boron-boron single bond can be viewed as a symmetric dimer of the parent boratabenzene anion as well as the first example of a diboron analogue of biphenyl. The solution electrochemistry of the bimetallic complex shows four stepwise redox events, indicating significant intramolecular interaction between the cobalt ions across the 1,1'-bis(boratabenzene) unit. The magnetic properties, as investigated by variable-temperature SQUID magnetometry, reveal weak intramolecular antiferromagnetic interactions. Density functional theory calculations support the experimental results and add insight into the various electronic states of the complex., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Curcumin, a phenolic compound, possesses many pharmacological activities and is under clinical evaluation to treat different diseases. However, conflicting data about its stability have been reported. In this study, the kinetic degradation of curcumin from a natural curcuminoid mixture under various conditions (pH, temperature, and dielectric constant of the medium) was investigated. Moreover, the degradation of pure curcumin at some selected conditions was also determined. To fully solubilize curcumin and to prevent precipitation of curcumin that occurs when low concentrations of co-solvent are present, a 50:50 (v/v) aqueous buffer/methanol mixture was used as standard medium to study its degradation kinetics. The results showed that degradation of curcumin both as pure compound and present in the curcuminoid mixture followed first order kinetic reaction. It was further shown that an increasing pH, temperature, and dielectric constant of the medium resulted in an increase in the degradation rate. Curcumin showed rapid degradation due to autoxidation in aqueous buffer pH = 8.0 with a rate constant of 280 × 10(-3) h(-1), corresponding with a half-life (t1/2) of 2.5 h. Dioxygenated bicyclopentadione was identified as the final degradation product. Importantly, curcumin loaded as curcuminoid mixture in ω-methoxy poly (ethylene glycol)-b-(N-(2-benzoyloxypropyl) methacrylamide) (mPEG-HPMA-Bz) polymeric micelles and in Triton X-100 micelles was about 300-500 times more stable than in aqueous buffer. Therefore, loading of curcumin into polymeric micelles is a promising approach to stabilize this compound and develop formulations suitable for further pharmaceutical and clinical studies.

A new compound with the formula L-B2-L wherein the stabilizing ligand (L) is 1,3-bis[diisopropylphenyl]-4,5-dihydroimidazol-2-ylidene (SIDip) has been synthesized, isolated, and characterized. The π-acidity of the SIDip ligand, intermediate between the relatively non-acidic IDip (1,3-bis[diisopropylphenyl]imidazol-2-ylidene) ligand and the much more highly acidic CAAC (1-[2,6-diisopropylphenyl]-3,3,5,5-tetramethylpyrrolidin-2-ylidene) ligand, gives rise to a compound with spectroscopic, electrochemical, and structural properties between those of L-B2-L compounds stabilized by CAAC and IDip. Reactions of all three L-B2-L compounds with CO demonstrate the differences caused by their respective ligands, as the π-acidities of the CAAC and SIDip carbenes enabled the isolation of bis(boraketene) compounds (L(OC)B-B(CO)L), which could not be isolated from reactions with B2(IDip)2. However, only B2(IDip)2 and B2(SIDip)2 could be converted into bicyclic bis(boralactone) compounds., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Cation-π interactions are one of the most important classes of noncovalent bonding, and are seen throughout biology, chemistry, and materials science. However, in almost every documented case, these interactions play only a supporting role to much stronger covalent or dative bonds, thus making examples of exclusive cation-π bonding exceedingly rare. In this study, a neutral diboryne molecule is found to encapsulate the light alkali metal cations Li(+) and Na(+) in the absence of a net charge, covalent bonds, or lone-pair donor groups. The resulting encapsulation complexes are, to our knowledge, the first structurally authenticated species in which a neutral molecule binds the light alkali metals exclusively through cation-π interactions., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Diborynes, molecules containing homoatomic boron-boron triple bonds, have been investigated by Raman spectroscopy in order to determine the stretching frequencies of their central B≡B units as an experimental measure of homoatomic bond strengths. The observed frequencies between 1600 and 1750 cm(-1) were assigned on the basis of DFT modeling and the characteristic pattern produced by the isotopic distribution of boron. This frequency completes the series of known stretches of homoatomic triple bonds, fitting into the trend established by the long-known stretching frequencies of C≡C and N≡N triple bonds in alkynes and dinitrogen, respectively. A quantitative analysis was carried out using the concept of relaxed force constants. The results support the classification of the diboryne as a true triple bond and speak to the similarities of molecules constructed from first-row elements of the p block. Also reported are the relaxed force constants of a recently reported diborabutatriene, which again fit into the trend established by the vibrational spectroscopy of organic cumulenes. As part of these studies, a new diboryne with decreased steric bulk was synthesized, and a computational study of the rotation of the stabilizing ligands indicated alkyne-like electronic isolation of the central B2 unit.

