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101.
Activity of Fluorine‐Containing Analogues of WC‐9 and Structurally Related Analogues against Two Intracellular Parasites: Trypanosoma cruzi and Toxoplasma gondii 下载免费PDF全文
María N. Chao Catherine Li Melissa Storey Dr. Bruno N. Falcone Dr. Sergio H. Szajnman Prof. Dr. Sergio M. Bonesi Prof. Dr. Roberto Docampo Prof. Dr. Silvia N. J. Moreno Prof. Dr. Juan B. Rodriguez 《ChemMedChem》2016,11(24):2690-2702
Two obligate intracellular parasites, Trypanosoma cruzi, the agent of Chagas disease, and Toxoplasma gondii, an agent of toxoplasmosis, upregulate the mevalonate pathway of their host cells upon infection, which suggests that this host pathway could be a potential drug target. In this work, a number of compounds structurally related to WC‐9 (4‐phenoxyphenoxyethyl thiocyanate), a known squalene synthase inhibitor, were designed, synthesized, and evaluated for their effect on T. cruzi and T. gondii growth in tissue culture cells. Two fluorine‐containing derivatives, the 3‐(3‐fluorophenoxy)‐ and 3‐(4‐fluorophenoxy)phenoxyethyl thiocyanates, exhibited half‐maximal effective concentration (EC50) values of 1.6 and 4.9 μm , respectively, against tachyzoites of T. gondii, whereas they showed similar potency to WC‐9 against intracellular T. cruzi (EC50 values of 5.4 and 5.7 μm , respectively). In addition, 2‐[3‐ (phenoxy)phenoxyethylthio]ethyl‐1,1‐bisphosphonate, which is a hybrid inhibitor containing 3‐phenoxyphenoxy and bisphosphonate groups, has activity against T. gondii proliferation at sub‐micromolar levels (EC50=0.7 μm ), which suggests a combined inhibitory effect of the two functional groups. 相似文献
102.
Discovery of Highly Potent Dual Orexin Receptor Antagonists via a Scaffold‐Hopping Approach 下载免费PDF全文
Dr. Bibia Heidmann Dr. John Gatfield Dr. Catherine Roch Dr. Alexander Treiber Dr. Simone Tortoioli Dr. Christine Brotschi Dr. Jodi T. Williams Dr. Martin H. Bolli Dr. Stefan Abele Dr. Thierry Sifferlen Dr. François Jenck Dr. Christoph Boss 《ChemMedChem》2016,11(19):2132-2146
Starting from suvorexant (trade name Belsomra), we successfully identified interesting templates leading to potent dual orexin receptor antagonists (DORAs) via a scaffold‐hopping approach. Structure–activity relationship optimization allowed us not only to improve the antagonistic potency on both orexin 1 and orexin 2 receptors (Ox1 and Ox2, respectively), but also to increase metabolic stability in human liver microsomes (HLM), decrease time‐dependent inhibition of cytochrome P450 (CYP) 3A4, and decrease P‐glycoprotein (Pgp)‐mediated efflux. Compound 80 c [{(1S,6R)‐3‐(6,7‐difluoroquinoxalin‐2‐yl)‐3,8‐diazabicyclo[4.2.0]octan‐8‐yl}(4‐methyl‐[1,1′‐biphenyl]‐2‐yl)methanone] is a potent and selective DORA that inhibits the stimulating effects of orexin peptides OXA and OXB at both Ox1 and Ox2. In calcium‐release assays, 80 c was found to exhibit an insurmountable antagonistic profile at both Ox1 and Ox2, while displaying a sleep‐promoting effect in rat and dog models, similar to that of the benchmark compound suvorexant. 相似文献
103.
