Structure elucidation and toxicological evaluation of cyclic Polyethersulfone oligomers present in extracts of membrane filters

Polyethersulfone (PES) is a widely used polymer in consumer and technical products. An important application is PES membranes used in the biopharmaceutical industry for sterilizing-grade filtration and for filtration of food and beverages. For both uses, detailed information about migrating compounds that can be extracted from the polymeric material into a liquid must be gathered. In the pharmaceutical industry, comprehensive extractables studies are required for contact materials, and the data is used in the qualification of the process equipment. PES is generated via polycondensation, which forms cyclic oligomers as a by-product of the reaction. However, no structural information is available for these cyclic oligomers so far. In this publication, we present the analytical determination of PES cyclic oligomers. Their presence in extracts of PES membrane filters is confirmed. The structure of the PES cyclic trimer is elucidated by X-ray and NMR investigation, obtained as crystals from the sublimation of the PES raw material. A strategy is shown to assess the toxicity of such cyclic oligomers and to derive a permitted daily exposure (PDE). The data will reduce the levels of unknowns in extractables and leachables screenings and supports the risk assessment of PES sterile filters

Beiträge zur Chemie der 4-Hydroxy-1,3-Thiazole

Die erste Publikation zum Thema Thiazole stammt vom 18. November 1887 und trägt den Titel „Über Verbindungen des Thiazoles (Thiophen der Pyridinreihe)“ von Arthur Rudolf Hantzsch, 1 in dem er definierte „unter Thiazolen verstehen wir diejenigen Stickstoff und Schwefel in ringförmiger Bindung enthaltenden Substanzen von Formel (CH)3NS, welche sich zum Pyridin verhalten wie das Thiophen zum Benzol“. Die so definierte neue Stoffklasse löste intensive Untersuchungen auf dem Gebiet der Heterocyclenchemie aus, oft verbunden mit heftig geführten Kontroversen. 2 So konnte unter anderem Tcherniacs offenkettige Struktur des α-Thiocyanoacetons („Rhodanpropimin“) zur Thiazolform berichtigt werden. 3 In Schema 1 sind die möglichen Nomenklatursysteme für Thiazole dargestellt, 4 wie es von den jeweiligen Autoren verwendet wurde. 5,6 Klassisch wird die 2-Position (CAS-System) auch als meso-Position bezeichnet. Die vorliegende Arbeit orientiert sich am CAS System

Water-soluble pristine C60 fullerene inhibits liver alterations associated with hepatocellular carcinoma in rat

Excessive production of reactive oxygen species is the main cause of hepatocellular carcinoma (HCC) initiation and progression. Water-soluble pristine C60 fullerene is a powerful and non-toxic antioxidant, therefore, its effect under rat HCC model and its possible mechanisms were aimed to be discovered. Studies on HepG2 cells (human HCC) demonstrated C60 fullerene ability to inhibit cell growth (IC50 = 108.2 μmol), to induce apoptosis, to downregulate glucose-6-phosphate dehydrogenase, to upregulate vimentin and p53 expression and to alter HepG2 redox state. If applied to animals experienced HCC in dose of 0.25 mg/kg per day starting at liver cirrhosis stage, C60 fullerene improved post-treatment survival similar to reference 5-fluorouracil (31 and 30 compared to 17 weeks) and inhibited metastasis unlike the latter. Furthermore, C60 fullerene substantially attenuated liver injury and fibrosis, decreased liver enzymes, and normalized bilirubin and redox markers (elevated by 1.7-7.7 times under HCC). Thus, C60 fullerene ability to inhibit HepG2 cell growth and HCC development and metastasis and to improve animal survival was concluded. C60 fullerene cytostatic action might be realized through apoptosis induction and glucose-6-phosphate dehydrogenase downregulation in addition to its antioxidant activity

Synthesis and Complexation of Well-Defined Labeled Poly(N,N-dimethylaminoethyl methacrylate)s (PDMAEMA)