Purpose: To investigate the effect of polyethylene glycol (PEG) in nanoparticles based on blends of hydroxylated aliphatic polyester, poly(D,L-lactic-co-glycolic-co-hydroxymethyl glycolic acid) (PLGHMGA) and PEG-PLGHMGA block copolymers on their degradation and release behavior., Methods: Protein-loaded nanoparticles were prepared with blends of varying ratios of PEG-PLGHMGA (molecular weight of PEG 2,000 and 5,000 Da) and PLGHMGA, by a double emulsion method with or without using poly(vinyl alcohol) (PVA) as surfactant. Bovine serum albumin and lysozyme were used as model proteins., Results: PEGylated particles prepared without PVA had a zeta potential ranging from ~ -3 to ~-35 mV and size ranging from ~200 to ~600 nm that were significantly dependent on the content and type of PEG-block copolymer. The encapsulation efficiency of the two proteins however was very low (<30%) and the particles rapidly released their content in a few days. In contrast, all formulations prepared with PVA showed almost similar particle properties (size: ~250 nm, zeta potential: ~-1 mV), while loading efficiency for both model proteins was rather high (80-90%). Unexpectedly, independent of the type of formulation, the nanoparticles had nearly the same release and degradation characteristics. NMR analysis showed almost a complete removal of PEG in 5 days which explains these marginal differences., Conclusions: Protein release and particle degradation are not substantially influenced by the content of PEG, likely because of the fast shedding of the PEG blocks. These PEG shedding particles are interesting system for intracellular delivery of drugs.

The complexation of two equivalents of a cyclic (alkyl)(amino)carbene (CAAC) to tetrabromodiborane, followed by reduction with four equivalents of sodium naphthalide, led to the formation of the CAAC-stabilized linear diboracumulene (CAAC)2B2. The capacity of the CAAC ligand to facilitate B2 →CAAC donation of π-electron density resulted in important differences between this species and a previously reported complex featuring a B≡B triple bond stabilized by cyclic di(amino)carbenes, including a longer B-B bond and shorter B-C bonds. Frontier orbital analysis indicated sharing of valence electrons across the entire linear C-B-B-C unit in (CAAC)2B2, which is supported by natural population analysis and cyclic voltammetry., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Hydrogels can provide a suitable environment for tissue formation by embedded cells, which makes them suitable for applications in regenerative medicine. However, hydrogels possess only limited mechanical strength, and must therefore be reinforced for applications in load-bearing conditions. In most approaches the reinforcing component and the hydrogel network have poor interactions and the synergetic effect of both materials on the mechanical properties is not effective. Therefore, in the present study, a thermoplastic polymer blend of poly(hydroxymethylglycolide-co-ε-caprolactone)/poly(ε-caprolactone) (pHMGCL/PCL) was functionalized with methacrylate groups (pMHMGCL/PCL) and covalently grafted to gelatin methacrylamide (gelMA) hydrogel through photopolymerization. The grafting resulted in an at least fivefold increase in interface-binding strength between the hydrogel and the thermoplastic polymer material. GelMA constructs were reinforced with three-dimensionally printed pHMGCL/PCL and pMHMGCL/PCL scaffolds and tested in a model for a focal articular cartilage defect. In this model, covalent bonds at the interface of the two materials resulted in constructs with an improved resistance to repeated axial and rotational forces. Moreover, chondrocytes embedded within the constructs were able to form cartilage-specific matrix both in vitro and in vivo. Thus, by grafting the interface of different materials, stronger hybrid cartilage constructs can be engineered., (Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Many metal-containing compounds, and some metal-free compounds, will bind carbon monoxide. However, only a handful of metal-containing compounds have been shown to induce the coupling of two or more CO molecules, potentially a method for the use of CO as a one-carbon-atom building block for the synthesis of organic molecules. In this work, CO was added to a boron-boron triple bond at room temperature and atmospheric pressure, resulting in a compound into which four equivalents of CO are incorporated: a flat, bicyclic, bis(boralactone). By the controlled addition of one CO to the diboryne compound, an intermediate in the CO coupling reaction was isolated and structurally characterized. Electrochemical measurements confirm the strongly reducing nature of the diboryne compound.

