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排序方式: 共有495条查询结果,搜索用时 15 毫秒
21.
Quentin Coquerel Claire Legendre Jacinthe Frangieh Stephan De Waard Jrme Montnach Leos Cmarko Joseph Khoury Charifat Said Hassane Dimitri Brard Benjamin Siegler Ziad Fajloun Harold De Pomyers Kamel Mabrouk Norbert Weiss Daniel Henrion Pascal Richomme Csar Mattei Michel De Waard Anne-Marie Le Ray Christian Legros 《Molecules (Basel, Switzerland)》2022,27(13)
Voltage-gated Na+ (NaV) channels are significant therapeutic targets for the treatment of cardiac and neurological disorders, thus promoting the search for novel NaV channel ligands. With the objective of discovering new blockers of NaV channel ligands, we screened an In-House vegetal alkaloid library using fluorescence cell-based assays. We screened 62 isoquinoline alkaloids (IA) for their ability to decrease the FRET signal of voltage sensor probes (VSP), which were induced by the activation of NaV channels with batrachotoxin (BTX) in GH3b6 cells. This led to the selection of five IA: liriodenine, oxostephanine, thalmiculine, protopine, and bebeerine, inhibiting the BTX-induced VSP signal with micromolar IC50. These five alkaloids were then assayed using the Na+ fluorescent probe ANG-2 and the patch-clamp technique. Only oxostephanine and liriodenine were able to inhibit the BTX-induced ANG-2 signal in HEK293-hNaV1.3 cells. Indeed, liriodenine and oxostephanine decreased the effects of BTX on Na+ currents elicited by the hNaV1.3 channel, suggesting that conformation change induced by BTX binding could induce a bias in fluorescent assays. However, among the five IA selected in the VSP assay, only bebeerine exhibited strong inhibitory effects against Na+ currents elicited by the hNav1.2 and hNav1.6 channels, with IC50 values below 10 µM. So far, bebeerine is the first BBIQ to have been reported to block NaV channels, with promising therapeutical applications. 相似文献
22.
Dr. Sébastien Lemouzy Florian Cuminet Dimitri Berne Dr. Sylvain Caillol Dr. Vincent Ladmiral Prof. Rinaldo Poli Dr. Eric Leclerc 《Chemistry (Weinheim an der Bergstrasse, Germany)》2022,28(48):e202201135
Vitrimers are a third class of polymers gathering the mechanical properties and solvent resistance of 3D thermosets and the reprocessability of thermoplastics. This unique behaviour is due to the triggering of certain covalent exchange reactions that allow the network to rearrange upon application of a stimulus. The constitutive feature of vitrimers is the adoption of a glass-like viscosity during the rearrangement of the network, often due to an associative mechanism for the exchange reaction. Transesterification networks are one of the most studied type of vitrimers that usually require the incorporation of a catalyst, implying the associated drawbacks. Following up on a recent report on catalyst-free transesterification vitrimers in which the ester functions are particularly reactive thanks to the presence of fluorine atoms in α- or β-position, parallel DFT calculations and an experimental kinetic study on model molecules are presented in order to quantitatively assess the effect of neighbouring fluorinated groups on the transesterification reaction rate. 相似文献
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An improved capillary electrophoresis method for in vitro monitoring of the challenging early steps of Aβ1–42 peptide oligomerization: Application to anti‐Alzheimer's drug discovery
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Dimitri Brinet Julia Kaffy Farid Oukacine Sarah Glumm Sandrine Ongeri Myriam Taverna 《Electrophoresis》2014,35(23):3302-3309
We report an improved CE method to monitor in vitro the self‐assembly of monomeric amyloid β‐peptide (42 amino acids amyloid β‐peptide, Aβ1–42) and in particular the crucial early steps involved in the formation of the neurotoxic oligomers. In order to start the kinetics from the beginning, sample preparation was optimized to provide samples containing exclusively the monomeric form. The CE method was also improved using a dynamic coating and by reducing the separation distance. Using this method, the disappearance of the monomer as well as the progressive formation of four species during the self‐assembly process can now be monitored and quantified over time. The hydrodynamic radius of the species present at the initial kinetics step was estimated around 1.8 nm by Taylor dispersion analysis while SDS‐PAGE analyses showed the predominance of the monomer. These results confirmed that the Aβ1–42 species present at this initial time was the monomer. Methylene blue, an anti‐Alzheimer disease candidate, was then evaluated. In spite of an oligomerization inhibition, the enhanced disappearance of the Aβ1–42 monomer provoked by methylene blue was demonstrated for the first time. This method, allowing the monomeric and smallest oligomeric species to be monitored, represents a new accurate and precise way to evaluate compounds for drug discovery. 相似文献
26.
