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81.
A series of 24 huprine derivatives diversely functionalized at position 9 have been synthesized and evaluated for their inhibitory activity against human recombinant acetylcholinesterase (AChE). These derivatives were prepared in one to five steps from huprine 1 bearing an ester function at position 9. Ten analogues ( 1 , 2 , 6 – 9 , 13 – 15 , and 23 ) are active in the low nanomolar range (IC50 <5 nM ), very close to the parent compound huprine X. Compounds 2 , 6 , and 7 show a very good selectivity for AChE, with AChE inhibitory activities 700–1160‐fold higher than those for butyrylcholinesterase (BChE). The inhibitory potency of these compounds decreases with the steric bulk of the substituents at position 9. According to docking simulations, small substituents fit into the acyl‐binding pocket, whereas the larger ones stick out of the active site gorge of AChE. Determination of the kinetic parameters of three of the most potent huprines ( 2 , 6 , and 7 ) showed that most of the difference in KD is accounted by a decrease in kon, which is correlated to the increase of the substituent size. A first in vivo evaluation has been performed in mice for the most active compound 2 (IC50=1.1 nM ) and showed a rather weak toxicity (LD50=40 mg kg?1) and an ability to cross the blood–brain barrier with doses above 15 mg kg?1. 相似文献
82.
Emilie Delattre Gilles Lemière Jean‐Roger Desmurs Benjamin Boulay Elisabet Duñach 《应用聚合物科学杂志》2014,131(17)
Poly(vinyl alcohol) has been functionalized with aldehydes in tetrahydrofuran (THF) with a good control of the grafting. A wide library of poly(vinyl acetals) could be obtained in order to study some structure/property correlations. The influence of the aldehyde nature on the functionalization rates has been studied, in particular for optical properties by measurement of the shininess for further applications in the cosmetic field. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40677. 相似文献
83.
Binding Mode and Structure–Activity Relationships around Direct Inhibitors of the Nrf2–Keap1 Complex 下载免费PDF全文
Dr. Eric Jnoff Dr. Claudia Albrecht Dr. John J. Barker Dr. Oliver Barker Dr. Edward Beaumont Dr. Steven Bromidge Dr. Frederick Brookfield Dr. Mark Brooks Dr. Christian Bubert Dr. Tom Ceska Vincent Corden Dr. Graham Dawson Dr. Stephanie Duclos Dr. Tara Fryatt Dr. Christophe Genicot Dr. Emilie Jigorel Dr. Jason Kwong Rosemary Maghames Innocent Mushi Dr. Richard Pike Dr. Zara A. Sands Dr. Myron A. Smith Dr. Christopher C. Stimson Dr. Jean‐Philippe Courade 《ChemMedChem》2014,9(4):699-705
An X‐ray crystal structure of Kelch‐like ECH‐associated protein (Keap1) co‐crystallised with (1S,2R)‐2‐[(1S)‐1‐[(1,3‐dioxo‐2,3‐dihydro‐1H‐isoindol‐2‐yl)methyl]‐1,2,3,4‐tetrahydroisoquinolin‐2‐carbonyl]cyclohexane‐1‐carboxylic acid (compound (S,R,S)‐ 1 a ) was obtained. This X‐ray crystal structure provides breakthrough experimental evidence for the true binding mode of the hit compound (S,R,S)‐ 1 a , as the ligand orientation was found to differ from that of the initial docking model, which was available at the start of the project. Crystallographic elucidation of this binding mode helped to focus and drive the drug design process more effectively and efficiently. 相似文献
84.
