Kirknunez2329

Various malignant human diseases show disturbed signaling pathways due to increased activity of proteins within the epigenetic machinery. Recently, various novel inhibitors for epigenetic regulation have been introduced which promise a great therapeutic benefit. Inhibitors for the bromo- and extra-terminal domain (BET) family were of particular interest after inhibitors had shown a strong antiproliferative effect. More recently, the focus has increasingly shifted to bromodomains (BDs) outside the BET family. Based on previously developed inhibitors, we have optimized a small series of 4-acyl pyrroles, which we further analyzed by ITC, X-ray crystallography, selectivity studies, the NCI60 cell-panel, and GI50 determinations for several cancer cell lines. The inhibitors address both, BET and BRD7/9 BDs, with very high affinity and show a strong antiproliferative effect on various cancer cell lines that could not be observed for BD family selective inhibitors. Furthermore, a synergistic effect on breast cancer (MCF-7) and melanoma (SK-MEL-5) was proven.Environmentally sensitive (ES) dyes have been used for many decades to study the lipid order of cell membranes, as different lipid phases play a crucial role in a wide variety of cell processes. Yet, the understanding of how ES dyes behave, interact, and affect membranes at the atomistic scale is lacking, partially due to the lack of molecular dynamics (MD) models of these dyes. Here, we present ground- and excited-state MD models of commonly used ES dyes, Laurdan and di-4-ANEPPDHQ, and use MD simulations to study the behavior of these dyes in a disordered and an ordered membrane. We also investigate the effect that these two dyes have on the hydration and lipid order of the membranes, where we see a significant effect on the hydration of lipids proximal to the dyes. These findings are combined with experimental fluorescence experiments of ordered and disordered vesicles and live HeLa cells stained by the aforementioned dyes, where the generalized polarization (GP) values were measured at different concentrations of the dyes. We observe a small but significant decrease of GP at higher Laurdan concentrations in vesicles, while the same effect is not observed in cell membranes. The opposite effect is observed with di-4-ANEPPDHQ where no significant change in GP is seen for vesicles but a very substantial and significant decrease is seen in cell membranes. Together, our results show the profound effect that ES dyes have on membranes, and the presented MD models will be important for further understanding of these effects.The development of short-wave infrared (SWIR) photonics based on GeSn alloys is of high technological interest for many application fields, such as the Internet of things or pollution monitoring. The manufacture of crystalline GeSn is a major challenge, mainly because of the low miscibility of Ge and Sn. The use of embedded GeSn nanocrystals (NCs) by magnetron sputtering is a cost-effective and efficient method to relax the growth conditions. We report on the use of GeSn/SiO2 multilayer deposition as a way to control the NC size and their insulation. The in situ prenucleation of NCs during deposition was followed by ex situ rapid thermal annealing. Epigenetic inhibitor The nanocrystallization of 20×(11nm_Ge0.865Sn0.135/1.5nm_SiO2) multilayers leads to formation of GeSn NCs with ∼16% Sn concentration and ∼9 nm size. Formation of GeSn domes that are vertically correlated contributes to the nanocrystallization process. The absorption limit of ∼0.4 eV in SWIR found by ellipsometry is in agreement with the spectral photosensitivity. The ITO/20×(GeSn NC/SiO2)/p-Si/Al diodes show a maximum value of the SWIR photosensitivity at a reverse voltage of 0.5 V, with extended sensitivity to wavelengths longer than 2200 nm. The multilayer diodes have higher photocurrent efficiency compared to diodes based on a thick monolayer of GeSn NCs.The energetics for proton reduction in FeFe-hydrogenase has been reinvestigated by theoretical modeling, in light of recent experiments. Two different mechanisms have been considered. In the first one, the bridging hydride position was blocked by the enzyme, which is the mechanism that has been supported by a recent spectroscopic study by Cramer et al. A major difficulty in the present study to agree with experimental energetics was to find the right position for the added proton in the first reduction step. It was eventually found that the best position was as a terminal hydride on the distal iron, which has not been suggested in any of the recent, experimentally based mechanisms. The lowest transition state was surprisingly found to be a bond formation between a proton on a cysteine and the terminal hydride. This type of TS is similar to the one for heterolytic H2 cleavage in NiFe hydrogenase. The second mechanism investigated here is not supported by the present calculations or the recent experiments by Cramer et al., but was still studied as an interesting comparison. In that mechanism, the formation of the bridging hydride was allowed. The H-H formation barrier is only 3.6 kcal/mol higher than for the first mechanism, but there are severe problems concerning the motion of the protons.The design of efficient computational tools for structure-guided ligand design is essential for the drug discovery process. We hereby present FragRep, a new web server for structure-based ligand design by fragment replacement. The input is a protein and a ligand structure, either from protein data bank or from molecular docking. Users can choose specific substructures they want to modify. The server tries to find suitable fragments that not only meet the geometric requirements of the remaining part of the ligand but also fit well with local protein environments. FragRep is a powerful computational tool for the rapid generation of ligand design ideas; either in scaffold hopping or bioisosteric replacing. The FragRep Server is freely available to researchers and can be accessed at http//xundrug.cn/fragrep.Cobalt complexes with 2-(diisopropylphosphinomethyl)pyridine (PN) ligands have been synthesized with the aim of demonstrating electrocatalytic proton reduction to dihydrogen with a well-defined hydride complex of an Earth-abundant metal. Reactions of simple cobalt precursors with 2-(diisopropylphosphino-methyl)pyridine (PN) yield [CoII(PN)2(MeCN)][BF4]21, [CoIII(PN)2(H)(MeCN)][PF6]22, and [CoIII(PN)2(H)(Cl)][PF6] 3. Complexes 1 and 3 have been characterized crystallographically. Unusually for a bidentate PN ligand, all three exhibit geometries with mutually trans phosphorus and nitrogen ligands. Complex 1 exhibits a distorted square-pyramidal geometry with an axial MeCN ligand in a low-spin electronic state. In complexes 2 and 3, the PN ligands lie in a plane leaving the hydride trans to MeCN or chloride, respectively. The redox behavior of the three complexes has been studied by cyclic voltammetry at variable scan rates and by spectroelectrochemistry. A catalytic wave is observed in the presence of trifluoroacetic acid (TFA) at an applied potential close to the Co(II/I) couple of 1.