Identification and Structure–Activity Relationship Studies of Small‐Molecule Inhibitors of the Methyllysine Reader Protein Spindlin1

The methyllysine reader protein Spindlin1 has been implicated in the tumorigenesis of several types of cancer and may be an attractive novel therapeutic target. Small‐molecule inhibitors of Spindlin1 should be valuable as chemical probes as well as potential new therapeutics. We applied an iterative virtual screening campaign, encompassing structure‐ and ligand‐based approaches, to identify potential Spindlin1 inhibitors from databases of commercially available compounds. Our in silico studies coupled with in vitro testing were successful in identifying novel Spindlin1 inhibitors. Several 4‐aminoquinazoline and quinazolinethione derivatives were among the active hit compounds, which indicated that these scaffolds represent promising lead structures for the development of Spindlin1 inhibitors. Subsequent lead optimization studies were hence carried out, and numerous derivatives of both lead scaffolds were synthesized. This resulted in the discovery of novel inhibitors of Spindlin1 and helped explore the structure–activity relationships of these inhibitor series.     

4‐Biphenylalanine‐ and 3‐Phenyltyrosine‐Derived Hydroxamic Acids as Inhibitors of the JumonjiC‐Domain‐Containing Histone Demethylase KDM4A

Overexpression of the histone lysine demethylase KDM4A, which regulates H3K9 and H3K36 methylation states, has been related to the pathology of several human cancers. We found that a previously reported hydroxamate‐based histone deacetylase (HDAC) inhibitor (SW55) was also able to weakly inhibit this demethylase with an IC₅₀ value of 25.4 μm . Herein we report the synthesis and biochemical evaluations, with two orthogonal in vitro assays, of a series of derivatives of this lead structure. With extensive chemical modifications on the lead structure, also by exploiting the versatility of the radical arylation with aryldiazonium salts, we were able to increase the potency of the derivatives against KDM4A to the low‐micromolar range and, more importantly, to obtain demethylase selectivity with respect to HDACs. Cell‐permeable derivatives clearly showed a demethylase‐inhibition‐dependent antiproliferative effect against HL‐60 human promyelocytic leukemia cells.     

Fourier‐Transform Rheology of Unvulcanized,Carbon Black Filled Styrene Butadiene Rubber

Rubber materials filled with reinforcing fillers display nonlinear rheological behavior at small strain amplitudes below γ₀ < 0.1. Nevertheless, rheological data are analyzed mostly in terms of linear parameters, such as shear moduli (G′, G″), which loose their physical meaning in the nonlinear regime. In this work styrene butadiene rubber filled with carbon black (CB) under large amplitude oscillatory shear (LAOS) is analyzed in terms of the nonlinear parameter I_3/1. Three different CB grades are used and the filler load is varied between 0 and 70 phr. It is found that I_3/1(φ) is most sensitive to changes of the total accessible filler surface area at low strain amplitudes (γ₀ = 0.32). The addition of up to 70 phr CB leads to an increase of I_3/1(φ) by a factor of more than ten. The influence of the measurement temperature on I_3/1 is pronounced for CB levels above the percolation threshold.

     

Microstructure of the HMX‐Based PBX KS32 after Mechanical Loading

Non‐destructive X‐ray diffraction techniques were applied in order to monitor the influence of mechanical and shock‐loading on the microstructure of the plastic‐bonded high explosive KS32. The investigations uncovered damage to embedded coarse HMX crystals and to the binder system HTPB‐IPDI. Damage to the crystals occurred already during the kneading process in terms of deformation twinning. On higher loading between 400 MPa (static) and 480 MPa (dynamic) also crystal fracture was observed. The change in the binder structure was found after both static and dynamic loading, but not in the cured, differently kneaded samples. Moreover, the change in binder structure after dynamic loading was verified by dynamic mechanical analysis, and interpreted as a partial damage of the binder rubber shell around the explosive particles. The results are compared to literature data from imaging techniques.     

