Multiple Chemical Features Impact Biological Performance Diversity of a Highly Active Natural Product-Inspired Library

A systematic, diversity-oriented synthesis approach was employed to access a natural product-inspired flavonoid library with diverse chemical features, including chemical properties, scaffold, stereochemistry, and appendages. Using Cell Painting, the effects of these diversity elements were evaluated, and multiple chemical features that predict biological performance diversity were identified. Scaffold identity appears to be the dominant predictor of performance diversity, but stereochemistry and appendages also contribute to a lesser degree. In addition, the diversity of chemical properties contributed to performance diversity, and the driving chemical property was dependent on the scaffold. These results highlight the importance of key chemical features that may inform the creation of small-molecule, performance-diverse libraries to improve the efficiency and success of high-throughput screening campaigns.     

Sintered silicon nitride/nano-silicon carbide materials based on preceramic polymers and ceramic powder

A flexible method is presented, which enables the fabrication of porous as well as dense Si₃N₄/nano-SiC components by using Si₃N₄ powder and a preceramic polymer (polycarbosilazane) as alternative ceramic forming binder. The SiCN polymer benefits consolidation as well as shaping of the green body and partially fills the interstices between the Si₃N₄ particles. Cross-linking of the precursor at 300 °C increases the mechanical stability of the green bodies and facilitates near net shape machining. At first, pyrolysis leads to porous ceramic bodies. Finally, subsequent gas pressure sintering results in dense Si₃N₄/nano-SiC ceramics. Due to the high ceramic yield of the polycarbosilazane binder, the shrinkage during sintering is significantly reduced from 20 to 15 lin.%. Investigations of the sintered ceramics reveal, that the microstructure of the Si₃N₄ ceramic contains approx. 6 vol.% nano-scaled SiC segregations, which are located both at the grain boundaries and as inclusions in the Si₃N₄ grains.     

Comparative Assessment of Complex Stabilities of Radiocopper Chelating Agents by a Combination of Complex Challenge and in vivo Experiments

For ⁶⁴Cu radiolabeling of biomolecules to be used as in vivo positron emission tomography (PET) imaging agents, various chelators are commonly applied. It has not yet been determined which of the most potent chelators—NODA‐GA ((1,4,7‐triazacyclononane‐4,7‐diyl)diacetic acid‐1‐glutaric acid), CB‐TE2A (2,2′‐(1,4,8,11‐tetraazabicyclo[6.6.2]hexadecane‐4,11‐diyl)diacetic acid), or CB‐TE1A‐GA (1,4,8,11‐tetraazabicyclo[6.6.2]hexadecane‐4,11‐diyl‐8‐acetic acid‐1‐glutaric acid)—forms the most stable complexes resulting in PET images of highest quality. We determined the ⁶⁴Cu complex stabilities for these three chelators by a combination of complex challenge and an in vivo approach. For this purpose, bioconjugates of the chelating agents with the gastrin‐releasing peptide receptor (GRPR)‐affine peptide PESIN and an integrin α_vβ₃‐affine c(RGDfC) tetramer were synthesized and radiolabeled with ⁶⁴Cu in excellent yields and specific activities. The ⁶⁴Cu‐labeled biomolecules were evaluated for their complex stabilities in vitro by conducting a challenge experiment with the respective other chelators as challengers. The in vivo stabilities of the complexes were also determined, showing the highest stability for the ⁶⁴Cu–CB‐TE1A‐GA complex in both experimental setups. Therefore, CB‐TE1A‐GA is the most appropriate chelating agent for *Cu‐labeled radiotracers and in vivo imaging applications.     

Reinforcement of a Magnesium‐Ammonium‐Phosphate Cement with Calcium Phosphate Whiskers

Self‐setting resorbable phosphate cements are characterized by an excellent biocompatibility and bioactivity. However, poor mechanical properties restrict their application. Most studies which characterize phosphate cements mechanically focus on strength measurements. Examinations of mechanical reliability and facture toughness were hardly performed. In this study, calcium phosphate whisker‐reinforced magnesium‐ammonium‐phosphate (struvite) cements were examined at the whisker–matrix interface and the measured strength, reliability and toughness values were correlated to these observations. Moreover, the toughening mechanisms were evaluated. It was shown that whisker incorporation is not beneficial for material strength. It led to a strength decrease from 29.8 to 21.8 MPa by the incorporation of 15 vol% calcium‐deficient hydroxyapatite (CDHA) whiskers compared to the pure struvite cement. Weibull statistics and microstructural observations revealed that this is caused by the whisker–matrix interface, which acts as a flaw. In contrast with that, the reliability increases upon whisker incorporation. Furthermore, the critical stress intensity factor K_IC as well as the work‐of‐fracture γ_wof increase from 0.52 to 0.60 MPam^1/2 and from 9.5 to 12.9 J/m² by the addition of 15 vol% CDHA whiskers compared to the original struvite cement. It was shown that whisker pull‐out and crack deflection are the main mechanisms responsible for this increase.     

