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101.
Pim J. de Vink Auke A. Koops Giulia D'Arrigo Gabriele Cruciani Francesca Spyrakis Luc Brunsveld 《Chemical science》2022,13(9):2744
Nuclear Receptors (NRs) are highly relevant drug targets, for which small molecule modulation goes beyond a simple ligand/receptor interaction. NR–ligands modulate Protein–Protein Interactions (PPIs) with coregulator proteins. Here we bring forward a cooperativity mechanism for small molecule modulation of NR PPIs, using the Peroxisome Proliferator Activated Receptor γ (PPARγ), which describes NR–ligands as allosteric molecular glues. The cooperativity framework uses a thermodynamic model based on three-body binding events, to dissect and quantify reciprocal effects of NR–coregulator binding (KID) and NR–ligand binding (KIID), jointly recapitulated in the cooperativity factor (α) for each specific ternary ligand·NR·coregulator complex formation. These fundamental thermodynamic parameters allow for a conceptually new way of thinking about structure–activity-relationships for NR–ligands and can steer NR modulator discovery and optimization via a completely novel approach.A cooperativity framework describes the formation of nuclear receptor ternary complexes and deconvolutes ligand and cofactor binding into intrinsic affinities and a cooperativity factor, providing a conceptually new understanding of NR modulation. 相似文献
102.
Inductively coupled plasma mass spectrometry of environmental and biological samples is often hampered by spectral and non-spectral interferences. Spectral interferences, caused by the limited resolution of the quadrupole mass spectrometer, can be eliminated in a variety of ways. For their identification inspection of a signal versus carrier gas flowrate is useful. Anion exchange allows the removal of most S and Cl containing compounds, which are at the origin of the majority of spectral interferences. Matrix modification, for example the addition of ethanol and subsequent optimization of the gas flow rates in a number of cases enables the reduction of the interferences to insignificant values. Often a mathematical correction based on isotopic signal ratios can be applied. Non-spectral interferences can be divided in reversible, that is occurring while the sample is being measured, and irreversible matrix effects, that is clogging of the nebulizer and sampling orifices or deposition on the torch or in the ion lens stack. The errors associated with non-spectral interferences can be eliminated by appropriate calibration procedures, adapted sample preparation or limitation of the amount of sample delivered to nebulizer, plasma and sampling devices, for example by the application of flow injection. Applications of all the elimination procedures are described for the analysis of sea-water, estuarine water, soil and sewage extracts, percolate water, urine, serum and wine. 相似文献
103.
Gu R Van Hecke K Van Meervelt L Toppet S Dehaen W 《Organic & biomolecular chemistry》2006,4(20):3785-3789
The oxidative coupling reactions of 6-pentyl-5,11-dihydroindolo[3,2-b]carbazole have been studied and as a result, a number of novel dimers of the indolo[3,2-b]carbazole derivative have been prepared, forming C-C coupled compound when treated with FeCl(3) x 6H(2)O or C-N coupled compounds and when oxidized with air or Pd(OAc)(2), respectively. 相似文献
104.
A new tricarborane building block based on pentaerythritol was prepared for applications in boron neutron capture therapy (BNCT). Its X-ray single-crystal structure revealed a high degree of steric congestion. To enable the attachment of the building block to other moieties, a succinimidyl linker has been introduced at the focal point, and a generation-2 hexacarborane-containing dendron carrying 60 boron atoms has been prepared using a 2,2-bis(hydroxymethyl)propionic acid core. 相似文献
105.
106.
Cuesta L Huertos MA Morales D Pérez J Riera L Riera V Miguel D Menéndez-Velazquez A García-Granda S 《Inorganic chemistry》2007,46(7):2836-2845
Complexes [Re(ONCMe2)(CO)3(bipy)] (1) and [Re(ONCMe2)(CO)3(phen)] (2), synthesized by reaction of the respective triflato precursors [Re(OTf)(CO)3(N-N)] (N-N = bipy, phen) with KONCMe2, feature O-bonded monodentate oximato ligands. Compound [Re(CO)3(phen)(HONCMe2)]BAr'4 (3), with a monodentate N-bonded oxime ligand, was prepared by reaction of [Re(OTf)(CO)3(phen)], HONCMe2, and NaBAr'4. Deprotonation of 3 afforded 2. The oximato complexes reacted with p-tolylisocyanate, p-tolylisothiocyanate, maleic anhydride, and tetracyanoethylene, affording the products of the insertion of the electrophile into the Re-O bond, compounds 4-7. One representative of each type of compound was fully characterized, including single-crystal X-ray diffraction. The reactions of 1 and 2 with dimethylacetylenedicarboxylate were found to involve first an insertion as the ones mentioned above but followed by incorporation of water, loss of acetone, and formation of the charge-separated neutral amido complexes 9 and 10. The structure of 9 and 10 was determined by X-ray diffraction, and key features of their electronic distribution were studied using a topological analysis of the electron density as obtained from the Fourier map. 相似文献
107.