Influence of a cyclic butylene terephthalate oligomer on the processability and thermoelectric properties of polycarbonate/MWCNT nanocomposites

The thermoelectric properties of melt-processed nanocomposites consisting of a polycarbonate (PC) thermoplastic matrix filled with commercially available carboxyl (–COOH) functionalized multi-walled carbon nanotubes (MWCNTs) were evaluated. MWCNTs carrying carboxylic acid moieties (MWCNT-COOH) were used due the p-doping that the carboxyl groups facilitate, via electron withdrawing from the electron-rich π-conjugated system. Preliminary thermogravimetric analysis (TGA) of MWCNT-COOH revealed that the melt-mixing was limited at low temperatures due to thermal decomposition of the MWCNT functional groups. Therefore, PC was mixed with 2.5 wt% MWCNT-COOH (PC/MWCNT-COOH) at 240 °C and 270 °C. In order to reduce the polymer melt viscosity, a cyclic butylene terephthalate (CBT) oligomer was utilized as an additive, improving additionally the electrical conductivity of the nanocomposites. The melt rheological characterization of neat PC and PC/CBT blends demonstrated a significant decrease of the complex viscosity by the addition of CBT (10 wt%). Optical and transmission electron microscopy (OM, TEM) depicted an improved MWCNT dispersion in the PC/CBT polymer blend. The electrical conductivity was remarkably higher for the PC/MWCNT-COOH/CBT composites compared to the PC/MWCNT-COOH ones. Namely, the PC/MWCNT-COOH/CBT processed at 270 °C exhibited the best values with electrical conductivity; σ = 0.05 S/m, Seebeck coefficient; S = 13.55 μV/K, power factor; PF = 7.60 × 10⁻⁶μW/m K⁻², and thermoelectric figure of merit; ZT = 7.94 × 10⁻⁹. The PC/MWCNT-COOH/CBT nanocomposites could be ideal candidates for large-scale thermal energy harvesting, even though the presently obtained ZT values are still too low for commercial applications.     

A combined experimental and theoretical approach to establish the relationship between shear force and clay platelet delamination in melt-processed polypropylene nanocomposites

In this article, a combined experimental and theoretical approach has been proposed to establish a relationship between the required shear force and the degree of delamination of clay tactoids during the melt-processing of polymer nanocomposites. Polypropylene (PP) was selected as a model polymer, and nanocomposites of PP with organically modified clay were prepared by a master batch dilution technique in a twin-screw extruder. The effect of PP throughput during the dilution of the master batch on the dispersion and orientation of clay platelets were studied in detail. Powder X-ray diffraction, small and wide angle X-ray scattering and high resolution transmission electron microscopy were used to study the structure and morphology of the obtained nanocomposites. The results showed that a lower feeding rate led to the orientation of clay platelets almost in the direction of extrusion. The adhesive force and the interaction energy between the clay platelets were theoretically calculated using the Hamaker approach. The analysis showed that the peeling mechanism is a practical explanation for the delamination of clay platelets during melt extrusion and that the dimensions of the clay platelet tactoids play an important role in the peeling due to the shear stress.     

Tropfenseparation aus der Gasphase in kleinskaligen Ringkammerzentrifugen

Here, the laminar fluid flow in small‐scale ring chamber centrifuges is investigated to describe the separation behavior of oil aerosols by means of models and laws of similitude. The key objective is the determination of the separation efficiency dependent on the centrifugal geometry, the material properties of the continuous and disperse phases as well as operational parameters such as angular velocity and volume flow. Experimental investigations were conducted to assess the range of validity, the usability and the accuracy of the models.     

Low-cost direct writing lithography system for the sub-micron range

Abstract

We have developed a fixed beam direct writing laser lithography system with a minimum feature size of 400nm at 457nm wavelength and a writing speed of 4·2mm/s with total system costs of less than 100 000 US$.