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Dr. Matthias Bischoff Dr. Peter Mayer Dr. Christian Meyners Prof. Dr. Felix Hausch 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(21):4677-4681
6-, 7-, and 8-membered rings are assembled from a linear precursor by successive cyclisation reactions to construct a tricyclic diazatricyclo[6.5.1.04, 9]-tetradecanedione scaffold. Advanced building blocks based on d -aspartic acid and l -pyroglutamic acid were combined by a sp3−sp2 Negishi coupling. A carbamate-guided syn-diastereoselective epoxidation followed by an intramolecular epoxide opening allowed the construction of the piperidine ring. An efficient one-pot hydroxyl-group protection twofold deprotection reaction prepared the ground for the cyclisation to the bicycle. A final deprotection of the orthogonal protecting groups and lactamisation led to the novel, sp3-rich tricycle. The final compound is a substrate mimic of peptidyl-prolyl cis-trans isomerases featuring a locked trans-amide bond. Cheminformatic analysis of 179 virtual derivatives indicates favourable physicochemical properties and drug-like characteristics. As proof of concept we, show a low micromolar activity in a fluorescence polarisation assay towards the FK506-binding protein 12. 相似文献
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Isoperimetric inequalities are applied to a moving-boundaryproblem for doubly-connected domains. This problem occurs forexample in electrochemistry, in which case the domains in questionare the electrolyte of an electrolytic cell. The two electrodessurrounding the electrolyte are assumed to grow or dissolve,at different rates in general, by electrochemical reaction.We obtain optimal estimates showing, for example, that the leastchange in volume of each electrode always occurs in sphericalsymmetry. 相似文献
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G. Hausch 《Journal of magnetism and magnetic materials》1979,10(2-3):163-169
A review of the elastic behaviour of Invar alloys is given. This includes (a) ferromagnetic alloys (Fe-Ni, Fe-Pt, stainless Invar); (b) antiferromagnetic alloys (Fe-Mn, Mn- and Cr-based alloys); (c) very weak ferromagnets (ZrZn2, Ni3Al, Ni-Pt); (d) amorphous alloys (Fe-B). It is shown that elastic anomalies (ΔE effects) can but need not occur simultaneously with a large thermal expansion anomaly. Various magnetoelastic contributions exist (ΔEλ, ΔEω, ΔEm) which are discussed in terms of existing theoretical models. The effect associated with a volume distortion, i.e. the bulk modulus anomaly, is shown to fit into the framework of the itinerant electron model. 相似文献
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Jürgen M. Kolos Sebastian Pomplun Sascha Jung Benedikt Rieß Patrick L. Purder Andreas M. Voll Stephanie Merz Monika Gnatzy Thomas M. Geiger Ingrid Quist-Lkken Jerome Jatzlau Petra Knaus Toril Holien Andreas Bracher Christian Meyners Paul Czodrowski Vera Krewald Felix Hausch 《Chemical science》2021,12(44):14758
Methyl groups can have profound effects in drug discovery but the underlying mechanisms are diverse and incompletely understood. Here we report the stereospecific effect of a single, solvent-exposed methyl group in bicyclic [4.3.1] aza-amides, robustly leading to a 2 to 10-fold increase in binding affinity for FK506-binding proteins (FKBPs). This resulted in the most potent and efficient FKBP ligands known to date. By a combination of co-crystal structures, isothermal titration calorimetry (ITC), density-functional theory (DFT), and 3D reference interaction site model (3D-RISM) calculations we elucidated the origin of the observed affinity boost, which was purely entropically driven and relied on the displacement of a water molecule at the protein–ligand–bulk solvent interface. The best compounds potently occupied FKBPs in cells and enhanced bone morphogenic protein (BMP) signaling. Our results show how subtle manipulation of the solvent network can be used to design atom-efficient ligands for difficult, solvent-exposed binding pockets.Enhancement by displacement. A single methyl group displaces a water molecule from the binding site of FKBPs, resulting in the most potent binders known, outperforming the natural products FK506 and rapamycin in biochemical and cellular assays. 相似文献
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