Homoatomic triple bonds between main-group elements have been restricted to alkynes, dinitrogen, and a handful of reactive compounds featuring trans-bent heavier elements of groups 13 and 14. Previous attempts to prepare a compound with a boron-boron triple bond that is stable at ambient temperature have been unsuccessful, despite numerous computational studies predicting their viability. We found that reduction of a bis(N-heterocyclic carbene)-stabilized tetrabromodiborane with either two or four equivalents of sodium naphthalenide, a one-electron reducing agent, yields isolable diborene and diboryne compounds. Crystallographic and spectroscopic characterization confirm that the latter is a halide-free linear system containing a boron-boron triple bond.

The synthesis and structural characterization of the first tin-bridged ansa half-sandwich complexes via a two-step protocol from Na[η(5)-C(5)H(5)Ru(CO)(2)] and in situ generated Na[η(5)-C(5)H(5)Ni(CO)] are presented. Both compounds are characterized by multinuclear NMR spectroscopy and single-crystal diffraction.

Purpose: To investigate the in vitro release of octreotide acetate, a somatostatin agonist, from microspheres based on a hydrophilic polyester, poly(D,L-lactide-co-hydroxymethyl glycolide) (PLHMGA)., Methods: Spherical and non-porous octreotide-loaded PLHMGA microspheres (12 to 16 μm) and loading efficiency of 60-70% were prepared by a solvent evaporation. Octreotide release profiles were compared with commercial PLGA formulation (Sandostatin LAR(®)); possible peptide modification with lactic, glycolic and hydroxymethyl glycolic acid units was monitored., Results: PLHMGA microspheres showed burst release (~20%) followed by sustained release for 20-60 days, depending on the hydrophilicity of the polymer. Percentage of released loaded peptide was high (70-90%); > 60% of released peptide was native octreotide. PLGA microspheres did not show peptide release for the first 10 days, after which it was released in a sustained manner over the next 90 days; > 75% of released peptides were acylated adducts., Conclusions: PLHMGA microspheres are promising controlled systems for peptides with excellent control over release kinetics. Moreover, substantially less peptide modification occurred in PLHMGA than in PLGA microspheres.

We report the synthesis and characterisation of unprecedented unstrained [2]diborametallocenophanes of zirconium and hafnium that bear the bulky octamethylfluorenyl (η(5)-C(29)H(36)) system, the proligands of which were pre-constructed by a two-step synthesis. The compounds were fully characterised by NMR spectroscopy, MALDI-TOF mass spectrometry and X-ray diffraction analysis. Typical reactivities relevant to olefin polymerisation such as methylation and chloride abstraction were also investigated. Finally, a sterically demanding bis(octamethylfluorenyl) metallocene was prepared., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: To study the release of a model protein, bovine serum albumin (BSA), from microspheres of an hydroxylated aliphatic polyester, poly(lactic-co-hydroxymethyl glycolic acid) (PLHMGA)., Methods: BSA-loaded microspheres were prepared by a double emulsion solvent evaporation method. The effect of copolymer composition and the molecular weight of the copolymer on in vitro release and degradation were studied. The integrity of the released BSA was studied by fluorescence spectroscopy and size exclusion chromatography (SEC)., Results: Microspheres prepared from PLHMGA with 50% hydroxymethyl glycolic acid (HMG) showed a burst release followed by a sustained release in 5-10 days. PLHMGA microspheres prepared from a copolymer with 35% and 25% HMG showed a sustained release of BSA up to 80% for 30 and 60 days, respectively. The release of BSA was hardly affected by the molecular weight of the polymer. Fluorescence spectroscopy and SEC showed that the released BSA preserved its structural integrity. Microspheres were fully degradable, and the degradation time increased from approximately 20 days to 60 days when the HMG content decreased from 50% to 25%., Conclusions: Taking the degradation and release data together, it can be concluded that the release of BSA from PLHMGA microspheres is governed by degradation of the microspheres.