We present the synthesis and characterization of well-defined polycationic copolymers containing thiazole dyes in the side chain. Atom transfer radical polymerization (ATRP) was used for the copolymerization of 3-azidopropyl methacrylate (AzPMA) and N,N-dimethylaminoethyl methacrylate (DMAEMA) of different composition. Thiazole-based alkyne-functionalized dyes (e.g., 5-methyl-4-(prop-2-yn-1-yloxy)-2-(pyridin-2-yl)thiazole, (MPPT)) were afterwards covalently attached using copper catalyzed azide alkyne cycloadditions (CuAAC) reaching contents of up to 9 mol % dye. Subsequent quaternization of the tertiary nitrogen of DMAEMA with strong methylation agents (e.g., methyl iodide) led to permanently charged polyelectrolytes. The materials were characterized by size exclusion chromatography, as well as NMR- and UV/VIS-spectroscopy. Particular attention is paid to the spectroscopic properties of the dyes in the side chain upon environmental changes such as pH and salinity. We anticipate the application of such precisely functionalized polyelectrolytes as temperature- and pH-responsive sensors in biomedical applications, e.g., within interpolyelectrolyte complexes. Concerning the latter, first complex formation results are demonstrated

The Residual Effect of C60 Fullerene on Biomechanical and Biochemical Markers of the Muscle Soleus Fatigue Development in Rats

Muscle fatigue as a defense body mechanism against overload is a result of the products of incomplete oxygen oxidation such as reactive oxygen species. Hence, C60 fullerene as a powerful nanoantioxidant can be used to speed up the muscle recovery process after fatigue. Here, the residual effect of C60 fullerene on the biomechanical and biochemical markers of the development of muscle soleus fatigue in rats for 2 days after 5 days of its application was studied. The known antioxidant N-acetylcysteine (NAC) was used as a comparison drug. The atomic force microscopy to determine the size distribution of C60 fullerenes in an aqueous solution, the tensiometry of skeletal muscles, and the biochemical analysis of their tissues and rat blood were used in this study. It was found that after the cessation of NAC injections, the value of the integrated muscle power is already slightly different from the control (5%–7%) on the first day, and on the second day, it does not significantly differ from the control. At the same time, after the cessation of C60 fullerene injections, its residual effect was 45%–50% on the first day, and 17%–23% of the control on the second one. A significant difference (more than 25%) between the pro- and antioxidant balance in the studied muscles and blood of rats after the application of C60 fullerene and NAС plays a key role in the long-term residual effect of C60 fullerene. This indicates prolonged kinetics of C60 fullerenes elimination from the body, which contributes to their long-term (at least 2 days) compensatory activation of the endogenous antioxidant system in response to muscle stimulation, which should be considered when developing new therapeutic agents based on these nanoparticles

Supporting Sustainability of Chemistry by Linking Research Data with Physically Preserved Research Materials

Results of scientific work in chemistry can usually be obtained in the form of materials and data. A big step towards transparency and reproducibility of the scientific work can be gained if scientists publish their data in a FAIR (Findable, Accessible, Interoperable, Reusable) manner in research data repositories. Nevertheless, in order to make chemistry as a discipline sustainable, obtaining FAIR data is insufficient and a comprehensive concept including the preservation of materials is needed. We describe in this article how we combined two infrastructures, a repository for research data (Chemotion repository) and an archive for chemical compounds (Molecule Archive), in order to offer a comprehensive infrastructure to find and access data and materials that were generated in chemistry projects. Samples play a key role in this concept: we describe how FAIR metadata of a virtual sample representation can be used to refer to the physically available sample stored in a materials’ archive and to link FAIR research data gained with the sample. We further describe the measures to make the physically available samples not only FAIR through the sample’s metadata but also accessible and reusable in the form of their material for others

Small molecules intercept Notch signaling and the early secretory pathway

Notch signaling has a pivotal role in numerous cell-fate decisions, and its aberrant activity leads to developmental disorders and cancer. To identify molecules that influence Notch signaling, we screened nearly 17,000 compounds using automated microscopy to monitor the trafficking and processing of a ligand-independent Notch–enhanced GFP (eGFP) reporter. Characterization of hits in vitro by biochemical and cellular assays and in vivo using zebrafish led to five validated compounds, four of which induced accumulation of the reporter at the plasma membrane by inhibiting γ-secretase. One compound, the dihydropyridine FLI-06, disrupted the Golgi apparatus in a manner distinct from that of brefeldin A and golgicide A. FLI-06 inhibited general secretion at a step before exit from the endoplasmic reticulum (ER), which was accompanied by a tubule-to-sheet morphological transition of the ER, rendering FLI-06 the first small molecule acting at such an early stage in secretory traffic. These data highlight the power of phenotypic screening to enable investigations of central cellular signaling pathways