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.     

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.

     

Dynamic behavior of nanometer-scale amorphous intergranular film in silicon nitride by in situ high-resolution transmission electron microscopy

We report about the dynamic behavior of a nanometer-scale amorphous intergranular film (IGF) in a Si₃N₄ ceramic by an in situ heating experiment in a high-resolution transmission electron microscopy (HRTEM). During the experiment the IGF gradually vanishes at 820 °C accompanied by the formation of crystal planes within the IGF. The IGF reappears after cooling back to room temperature. The results cannot be explained within the framework of a force balance model. We argue that the dynamic behavior of the IGF in our experiment originates from the open system observed.     

Kinetic Analysis of Terminal and Unactivated C?H Bond Oxyfunctionalization in Fatty Acid Methyl Esters by Monooxygenase‐Based Whole‐Cell Biocatalysis

The alkane monooxygenase AlkBGT from Pseudomonas putida GPo1 constitutes a versatile enzyme system for the ω‐oxyfunctionalization of medium chain‐length alkanes. In this study, recombinant Escherichia coli W3110 expressing alkBGT was investigated as whole‐cell catalyst for the regioselective biooxidation of fatty acid methyl esters to terminal alcohols. The ω‐functionalized products are of general economic interest, serving as building blocks for polymer synthesis. The whole‐cell catalysts proved to functionalize fatty acid methyl esters with a medium length alkyl chain specifically at the ω‐position. The highest specific hydroxylation activity of 104 U g_CDW⁻¹ was obtained with nonanoic acid methyl ester as substrate using resting cells of E. coli W3110 (pBT10). In an optimized set‐up, maximal 9‐hydroxynonanoic acid methyl ester yields of 95% were achieved. For this specific substrate, apparent whole‐cell kinetic parameters were determined with a V_max of 204±9 U g_CDW⁻¹, a substrate uptake constant (K_S) of 142±17 μM, and a specificity constant V_max/K_S of 1.4 U g_CDW⁻¹ μM ⁻¹ for the formation of the terminal alcohol. The same E. coli strain carrying additional alk genes showed a different substrate selectivity. A comparison of biocatalysis with whole cells and enriched enzyme preparations showed that both substrate availability and enzyme specificity control the efficiency of the whole‐cell bioconversion of the longer and more hydrophobic substrate dodecanoic acid methyl ester. The efficient coupling of redox cofactor oxidation and product formation, as determined in vitro, combined with the high in vivo activities make E. coli W3110 (pBT10) a promising biocatalyst for the preparative synthesis of terminally functionalized fatty acid methyl esters.     

Mechanical performance of hybrid rice straw/sea weed polypropylene composites

Rice straw (Rs)/polypropylene (PP) composites were prepared in the different ratio of 5 : 95, 10 : 90, 15 : 85, 20 : 80, 25 : 75, and 30 : 70 (Rs wt % : PP wt %) by an injection molding process. This work investigated the tensile strength (TS), bending strength (BS), and impact strength (IS) of the composites. From the results, it is observed that Rs20 : PP80 mixture composite showed better performance with mechanical properties (TS = 26.2 MPa, BS = 58 N/mm², and IS = 1.7 KJ/mm²) among the composites prepared. Two hybrid composites were also fabricated using 20% Rs, 10% seaweed with 70% PP and 20% Rs, 30% seaweed with 70% PP. In between the two hybrid composites, superior mechanical behavior showed by the hybrid composite in ratio of Rs20 : Sw10 : PP70 with enhanced results such as TS = 28 MPa, BS = 68 N/mm², and IS = 2.5 KJ/mm². Water uptake, simulating weathering, and soil degradation test of different composites were also performed. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Synthesis,Characterization, and Reactivity of Lanthanide Complexes with Bulky Silylallyl Ligands

The synthesis of new lanthanide allyl complexes of enhanced stability and solubility in saturated hydrocarbons based on silyl-substituted allyl ligands is reported. Thus the potassium salt K(CH₂CHCHSiMe₃) ( 1 ) reacts with YCl₃ in tetrahydrofuran to give the tris-allyl complex Y(CH₂CHCHSiMe₃)₃ ( 2 ), while K(CH₂CHCHSiMe₂^tBu) ( 3 ) affords Y(CH₂CHCHSiMe₂^tBu)₃(THF)_1.5 ( 4 ). Slow re-crystallization of 4 from light petroleum in the presence of tert-butylcyanide led to multiple insertion to give the sec-amido complex Y{NHC(^tBu)(CH)₃SiMe₂^tBu}₂{η₂-NHC(^tBu)CH=CHCH₂SiMe₂^tBu)CH(CHCHSiMe₂^tBu)C^tBuNH}(THF)·(CH₃CH(Me)(CH₂)₂CH₃) ( 5 ), which was crystallographically characterized. The reaction of ScCl₃(THF)₃ with two equivalents of Li{1,3-C₃H₃(SiMe₃)₂} in tetrahydrofuran gives the bis-allyl complex {1,3-C₃H₃(SiMe₃)₂}₂Sc(μ-Cl)₂Li(THF)₂ ( 6 ), while the analogous reaction of K{1,3-C₃H₃(SiMe₃)₂} ( 7 ) with either LaCl₃ or YCl₃ in tetrahydrofuran affords the bis-allyl complexes MCl{1,3-C₃H₃(SiMe₃)₂}₂(THF)_x (8, M = La, x = 1; 9, M = Y, x = 0). An attempt to prepare the similar neodymium complex gave the mono-allyl complex NdI₂{1,3-C₃H₃(SiMe₃)₂}(THF)_1.25 ( 10 ). The reactions of 8 and 9 with triisobutyl aluminum in benzene-d₆ show allyl exchange between lanthanide and aluminum. Complexes 8 , 9 , and 10 have been tested with a variety of activator systems as catalysts for the polymerization of 1,3-butadiene.     

Near Field Blast Load

The momentum equation used by the author to describe the transferred momentum in the near field of detonating high explosive charges can be very well applied to the test results of steel disks at very near distances to detonating high explosive cylinders of the publication of Weaver and Walters⁽¹⁾.     

Aging Behavior of Propellants investigated by heat generation,stabilizer consumption,and molar mass degradation

Four double-base rocket propellants and a single-base gun propellant were tested to find out stabilizer consumption molar mass degradation, and heat generation between 50 °C and 90 °C and between 40 °C and 110 °C, respectively. Stabilizer depletion was measured by high performance liquid chromatography (HPLC), molar mass degradation by gel permeation chromatography (GPC), and heat generation by microcalorimetry. The conditioning times at different temperatures were determined with one of the rocket propellants, and the influence of the long-term storage on heat generation at 60 °C for 2191 dys was investigated. A correlated experiment between stabilizer consumption and heat generation showed that heat production does not increase substantially until the stabilizer has been consumed almost completely. The experimental data of molar mass degradation are described by a kinetic model based on statistical chain scission, and the stabilizer decrease by a first order reaction. For the gun propellant the Arrhenius plots of the reaction rate constants show two temperatures of teh stabilizer consumption, molar mass degradation and heat generation were determined.