A novel class of NF-kappaB pathway signaling inhibitors was discovered by virtual screening, medicinal chemistry, and QSAR analysis. An initial set of compounds inhibited NF-kappaB signaling in a whole cell reporter gene assay in the micro-molar range. Activity was improved step by step by medicinal chemistry to yield nano-molar signaling inhibitors.

Purpose: Previously, we have shown that complexes of plasmid DNA with the biodegradable polymer poly(2-dimethylamino ethylamino)phosphazene (p(DMAEA)-ppz) mediated tumor selective gene expression after intravenous administration in mice. In this study, we investigated the effect of p(DMAEA)-ppz molecular weight on both in vitro and in vivo tumor transfection, as well as on complex induced toxicity., Materials and Methods: p(DMAEA)-ppz with a broad molar mass distribution was fractionated by preparative size exclusion chromatography. Polyplexes consisting of plasmid DNA and the collected polymer fractions were tested for biophysical properties, (cyto)toxicity and transfection activity., Results: Four p(DMAEA)-ppz fractions were collected with weight average molecular weights ranging from 130 to 950 kDa, and with narrow molecular mass distributions (Mw/Mn from 1.1 to 1.3). At polymer-to-DNA (N/P) ratios above 6, polyplexes based on these polymers were all positively charged (zeta potential 25-29 mV), and had a size of 80-90 nm. The in vitro cytotoxicity of the polyplexes positively correlated with polymer molecular weight. The in vitro transfection activity of the different polyplexes depended on their N/P ratio, and was affected by the degree of cytotoxicity, as well as the colloidal stability of the different polyplexes. Intravenous administration of polyplexes based on the high molecular weight polymers led to apparent toxicity, as a result of polyplex-induced erythrocyte aggregation. On the other hand, administration of polyplexes based on low molecular weight p(DMAEA)-ppz's (Mw 130 kDa) did not show signs of toxicity and resulted in tumor selective gene expression., Conclusion: Polymer molecular weight fractionation enabled us to optimize the transfection efficiency/toxicity ratio of p(DMAEA)-ppz polyplexes for in vitro and in vivo tumor transfection.

Hydrogel formation by physical cross-linking is a developing area of research toward materials suitable for pharmaceutical and biomedical applications. Polymers exhibiting lower critical solution temperature (LCST) behavior in aqueous solution are used in this study to prepare hydrogels. Four triblock copolymers (ABA) with thermosensitive poly(N-(2-hydroxypropyl) methacrylamide lactate) A-blocks and a hydrophilic poly(ethylene glycol) B-block have been synthesized. The molecular weight of the hydrophilic PEG block was fixed at 10 kDa, whereas the molecular weight of the pHPMAm-lactate block was varied between 10 and 20 kDa. The rheological characteristics of these polymer hydrogels were studied as a function of temperature, concentration, and the length of the thermosensitive blocks. Gelation occurred rapidly upon increasing the temperature to 37 degrees C, which makes this system suitable as an injectable formulation. The gels became stronger with increasing temperature and concentration, and moreover they behaved as critical gels, which means that G' and G' ' follow power laws over the entire frequency range. Surprisingly, with increasing length of the thermosensitive blocks, weaker hydrogels were formed. This trend can be explained by the cross-link density of the physical network, which increases with decreasing length of the thermosensitive blocks.

Purpose: This study was performed to develop a reliable aqueous size-exclusion chromatography (SEC) method to obtain the absolute molar masses and distributions of various cationic polymers used in gene delivery., Methods: Water-soluble cationic [2-(dimethylamino) ethyl methacrylate] polymers (PDEs) with different molar masses and low polydispersities were synthesized by living polymerization and these were used to optimize the SEC conditions. Online coupled multiangle light scattering (MALS) detection was applied to obtain the absolute molar masses. Narrow fractions of high molar mass were obtained by semipreparative SEC., Results: It was found that 0.3 M NaAc (pH 4.4) is a suitable eluent in combination with Shodex OHpak SB columns for SEC analysis of PDEs and other cationic polymers, such as poly(L-lysine) and poly(ethylene imine). The absolute molar masses of different PDEs were determined directly using SEC-MALS. A calibration curve was established using narrow PDEs., Conclusions: A reliable routine method for molar-mass characterization of cationic polymers was established. Because standards of known molar masses with narrow distributions are not commercially available for most polymers used in pharmaceutics and biotechnology, the procedure described in this work can also be applied for molar-mass characterization of other water-soluble polymers.