Bumhee Lim Yangyang Cheng Takehiro Kato Anh-Tuan Pham Eliott Le Du Abhaya Kumar Mishra Elija Grinhagena Dimitri Moreau Naomi Sakai Jerome Waser Stefan Matile 《Helvetica chimica acta》2021,104(8):e2100085
Thiol-mediated uptake is emerging as method of choice to penetrate cells. This study focuses on irreversible covalent inhibitors of thiol-mediated uptake. High-content high-throughput screening of the so far largest collection of hypervalent iodine reagents affords inhibitors that are more than 250 times more active than Ellman’s reagent and rival the best dynamic covalent inhibitors. Comparison with other irreversible reagents reveals that inhibition within one series follows reactivity, whereas inhibition across series deviates from reactivity. These trends support that molecular recognition, besides dynamic covalent exchange, contributes significantly to thiol-mediated uptake. The most powerful inhibitors besides the best hypervalent iodine reagents were Fukuyama’s nosyl protecting group and super-cinnamaldehydes that have been introduced as irreversible activators of the pain receptor TRPA1. Considering that several viruses use different forms of thiol-mediated uptake to enter cells, the identification of new irreversible inhibitors of thiol-mediated uptake is of general interest for the discovery of new antivirals. 相似文献
27.
Abil E. Aliev Alex J. Sinclair Shen Zhou John D. Wilden Stephen Caddick Dimitri M. Kullmann Dmitri A. Rusakov 《Journal of Physical Organic Chemistry》2009,22(6):607-612
While developing a synthesis towards tagged dizocilpine (MK‐801) analogues, we observed highly restricted inversion of a nitrogen centre in a number hydroxylamines obtained as key intermediates. These compounds are shown to possess some of the structural elements which are expected to significantly hinder the nitrogen inversion, potentially leading to hydroxylamines with a chiral nitrogen centre. Free energy barriers (ΔG≠) of the nitrogen inversion were estimated to be ca. 22 kcal mol?1 at temperatures near 420 K using variable temperature NMR measurements in DMSO‐d6. Further density functional studies of a number model systems were undertaken in order to better rationalize the measured inversion barriers and follow the role of various structural factors in raising the barrier height of the nitrogen inversion process. Copyright © 2008 John Wiley & Sons, Ltd. 相似文献
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Fluidization of Nano-size Particles 总被引:2,自引:0,他引:2
Fluidization and collapsing bed experiments were performed with 'Tullanox', 10nm diameter fumed silica. The minimum fluidization velocity was determined to be 0.0115m/s at the unusually low volume fraction of solids of 0.0077. The solids volume fraction was measured using a -ray densitometer. Fluidization was without large bubbles, with a high bed expansion ratio. The highest granular temperature was of the order of that of Geldart B particles, as measured by Cody et al. (1996). The sedimentation process was simulated using a two-fluid hydrodynamic model. The input into the model was a measured solids stress modulus and an agglomerate size determined from the settling curves. With these two rheological parameters, there was good agreement between the sedimentation theory and the experiment. This study shows that the standard collapse bed experiment used in industry is a good test of rheological properties of particles. 相似文献
30.
Dimitri P. Bertsekas 《Computational Optimization and Applications》1999,12(1-3):41-51
Given a single feasible solution
and a single infeasible solution
of a mathematical program, we provide an upper bound to the optimal dual value. We assume that
satisfies a weakened form of the Slater condition. We apply the bound to convex programs and we discuss its relation to Hoffman-like bounds. As a special case, we recover a bound due to Mangasarian [11] on the distance of a point to a convex set specified by inequalities. 相似文献