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101.
Dr. Andreas Lingel Dr. Anna Vulpetti Dr. Tony Reinsperger Dr. Andrew Proudfoot Regis Denay Alexandra Frommlet Christelle Henry Dr. Ulrich Hommel Dr. Alvar D. Gossert Prof. Dr. Burkhard Luy Dr. Andreas O. Frank 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(35):14919-14927
Fragment-based lead discovery has become a fundamental approach to identify ligands that efficiently interact with disease-relevant targets. Among the numerous screening techniques, fluorine-detected NMR has gained popularity owing to its high sensitivity, robustness, and ease of use. To effectively explore chemical space, a universal NMR experiment, a rationally designed fragment library, and a sample composition optimized for a maximal number of compounds and minimal measurement time are required. Here, we introduce a comprehensive method that enabled the efficient assembly of a high-quality and diverse library containing nearly 4000 fragments and screening for target-specific binders within days. At the core of the approach is a novel broadband relaxation-edited NMR experiment that covers the entire chemical shift range of drug-like 19F motifs in a single measurement. Our approach facilitates the identification of diverse binders and the fast ligandability assessment of new targets. 相似文献
102.
Christelle Nguyen Hang Korng Ea Dominique Thiaudiere Solenn Reguer Didier Hannouche Michel Daudon Frédéric Lioté Dominique Bazin 《Journal of synchrotron radiation》2011,18(3):475-480
Calcium (Ca2+)‐containing crystals (CCs), including basic Ca2+ phosphate (BCP) and Ca2+ pyrophosphate dihydrate (CPPD) crystals, are associated with severe forms of osteoarthritis (OA). Growing evidence supports a role for abnormal articular cartilage mineralization in the pathogenesis of OA. However, the role of Ca2+ compounds in this mineralization process remains poorly understood. Six patients, who underwent total knee joint replacement for primary OA, have been considered in this study. Cartilage from femoral condyles and tibial plateaus in the medial and lateral compartments was collected as 1 mm‐thick slices cut tangentially to the articular surface. First, CCs presence and biochemical composition were assessed using Fourier transform infrared spectroscopy (FT‐IR). Next, Ca2+ compound biochemical form was further assessed using X‐ray absorption spectroscopy (XAS) performed at the Ca2+K‐absorption edge. Overall, 12 cartilage samples were assessed. Using FT‐IR, BCP and CPPD crystals were detected in four and three out of 12 samples, respectively. Ca2+ compound biochemical forms differed between areas with versus without CCs, when compared using XAS. The complete set of data shows that XANES spectroscopy can be used to accurately characterize sparse CCs in human OA cartilage. It is found that Ca2+ compounds differ between calcified and non‐calcified cartilage areas. In calcified areas they appear to be mainly involved in calcifications, namely Ca2+ crystals. 相似文献
103.
Freund C Porzio W Giovanella U Vignali F Pasini M Destri S Mech A Di Pietro S Di Bari L Mineo P 《Inorganic chemistry》2011,50(12):5417-5429
The synthesis and the molecular and photophysical characterization, together with solid state and solution structure analysis, of a series of europium complexes based on β-diketonate ligands are reported. The Eu(III) complex emission, specifically its photoluminescence quantum yield (PL-QY), can be tuned by changing ligands which finely modifies the environment of the metal ion. Steady-state and time-resolved emission spectroscopy and overall PL-QY measurements are reported and related to geometrical features observed in crystal structures of some selected compounds. Moreover, paramagnetic NMR, based on the analogous complexes with other lanthanides, are use to demonstrate that there is a significant structural reorganization upon dissolution, which justifies the observed differences in the emission properties between solid and solution states. The energy of the triplet levels of the ligands and the occurrence of nonradiative deactivation processes clearly account for the luminescence efficiencies of the complexes in the series. 相似文献
104.
A capillary electrophoresis competitive immunoassay was developed for the simultaneous quantitation of insulin, glucagon, and islet amyloid polypeptide (IAPP) secretion from islets of Langerhans. Separation buffers and conditions were optimized for the resolution of fluorescein isothiocyanate (FITC)-labeled glucagon and IAPP immunoassay reagents, which were excited with the 488 nm line of an Ar(+) laser and detected at 520 nm with a photomultiplier tube (PMT). Cy5-labeled insulin immunoassay reagents were excited by a 635 nm laser diode module and detected at 700 nm with a separate PMT. Optimum resolution was achieved with a 20mM carbonate separation buffer at pH 9.0 using a 20 cm effective separation length with an electric field of 500 V/cm. Limits of detection for insulin, glucagon, and IAPP were 2, 3, and 3 nM, respectively. This method was used to monitor the simultaneous secretion of these peptides from as few as 14 islets after incubation in 4, 11, and 20 mM glucose for 6h. For insulin and IAPP, a statistically significant increase in secretion levels was observed, while glucagon levels were significantly reduced in the 4 and 11 mM glucose conditions. To further demonstrate the utility of the assay, the Ca(2+)-dependent secretion of these peptides was demonstrated which agreed with published reports. The ability to examine the secretion of multiple peptides may allow for the determination of regulation of secretory processes within islets of Langerhans. 相似文献
105.