Human dihydroorotate dehydrogenase (DHODH) represents an important target for the treatment of hyperproliferative and inflammatory diseases. In the cell DHODH catalyzes the rate-limiting step of the de novo pyrimidine biosynthesis. DHODH inhibition results in beneficial immunosuppressant and antiproliferative effects in diseases such as rheumatoid arthritis. Here, we present high-resolution X-ray structures of human DHODH in complex with a novel class of low molecular weight compounds that inhibit the enzyme in the nanomolar range. Some compounds showed an interesting dual binding mode within the same cocrystal strongly depending on the nature of chemical substitution. Measured in vitro activity data correlated with the prevailing mode of binding and explained the observed structure-activity relationship. Additionally, the X-ray data confirmed the competitive nature of the inhibitors toward the putative ubiquinone binding site and will guide structure-based design and synthesis of molecules with higher activity.

A previously discovered DHODH inhibitor series was further improved by replacing the cyclopentene ring by aromatic heterocycles. Different isomers of these compounds were prepared by the directed ortho-metallation procedure. The compounds are more active than the corresponding cyclopentene analogs and show potent effects on PBMC's proliferation.

Novel DHODH inhibitors were developed based on a previously described series by introduction of heteroatoms into the cyclopentene ring and hydroxyl groups attached to it. Also, the hydrophobic biphenyl side chain was replaced with benzyloxy phenyl groups. Activities on human, rat, and mouse enzymes indicate a species specificity of these inhibitors.

The rheology of reversible coordination polymer networks in aqueous solution is studied. The polymers are formed by neodymium(III) ions and bifunctional ligands, consisting of two pyridine-2,6-dicarboxylate groups connected at the 4-positions by an ethylene oxide spacer. Neodymium(III) ions can bind three of these terdendate ligand groups. At high concentrations, the polymer networks yield viscoelastic materials, which can be described with the Maxwell model. The scaling of the elastic modulus, relaxation time, and zero-shear viscosity with concentration are in good agreement with the predictions of Cates' model that describes the dynamics of linear equilibrium polymers. This indicates that the networks have only few cross-links and can be described as linear equilibrium polymers. The gels are also thermo-reversible. At high temperatures, fast relaxation was found, resulting in liquidlike behavior. Upon cooling, the viscoelastic properties returned immediately. From the temperature dependence of the relaxation time, an activation energy of 49 kJ/mol was determined for the breaking and reptation of the polymers.

A new naphthylisoquinoline alkaloid, ancistrolikokine D, and the likewise 5,8'-coupled alkaloid ancistroealaine A, as well as two further, biosynthetically related, but nitrogen-free natural products, ancistronaphthoic acid B and cis-isoshinanolone, have been isolated from Ancistrocladus likoko J. LEACUTE;ONARD (Ancistrocladaceae). The 5,8'-coupling of the new alkaloids and of the alkaloids isolated earlier hints at a close phylogenetic relationship of A. likoko to other Central African Ancistrocladus species. The compounds show moderate activities against Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei rhodesiense.

Three new naphthylisoquinoline alkaloids, ancistrolikokines A-C (1-3), have been isolated and structurally assigned from Ancistrocladus likoko, as well as the known compound korupensamine A (4). Their 5,8'-coupling hints at a close biogenetic relationship of A. likoko to other Central African Ancistrocladus species. Compounds 1-4 showed good to moderate antimalarial activities when evaluated in vitro against the NF54 and K1 strains of Plasmodium falciparum.

The isolation and structural elucidation of a new naphthylisoquinoline alkaloid, 8-O-methyldioncophyllinol B, from Triphyophyllum peltatum (Hutch. et Dalz.) Airy Shaw (Dioncophyllaceae) is described, together with the revised structures of other 'B-type' compounds previously misidentified as dioncophylline D, dioncophyllinol D, and 8-O-methyldioncophylline D. All of the presently described structures are 7,6'-coupled and thus have to be addressed as 'B-type' naphthylisoquinoline alkaloids. This is in contrast to the initially defined 'D-type' structures, which are 7,8'-coupled as confirmed by a total synthesis of dioncophylline D. Some of these natural and synthetic naphthylisoquinolines were found to display good in vitro antiplasmodial activities.