Structure-Based Design,Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors

The chromatin reader protein Spindlin1 plays an important role in epigenetic regulation, through which it has been linked to several types of malignant tumors. In the current work, we report on the development of novel analogs of the previously published lead inhibitor A366. In an effort to improve the activity and explore the structure–activity relationship (SAR), a series of 21 derivatives was synthesized, tested in vitro, and investigated by means of molecular modeling tools. Docking studies and molecular dynamics (MD) simulations were performed to analyze and rationalize the structural differences responsible for the Spindlin1 activity. The analysis of MD simulations shed light on the important interactions. Our study highlighted the main structural features that are required for Spindlin1 inhibitory activity, which include a positively charged pyrrolidine moiety embedded into the aromatic cage connected via a propyloxy linker to the 2-aminoindole core. Of the latter, the amidine group anchor the compounds into the pocket through salt bridge interactions with Asp184. Different protocols were tested to identify a fast in silico method that could help to discriminate between active and inactive compounds within the A366 series. Rescoring the docking poses with MM-GBSA calculations was successful in this regard. Because A366 is known to be a G9a inhibitor, the most active developed Spindlin1 inhibitors were also tested over G9a and GLP to verify the selectivity profile of the A366 analogs. This resulted in the discovery of diverse selective compounds, among which 1s and 1t showed Spindlin1 activity in the nanomolar range and selectivity over G9a and GLP. Finally, future design hypotheses were suggested based on our findings.     

Fracture and property relationships in the double diboride ceramic composites by spark plasma sintering of TiB2 and NbB2

Bulk titanium diboride–niobium diboride ceramic composites were consolidated by spark plasma sintering (SPS) at 1950°C. SPS resulted in dense specimens with a density exceeding 98% of the theoretical density and a multimodal grain size ranging from 1 to 10 μm. During the SPS consolidation, the pressure was applied and released at 1950 and 1250°C, respectively. This allowed obtaining a two-phase composite consisting of TiB₂ and NbB₂. For these ceramics composites, we evaluated the flexural strength and fracture toughness and room and elevated temperatures. Room-temperature strength of thus produced bulks was between 300 and 330 MPa, at 1200°C or 1600°C an increase in strength up to 400 MPa was observed. Microstructure after flexure at elevated temperatures revealed the appearance of the needle-shape subgrains of NbB₂, an evidence for ongoing plastic deformation. TiB₂–NbB₂ composites had elastic loading stress curves at 1600°C, and at 1800°C fractured in the plastic manner, and strength was ranged from 300 to 450 MPa. These data were compared with a specimen where a (Ti,Nb)B₂ solid solution was formed during SPS to explain the behavior of TiB₂–NbB₂ ceramic composites at elevated temperatures.     

Al-rich region of Al–Pd–Ru at 1000 to 1100 °C

Partial isothermal sections of the Al–Pd–Ru phase diagram at 1000, 1050 and 1100 °C are presented here. The Al–Pd orthorhombic -phases dissolve up to 15.5 at.% Ru, Al₁₃Ru₄ <2.5 at.% Pd and Al₂Ru up to 1 at.% Pd. Between 66 and 75 at.% Al, ternary quasiperiodic icosahedral phase and three cubic phases: C (, a = 0.7757 nm), C₁ (, a = 1.5532 nm) and C₂ (, a = 1.5566 nm) were revealed. An additional complex cubic structure with a ≈ 3.96 nm was found to be formed at compositions close to those of the icosahedral phase.     

I. Synthesis ofsn-glycerol-cyclic-phosphodiester isomers

A procudure for the synthesis of stereochemically puresn-glycerol-cyclic-phosphodiesters has been developed. The process involves the following sequence of reactions: benzyl-sn-glycerol→benzyl-sn-glycerol-cyclic(phenyl)-phosphodiester→sn-glycerol-cyclic-phosphodiester. The following isomers have been synthesized:sn-glycerol-2,3-1,2-, 1,3-cyclic-phosphodiesters and the racemic mixturer. The 2,3- and 1,2-cyclic-phosphodiesters of glycerol are optically active antipodes. They are five-membered ring asymmetrical compounds, with specific rotations of −1.6°±0.1° and +1.6°±0.1°, respectively. These two enantiomers and their racemate are thick liquids and are unstable; therefore they were converted into Ba(glycerol-cyclic-phosphodiester)₂ salts, which can be better stored. The six-membered ringsn-glycerol-1,3-cyclic-phosphodiester is a crystalline, stable compound. The physical and chemical properties of these cyclic-phosphodiesters of glycerol are described and their chemical analyses are reported.     

Ternary compounds in the magnesium–titanium hydrogen storage system

Mg–Ti–H samples were mechano-chemically synthesized by ball milling in argon atmosphere or under elevated hydrogen pressure. The detailed reaction mechanism during hydrogen release and uptake during continuous cycling was investigated by in-situ synchrotron radiation powder X-ray diffraction (SR-PXD) experiments. The thermal behaviour of the samples and hydrogen desorption properties were examined by simultaneous thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and mass spectrometry (MS) measurements. A ternary Ti–Mg–H compound with a fcc lattice form during mechano-chemical sample preparation in hydrogen atmosphere using metal powders, but not using metal hydrides as reactants. The amount of β-MgH₂ increases during the first hydrogen absorption cycle at 300 °C at the expense of the high-pressure polymorph, γ-MgH₂ and the amount of β-MgH₂ remain constant during the following hydrogenations. This study reveals that the ternary compound tends to absorb increasing amounts of magnesium in the dehydrogenated state during cycling. A strong coupling between the amounts of magnesium in the ternary Ti–Mg–H phase and the formation of magnesium and magnesium hydride during hydrogen release and uptake at 300 °C is observed. The composition and the amount of the Ti–Mg–H phase appear to be similar in the hydrogenated state. Fast absorption–desorption kinetics at 300 °C and lower onset temperatures for hydrogen release is observed for all investigated samples (lowest onset temperature of desorption T_on = 217 °C).     

High-temperature strength behavior of tantalum diboride to 2000°C

This study investigated the high-temperature strength of spark plasma sintered tantalum diboride (TaB₂) for the first time. TaB₂ exhibited a unique elastic fracture behavior below 1900°C, unlike other transition metal diborides. The consolidation process involved spark plasma sintering at 2000–2200°C yielding dense TaB₂ samples. The flexural strength was measured at elevated temperatures up to 2000°C, showing a quite high flexural strength of 400 ± 20 MPa at 1900°C. These findings provide valuable insights into the high-temperature behavior of TaB₂, highlighting its potential for advanced applications.     

Aldehyde-Based Inhibitors of the Peptidoglycan O-Acetylesterase Ape

The O-acetylation of the muramic acid residues in peptidoglycan (PG) is a modification that protects the bacteria from lysis due to the action of lysozyme. In Gram-negative bacteria, deacetylation is required to allow lytic transglycosylases to promote PG cleavage during cell growth and division. This deacetylation is catalyzed by O-acetylpeptidoglycan esterase (Ape) which is a serine esterase and employs covalent catalysis via a serine-linked acyl enzyme intermediate. Loss of Ape activity affects the size and shape of bacteria and dramatically reduces virulence. In this work, we report the first rationally designed aldehyde-based inhibitors of Ape from Campylobacter jejuni. The most potent of these acts as a competitive inhibitor with a K_i value of 13 μM. We suspect that the inhibitors are forming adducts with the active site serine that closely mimic the tetrahedral intermediate of the normal catalytic cycle. Support for this notion is found in the observation that reduction of the aldehyde to an alcohol effectively abolishes the inhibition.