de Kerchove AJ Elimelech M 《Langmuir : the ACS journal of surfaces and colloids》2005,21(14):6462-6472
Bacterial cells and other biological particles carry charged macromolecules on their surface that form a "soft" ion-permeable layer. In this paper, we test the applicability of an electrokinetic theory for soft particles to characterize the electrophoretic mobility (EPM) and adhesion kinetics of bacterial cells. The theory allows the calculation of two parameters--the electrophoretic softness and the fixed charged density--that define the characteristics of the polyelectrolyte layer at the soft particle surface. The theory also allows the calculation of an outer-surface potential that may better predict the electrostatic interaction of soft particles with solid surfaces. To verify its relevance for bacterial cells, the theory was applied to EPM measurements of two well-characterized Escherichia coli K12 mutants having lipopolysaccharide (LPS) layers of different lengths and molecular compositions. Results showed that the obtained softness and fixed charge density were not directly related to the known characteristics of the LPS of the selected strains. Interaction energy profiles calculated from Derjaguin-Landau-Verwey-Overbeek (DLVO) theory were used to interpret bacterial deposition (adhesion) rates on a pure quartz surface. The outer surface potential failed to predict the low attachment efficiencies of the two bacterial strains. The lack of success in the application of the theory for soft particles to bacterial cells is attributed to chemical and physical heterogeneities of the polyelectrolyte layer at the cell surface. 相似文献
108.
Ataloglou T Bourikas K Vakros J Kordulis C Lycourghiotis A 《The journal of physical chemistry. B》2005,109(10):4599-4607
In the present work we studied, for the first time, the kinetics of adsorption of the Co(H(2)O)(6)(2+) species on the "electrolytic solution/gamma-Al(2)O(3)" interface at pH = 7 and 25 degrees C for a very broad range of Co(II) surface concentrations ranged from 0.03 to 6 theoretical Co(H(2)O)(6)(2+) surface layers. Moreover, we studied the surface dissolution of gamma-alumina in the presence of the Co(H(2)O)(6)(2+) ions in the impregnating solution, the contribution of the Co(II) desorption on the whole deposition process and the deposition isotherm. It was found that under the conditions where the deposition has taken place, the dissolution of the gamma-alumina surface is negligible even in the presence of the Co(H(2)O)(6)(2+) species in the impregnating solution. It was, moreover, inferred that the Co(II) desorption does not participate significantly to the whole deposition process. It was found that the deposition kinetics may be described by the following kinetic expression r(Co,bulk) = k'C(Co,bulk)(2), which relates the rate of disappearance of the Co(H(2)O)(6)(2+) ions from the impregnating solution, r(Co,bulk,) with their concentration C(Co,bulk). This kinetic expression may be derived assuming the following deposition scheme: nS + 2[Co(H(2)O)(6)(2+)] --> S(n) - [Co(H(2)O)(x,x)(<)(6)(2+)](2), where S represents the surface reception sites. The above expressions indicated that two Co(H(2)O)(6)(2+) ions are involved, from the side of the interface, in the reaction with the reception sites. It seems probable that the deposition step involves the simultaneous adsorption and dimerization of the two interfacial Co(H(2)O)(6)(2+) ions through (hydr)oxobridges. On the other hand, the sigmoidal form of the deposition isotherm and the dependence of the apparent rate constant, k', on the interfacial Co(II) concentration suggested that the already deposited Co(II) species may be involved in the reception sites, S, promoting the adsorption and resulting to the formation of multinuclear complexes and Co(II) surface precipitates. Finally, reasonable interface potential values for oxides were determined for the first time using kinetic results. 相似文献
109.
4-Hydroxy-5,5-dimethylimidazolines tethered at N-1 to an aryl sulfide undergo an unprecedented acid-catalysed domino reaction, involving double methyl transposition, heterocyclisation, isomerisation of thiazetidinium ion and, finally, pi-cyclisation. In this way a one-pot synthesis of original tricyclic N,S-acetals was developed. The same triheterocyclic products can be prepared also starting from the corresponding 5-hydroxy isomers (in this case the cascade of reactions does not involve methyl transposition). 相似文献
110.
Dr. Lech‐Gustav Milroy Dr. Maria Bartel Dr. Morkos A. Henen Dr. Seppe Leysen Joris M. C. Adriaans Prof. Dr. Luc Brunsveld Dr. Isabelle Landrieu Dr. Christian Ottmann 《Angewandte Chemie (International ed. in English)》2015,54(52):15720-15724
The discovery of novel protein–protein interaction (PPI) modulators represents one of the great molecular challenges of the modern era. PPIs can be modulated by either inhibitor or stabilizer compounds, which target different though proximal regions of the protein interface. In principle, protein–stabilizer complexes can guide the design of PPI inhibitors (and vice versa). In the present work, we combine X‐ray crystallographic data from both stabilizer and inhibitor co‐crystal complexes of the adapter protein 14‐3‐3 to characterize, down to the atomic scale, inhibitors of the 14‐3‐3/Tau PPI, a potential drug target to treat Alzheimer’s disease. The most potent compound notably inhibited the binding of phosphorylated full‐length Tau to 14‐3‐3 according to NMR spectroscopy studies. Our work sets a precedent for the rational design of PPI inhibitors guided by PPI stabilizer–protein complexes while potentially enabling access to new synthetically tractable stabilizers of 14‐3‐3 and other PPIs. 相似文献