106.
Chevallier F Halauko YS Pecceu C Nassar IF Dam TU Roisnel T Matulis VE Ivashkevich OA Mongin F 《Organic & biomolecular chemistry》2011,9(12):4671-4684
A series of N-aryl and N-heteroaryl pyrazoles have been deproto-metallated using a 2,2,6,6-tetramethylpiperidino-based mixed lithium-zinc combination. Mono-, di-, and tri-iodides have been obtained after subsequent trapping with iodine, depending on the substrate and on the quantity of base used. The results have been discussed in the light of the CH acidities of the substrates, determined both in the gas phase and in THF solution using the DFT B3LYP method. 相似文献
107.
Janulyte A Zerega Y Carette M Reynard C Andre J 《Journal of mass spectrometry : JMS》2011,46(2):136-143
With a three-dimensional (3D) quadrupole ion trap running in a Fourier transform operating mode, the detected signal is an image of the collective motion of the confined ions. Consequently, it is assumed that the image signal is the sum of the axial trajectories of the simultaneously confined ions. The resulting frequency spectrum after Fourier transformation comprises frequency peaks at the axial secular frequencies of the confined species according to their mass/charge ratio. With a singly confined species, the maximal amplitude of the image signal is proportional to the amplitude of the secular axial frequency peak. The matrix method is employed to express the axial trajectory sampled at the confinement field period. In that case, the expression of the image signal, as well as its maximal amplitude, is calculated as a function of the trap operating conditions and initial axial positions and axial velocities of the ions. The initial position and velocity distributions are connected to the injection mode. With the steady ion flow injection mode (SIFIM) and an initial phase of the confinement field equal to kπ, the maximal amplitude of the image signal is proportional to either the sum of the initial axial positions or the number of confined ions and the mean value of the initial axial positions. By simulation, amplitude fluctuation of the frequency peak is then calculated for a number of ions ranging between some tens to some thousands of ions injected by SIFIM. The peak amplitude fluctuations induced by the fluctuations of the number of ions are seven times greater than those induced by the fluctuations of the distribution of the initial axial positions. 相似文献
108.
Pujol AM Gateau C Lebrun C Delangle P 《Chemistry (Weinheim an der Bergstrasse, Germany)》2011,17(16):4418-4428
A series of tripodal ligands derived from nitrilotriacetic acid and extended by three converging, metal-binding, cysteine chains was synthesised. Their ability to bind soft metal ions thanks to their three thiolate functions was investigated by means of complementary analytical and spectroscopic methods. Three ligands that differ by the nature of the carbonyl group next to the coordinating thiolate functions were studied: L(1) (ester), L(2) (amide) and L(3) (carboxylate). The negatively charged derivative L(3), which bears three carboxylate functions close to the metal binding site, gives polynuclear copper(I) complexes of low stability. In contrast, the ester and amide derivatives L(1) and L(2) are efficient Cu(I) chelators with very high affinities, close to that reported for the metal-sequestering metallothioneins (log K≈19). Interestingly, these two ligands form mononuclear copper complexes with a unique MS(3) coordination in water solution. An intramolecular hydrogen-bond network involving the amide functions in the upper cavity of the tripodal ligands stabilises these mononuclear complexes and was evidenced by the very low chemical-shift temperature coefficient of the secondary amide protons. Moreover, L(1) and L(2) display large selectivities for the targeted metal ion that is, Cu(I), with respect to bioavailable Zn(II). Therefore the two sulfur-based tripods L(1) and L(2) are of potential interest for intracellular copper detoxication in vivo, without altering the homeostasis of the essential metal ion Zn(II). 相似文献
109.
Natalya A. Vodolazkaya Christelle Despas Bénédicte Lebeau Claire Marichal Alain Walcarius 《Journal of Sol-Gel Science and Technology》2012,63(3):587-594
New hybrid organic–inorganic materials exhibiting ordered mesoporous structures have been synthesized by co-condensation of tetraethoxysilane and various alkyltrimethoxysilanes with increasing length of the hydrocarbon chain (propyl, octyl, hexadecyl), in water–ethanol solution containing ammonia, in the presence of a cationic surfactant (cetyltrimethylammonium bromide) as templating agent. The obtained hybrid materials were characterized by using several physico-chemical techniques, such as X-ray diffraction, N2 adsorption, 29Si MAS NMR, SEM and elemental analysis. It was shown that the direct synthesis procedure allows obtaining ordered hybrid mesoporous silica with various contents of organic functions, from 5 to 20 %. Moreover, increasing the chain length of the organic group, from propyl to octyl and hexadecyl leads to a change of the pore structure from hexagonal p6mm MCM-41 type architecture to cubic Ia3d MCM-48 type mesostructure. 相似文献
110.