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Abstract: The structure-based design of small-molecule inhibitors targeting protein–protein interactions (PPIs) remains a huge challenge as the drug must bind typically wide and shallow protein sites. A PPI target of high interest for hematological cancer therapy is myeloid cell leukemia 1 (Mcl-1), a prosurvival guardian protein from the Bcl-2 family. Despite being previously considered undruggable, seven small-molecule Mcl-1 inhibitors have recently entered clinical trials. Here, we report the crystal structure of the clinical-stage inhibitor AMG-176 bound to Mcl-1 and analyze its interaction along with clinical inhibitors AZD5991 and S64315. Our X-ray data reveal high plasticity of Mcl-1 and a remarkable ligand-induced pocket deepening. Nuclear Magnetic Resonance (NMR)-based free ligand conformer analysis demonstrates that such unprecedented induced fit is uniquely achieved by designing highly rigid inhibitors, preorganized in their bioactive conformation. By elucidating key chemistry design principles, this work provides a roadmap for targeting the largely untapped PPI class more successfully.

Open Access

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Abstract: Herein, the alcoholysis of furfuryl alcohol in a series of SBA-15-pr-SO3H catalysts with different pore sizes is reported. Elemental analysis and NMR relaxation/diffusion methods show that changes in pore size have a significant effect on catalyst activity and durability. In particular, the decrease in catalyst activity after catalyst reuse is mainly due to carbonaceous deposition, whereas leaching of sulfonic acid groups is not significant. This effect is more pronounced in the largest-pore-size catalyst C3, which rapidly deactivates after one reaction cycle, whereas catalysts with a relatively medium and small average pore size (named, respectively, C2 and C1) deactivate after two reaction cycles and to a lesser extent. CHNS elemental analysis showed that C1 and C3 experience a similar amount of carbonaceous deposition, suggesting that the increased reusability of the small-pore-size catalyst can be attributed to the presence of SO3H groups mostly present on the external surface, as corroborated by results on pore clogging obtained by NMR relaxation measurements. The increased reusability of the C2 catalyst is attributed to a lower amount of humin being formed and, at the same time, reduced pore clogging, which helps to maintain accessible the internal pore space.

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Abstract: N-9-Fluorenylmethyloxycarbonyl (Fmoc)- and C-tertiary butyl (t-Bu)-protected glutamate (L-2), bearing a phenanthroline moiety at the side residue, forms 1D supramolecular assemblies via H-bonding as well as undergoing π-stacking interactions to afford crystals or gels that depend on the shape-complementarity of coexisting alcohols, as demonstrated by structural analyses on these assemblies by means of single-crystal X-ray diffractometry and supplemented with small- and wide-angle X-ray scattering data. Moreover, the rheological measurements on the gels help to define a model for when gels and crystals are expected and found. These observations and conclusions highlight an important, but not very appreciated, aspect of solute–solvent interactions within supramolecular assemblies that can allow the constituent-aggregating molecules in some systems to exhibit high selectivity toward the structures of their solvents. The consequences of this selectivity, as demonstrated here by single-crystal and powder X-ray diffraction data, can lead to self-assembled structures which alter completely the bulk phase properties and morphology of the materials. In that regard, rheological measurements have helped to develop a model to explain when gels and phase-separated mixtures of crystals and solvents are expected.

Open Access

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Abstract: Tetragonal CuMnAs is a room temperature antiferromagnet with an electrically reorientable Néel vector and a Dirac semimetal candidate. Direct measurements of the electronic structure of single-crystalline thin films of tetragonal CuMnAs using angle-resolved photoemission spectroscopy (ARPES) are reported, including Fermi surfaces (FS) and energy-wavevector dispersions. After correcting for a chemical potential shift of ≈− 390 meV (hole doping), there is excellent agreement of FS, orbital character of bands, and Fermi velocities between the experiment and density functional theory calculations. In addition, 2×1 surface reconstructions are found in the low energy electron diffraction (LEED) and ARPES. This work underscores the need to control the chemical potential in tetragonal CuMnAs to enable the exploration and exploitation of the Dirac fermions with tunable masses, which are predicted to be above the chemical potential in the present samples.

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Abstract: In this thesis, the static and dynamic properties of magnetic multilayer samples were studied using a variety of experimental techniques, based both at Exeter and the Diamond Light Source (DLS) and Advanced Light Source (ALS) synchrotron facilities. The exchange interaction, which acts to align spins, is a fundamental part in these magnetic multilayer samples. First, the glancing angle deposition (GLAD) technique was investigated as a tool for creating magnetic multilayers with exciting new exchange interactions. For this, Co thin films were grown by DC magnetron sputtering to tailor the magnetic anisotropy of the samples. These Co samples were structurally characterized using x-ray diffraction (XRD) and transmission electron microscopy (TEM). Vibrating sample magnetometry (VSM) was then performed to investigate the magnetic properties of the thin films as a result of the GLAD technique. From this, the necessary conditions for effective anisotropy control using the GLAD technique were identified. Synchrotron x-ray measurements, such as x-ray magnetic circular / linear dichroism (XMCD/XMLD) for static measurements, are vital for investigating magnetic multilayer samples with elemental resolution. To add depth-sensitivity to the synchrotron measurements, the idea of an ultra-thin Mn “spy layer” was investigated by inserting different thicknesses (tMn) of Mn into the NiFe layer in a FePt / NiFe bilayer. The effect on the static magnetic properties was studied using VSM and XMCD hysteresis loops before structural information was obtained using scanning transmission electron microscopy (STEM). The magnetization dynamics were probed using vector network analyzer ferromagnetic resonance (VNA-FMR) and element resolved x-ray ferromagnetic resonance (XFMR) measurements. From this, the ideal “spy layer” thickness of Mn was found to lie in the region 0Å < tMn < 5Å . Spin currents are a dynamic process found in magnetic multilayers and are driven by the exchange interaction. The measurement of a transverse charge current generated via the inverse spin Hall effect (ISHE) has become the principal technique for observing spin currents. During ISHE measurements, parasitic microwave effects were observed and a method to separate out the inverse spin Hall effect was identified. This method was then tested for a reference YIG / Pt bilayer. A more complex NiFe / NiO / Pd / FeCo sample was then studied using this procedure and the ISHE voltage was identified, despite the presence of additional parasitic effects. In addition to the DC spin current component, there is an AC spin current contribution. The AC spin current component was also investigated for the NiFe / NiO / Pd / FeCo sample series using XMCD, XMLD and XFMR measurements. The XMCD and XMLD data revealed the Ni and (Fe)Co spins possess perpendicular in-plane coupling relative to the magnetic moments within the NiO layer. To understand the magnetization dynamics in these samples, an evanescent spin wave model was invoked. This provides crucial insights for interpreting spin current propagation through NiO. Through the combination of work described above, new avenues for the fabrication of magnetic multilayers and the measurement of the magnetization dynamics in such systems are presented to yield a more complete understanding of the crucial role of the exchange interaction in the magnetization dynamics of magnetic multilayers.