Polymerization Catalysis in Liquid Propylene: High Activities and Molecular Weights in Propylene/CO Copolymerization Reactions

Summary: The dicationic [(dppp)Pd(NCCH₃)₂](BF₄)₂ catalyst (dppp = 1,3‐bis(diphenylphosphino)propane) was applied in a liquid monomer, two phase process for the CO/propene copolymerization reaction. For the first time it was possible to synthesize propene/CO copolymers with an activity up to 7 500 g/(mol · h) and molecular weights of 500 000 g/mol. Activities up to 40 000 g/(mol · h) could be obtained with the use of the unsymmetric catalyst [(CF₃‐dppp)Pd(NCCH₃)](BF₄)₂ (CF₃‐dppp = 1‐diphenylphosphino‐3‐bis[3,5‐di(trifluormethyl)phenyl]phosphinopropane) in homogeneous liquid propene solution.

Granules found after copolymerization.     

Polymerelektrolytmembranen für Hoch‐ und Niedertemperatur‐Brennstoffzellen aus strahlungsinduzierter Pfropfcopolymerisation

Radiation‐induced graft copolymerization of hydroxyethyl methacrylate with hydroxyethyl acrylate, acrylic acid or glycidyl methacrylate on ethylene tetrafluoroethylene (ETFE) films allow for tailor‐made synthesis of membranes for high and low temperature fuel cell applications. According to the operating temperatures proton conductivity may be achieved via doping with phosphoric acid or a two‐step sulfonation of the functional monomers. Fuel cell tests provide power densities and internal resistances, which indicate that the membranes are suitable for high and low temperature fuel cells.     

Erosion behavior of EB-PVD 7YSZ coatings under corrosion/erosion regime: Effect of TBC microstructure and the CMAS chemistry

Aero-engines operating in dust-laden environments often encounter a lot of dust/sand that causes a severe problem to the TBCs by means of erosion. As the turbine entry temperatures are rising, molten sand is also a big concern to the life-time of TBCs.This paper deals with the TBC behavior under the combined influence of erosion and corrosion attack. Variations in TBC morphology, CMAS infiltration time and CMAS composition and their influence on the erosion resistance at room temperature were investigated. Two different EB-PVD 7YSZ morphologies consisting of a different porosity arrangement were tested in the erosion/corrosion regime. The more ‘Feathery’ structure has a better resistance to erosion compared to a more columnar ‘Normal’ structure, which leads to less degradation of the TBC. However, under the influence of CMAS infiltration the effect was found to be reversed. In general, CMAS-infiltrated EB-PVD TBCs exhibit a higher erosion resistance than the non-infiltrated ones.     

RAFT-derived polymer-drug conjugates: poly(hydroxypropyl methacrylamide) (HPMA)-7-ethyl-10-hydroxycamptothecin (SN-38) conjugates

A series of well‐defined polymer–drug conjugates were prepared in order to modify the physical properties of a known cytotoxic drug, 7‐ethyl‐10‐hydroxycamptothecin (SN‐38), the active metabolite of irinotecan (CPT‐11). Reversible addition–fragmentation chain transfer (RAFT) polymerisation was used to covalently and site‐specifically append a defined N‐(2‐hydroxypropyl)methacrylamide (HPMA) polymer to SN‐38 using a graft‐from process. These poly‐HPMA–SN‐38 conjugates displayed excellent aqueous solubility and stability, whilst retaining the cytotoxic activity of the parent SN‐38. In vitro co‐culture assays containing both cancer and noncancer cell lines demonstrated the specificity of RAFT‐derived poly‐HPMA–SN‐38 conjugates for cancerous cells. The concept of post‐optimisation modification of small‐molecule drugs through a graft‐from polymer conjugation method is introduced.     

Protein Engineering of the Progesterone Hydroxylating P450‐Monooxygenase CYP17A1 Alters Its Regioselectivity

The CYP171 enzyme is known to catalyse a key step in the steroidogenesis of mammals. The substrates progesterone and pregnenolone are first hydroxylated at the C17 position, and this is followed by cleavage of the C17?C20 bond to yield important precursors for glucosteroids and androgens. In this study, we focused on the reaction of the bovine CYP17A1 enzyme with progesterone as a substrate. On the basis of a created homology model, active‐site residues were identified and systematically mutated to alanine. In whole‐cell biotransformations, the importance of the N202, R239, G297 and E305 residues for substrate conversion was confirmed. Additionally, mutation of the L206, V366 and V483 residues enhanced the formation of the 16α‐hydroxyprogesterone side product up to 40 % of the total product formation. Furthermore, residue L105 was found not to be involved in this side activity, which contradicts a previous study with the human enzyme.