Jiří Čulík Marie Jurková Tomáš Horák Pavel Čejka Vladimír Kellner Josef Dvořák Pavel Karásek Michal Roth 《Journal of the Institute of Brewing》2009,115(3):220-225
The EBC method 7.7, currently used for determination of bitter acids in hop products, is a time‐consuming and laborious extraction technique. In this paper, our aim was to propose a new extraction method based on Pressurized Solvent Extraction (PSE) sometimes also called Pressurized Fluid Extraction (PFE) or Accelerated Solvent Extraction (ASE). Compared to conventional extractions, PSE offers a number of important benefits. PSE on OnePSE® automated extractor was used for extraction of α‐ and β‐acids from hops and hop products and the parameters influencing extraction efficiency and the influence of the sample preparation method were studied. The quantitative determination of α‐ and β‐acids in the extracts was accomplished by using an HPLC apparatus equipped with diode array detector. The experimental results were compared with those obtained by the standard EBC 7.7 method and the two methods were found to be fully compatible 相似文献
85.
Characteristic time,developers’ behavior and leapfrogging dynamics of high-rise buildings 总被引:1,自引:1,他引:0
This paper suggests a plausible explanation for the spatial evolution of high-rise buildings. Contrary to intuitive expectations
the histograms and spatial distribution in cities indicate peculiar and non-continuous patterns. These patterns evolve as
a result of developers’ behavior in real-estate markets. One of the critical variables in decision-making of developers is
time. Despite obvious differences in land prices within a particular real-estate market, differences in costs and prices are
relatively small in comparison to differences in their time incidence. The paper presents a simple search model of land developer
that suggests interesting explanation of the spatial sprawl of cities. The central parameter in our model is “characteristic
time”, the period of time from the acquisition of initial property rights in the land and until the first return on the investment
is realized. The model leads to leapfrogging patterns, particularly during downturn periods and explains the appearance of
high-rise buildings in the urban periphery. 相似文献
86.
87.
[Correction Notice: An erratum for this article was reported in Vol 3(1) of Psychological Trauma: Theory, Research, Practice, and Policy (see record 2010-26899-001). There were citation errors in the last sentence of the first column of text on page 9, and a reference was omitted from the reference list. The sentence should have read: “This result is consistent with other work that has found support for the anxious and dissociative reaction associated with trauma among Latinos and how it may relate to “ataque de nervios” (Hinton, Chong, Pollack, Barlow, & McNally, 2008; Lewis-Fernandez et al., 2002; Schechter et al., 2000; Tolin, Robinson, Gaztambide, Horowitz, & Blank, 2007).] [Correction Notice: An erratum for this article was reported in of Psychological Trauma: Theory, Research, Practice, and Policy (see record 2010-26899-001). In the original article there were citation errors in the last sentence of the first column of text on page 9, and a reference was omitted from the reference list. The sentence should have read: “This result is consistent with other work that has found support for the anxious and dissociative reaction associated with trauma among Latinos and how it may relate to “ataque de nervios” (Hinton, Chong, Pollack, Barlow, & McNally, 2008; Lewis-Fernandez et al., 2002; Schechter et al., 2000; Tolin, Robinson, Gaztambide, Horowitz, & Blank, 2007).] Research on the victimization of Latino women and the subsequent psychological impact has been limited by focusing on individual forms of victimization, primarily partner violence or sexual assault. Another deficiency includes mainly using convenience and/or geographically restricted samples, which impacts the generalizability of the results. To overcome these research limitations, the Sexual Assault Among Latinas (SALAS) study aimed to evaluate the broader scope of victimization among Latino women. The study surveyed a national sample of 2,000 Latino women using random digit dial methodology. Women were asked about various forms of victimization in childhood and adulthood including physical assaults, sexual assaults, stalking, threats, and witnessed violence, as well as psychological symptomatology including depression, anxiety, anger, and dissociation. This analysis found that victimized women were more likely to experience some form of polyvictimization and/or revictimization throughout their lives, with only 36% of victimized women experiencing one form of victimization in childhood or adulthood alone. Furthermore, multiple victimization experiences significantly increased the proportion of women who experienced psychological distress symptoms in the clinical range. For almost all evaluated symptoms, the multiple forms of victimization or varying victimization patterns significantly predicted clinical levels of psychological distress over any specific form or single incident of victimization. The results suggest that victimized Latino women experience multiple forms of victimization and that the evaluation of a broader spectrum of victimization better accounts for pathological symptomatology. Clinical implications for Latino women and future research directions are discussed. (PsycINFO Database Record (c) 2011 APA, all rights reserved) 相似文献
88.
Irene Papanayotou Beimeng Sun Amy F. Roth Nicholas G. Davis 《Yeast (Chichester, England)》2010,27(10):801-816
Yeast cell lysates produced by mechanical glass bead disruption are widely used in a variety of applications, including for the analysis of native function, e.g. protein–protein interaction, enzyme assays and membrane fractionations. Below, we report a striking case of protein denaturation and aggregation that is induced by this lysis protocol. Most of this analysis focuses on the type 1 casein kinase Yck2, which normally tethers to the plasma membrane through C‐terminal palmitoylation. Surprisingly, when cells are subjected to glass bead disruption, non‐palmitoylated, cytosolic forms of the kinase denature and aggregate, while membrane‐associated forms, whether attached through their native palmitoyl tethers or through a variety of artificial membrane‐tethering sequences, are wholly protected from denaturation and aggregation. A wider look at the yeast proteome finds that, while the majority of proteins resist glass bead‐induced aggregation, a significant subset does, in fact, succumb to such denaturation. Thus, yeast researchers should be aware of this potential artifact when embarking on biochemical analyses that employ glass bead lysates to look at native protein function. Finally, we demonstrate an experimental utility for glass bead‐induced aggregation, using its fine discrimination of membrane‐associated from non‐associated Yck2 forms to discern fractional palmitoylation states of Yck2 mutants that are partially defective for palmitoylation. Copyright © 2010 John Wiley & Sons, Ltd. 相似文献
89.
Partition coefficients of phenol, salicylic acid, and several environmentally important chloro- and nitrophenols in a supercritical CO2-water system were measured using direct cocurrent extraction of aqueous solutions of the individual solutes with CO2. Partitioning data on the nitrophenols and salicylic acid were obtained for the first time. To bypass the troublesome and error-prone analysis of the CO2-rich phase, the present method employed only the solute concentrations in the aqueous phase before and after extraction to determine the partition coefficient. Unlike most previous engineering studies of phenol partitioning in a CO2-water system, the concentrations of phenolic solutes approached infinite dilution in both phases. This makes the results relevant to analytical-scale SFE of environmental water samples with CO2. Because of effective infinite dilution of the solutes, the partition coefficients provide a direct measure of relative CO2-philicity/hydrophilicity of the individual phenols. Compared to the octanol-water partition coefficients of substituted phenols, the CO2-water partition coefficients are more sensitive to substitution in the position neighboring the hydroxyl group. 相似文献
90.
This review focuses on the role of oestrogen in male sexual behaviour using oestrogen receptor alpha and beta knockout (ERalphaKO and ERbetaKO) mouse models. ERbetaKO mice are capable of mating and producing offspring, whereas ERalphaKO mice are unable to do either. When ERalphaKO males are treated with testosterone or dihydrotestosterone (DHT), < 50% display mounting behaviour, few intromit and none ejaculate. However, concurrent treatment with testosterone and a dopamine agonist instates masculine sexual behaviour in both male and female ERalphaKO mice. Dopamine content in the preoptic area and associated regions is not affected by oestrogen receptor alpha gene disruption. However, expression of neuronal nitric oxide synthase immunoreactivity is severely reduced in ERalphaKO males compared with wild-type males. These findings, together with studies conducted in aromatase knockout mice, are at odds with the dogma that oestrogen is required during development for expression of male sexual behaviour in adults. However, they do support a role for oestrogens, mediated by oestrogen receptor alpha, in regulation and production of neuronal nitric oxide synthase, which in turn may control dopamine agonist release. As has been shown in male rats, in mice dopamine agonist release is likely to be an essential component of the neural pathway that mediates male sexual behaviour. 相似文献