Mallory Batty Rachel Pugh Ilampirai Rathinam Joshua Simmonds Edwin Walker Amanda Forbes Shailendra Anoopkumar-Dukie Catherine M. McDermott Briohny Spencer David Christie Russ Chess-Williams 《International journal of molecular sciences》2016,17(8)
This review evaluates the role of α-adrenoceptor antagonists as a potential treatment of prostate cancer (PCa). Cochrane, Google Scholar and Pubmed were accessed to retrieve sixty-two articles for analysis. In vitro studies demonstrate that doxazosin, prazosin and terazosin (quinazoline α-antagonists) induce apoptosis, decrease cell growth, and proliferation in PC-3, LNCaP and DU-145 cell lines. Similarly, the piperazine based naftopidil induced cell cycle arrest and death in LNCaP-E9 cell lines. In contrast, sulphonamide based tamsulosin did not exhibit these effects. In vivo data was consistent with in vitro findings as the quinazoline based α-antagonists prevented angiogenesis and decreased tumour mass in mice models of PCa. Mechanistically the cytotoxic and antitumor effects of the α-antagonists appear largely independent of α 1-blockade. The proposed targets include: VEGF, EGFR, HER2/Neu, caspase 8/3, topoisomerase 1 and other mitochondrial apoptotic inducing factors. These cytotoxic effects could not be evaluated in human studies as prospective trial data is lacking. However, retrospective studies show a decreased incidence of PCa in males exposed to α-antagonists. As human data evaluating the use of α-antagonists as treatments are lacking; well designed, prospective clinical trials are needed to conclusively demonstrate the anticancer properties of quinazoline based α-antagonists in PCa and other cancers. 相似文献
104.
Venkat N. Vangaveti Venkatesh M. Shashidhar Catherine Rush Usman H. Malabu Roy R. Rasalam Fiona Collier Bernhard T. Baune Richard L. Kennedy 《Lipids》2014,49(12):1181-1192
Macrophage apoptosis, a key process in atherogenesis, is regulated by oxidation products, including hydroxyoctadecadienoic acids (HODEs). These stable oxidation products of linoleic acid (LA) are abundant in atherosclerotic plaque and activate PPARγ and GPR132. We investigated the mechanisms through which HODEs regulate apoptosis. The effect of HODEs on THP‐1 monocytes and adherent THP‐1 cells were compared with other C18 fatty acids, LA and α‐linolenic acid (ALA). The number of cells was reduced within 24 hours following treatment with 9‐HODE (p < 0.01, 30 μM) and 13 HODE (p < 0.01, 30 μM), and the equivalent cell viability was also decreased (p < 0.001). Both 9‐HODE and 13‐HODE (but not LA or ALA) markedly increased caspase‐3/7 activity (p < 0.001) in both monocytes and adherent THP‐1 cells, with 9‐HODE the more potent. In addition, 9‐HODE and 13‐HODE both increased Annexin‐V labelling of cells (p < 0.001). There was no effect of LA, ALA, or the PPARγ agonist rosiglitazone (1μM), but the effect of HODEs was replicated with apoptosis‐inducer camptothecin (10μM). Only 9‐HODE increased DNA fragmentation. The pro‐apoptotic effect of HODEs was blocked by the caspase inhibitor DEVD‐CHO. The PPARγ antagonist T0070907 further increased apoptosis, suggestive of the PPARγ‐regulated apoptotic effects induced by 9‐HODE. The use of siRNA for GPR132 showed no evidence that the effect of HODEs was mediated through this receptor. 9‐HODE and 13‐HODE are potent—and specific—regulators of apoptosis in THP‐1 cells. Their action is PPARγ‐dependent and independent of GPR132. Further studies to identify the signalling pathways through which HODEs increase apoptosis in macrophages may reveal novel therapeutic targets for atherosclerosis. 相似文献
105.
Poly(Tetrasubstituted Aryl Imidazole)s (PTAIs), a new class of poly(heteroaromatic) polymers was prepared via a cascade polycondensation process, under microwave irradiation. These polymers were obtained by the tetrasubstituted aryl imidazole ring formation involving bis(aryl α-diketone)s, bis(arylaldehyde)s, mono(arylamine)s and ammonium acetate. The polymerization performed under microwave irradiation allowed to get high molecular weight PTAIs in very short reaction times. The chemical structure of these PTAIs was confirmed by NMR spectroscopy. Thermogravimetric analyses (TGA) showed a very good grade of thermal stability of these polymers. Glass transition temperatures (Tg) of PTAIs ranging from 155 °C to 265 °C were determined by Differential Scanning Calorimetry (DSC). 相似文献
106.
Ian Mabbett Jon Elvins Catherine Gowenlock Carol Glover Paul Jones Geraint Williams David Worsley 《Progress in Organic Coatings》2014
Near infrared (NIR) is becoming a popular option for rapid cure of coatings in the coil coating industry particularly where fast line speeds are required. The technology has the potential to reduce the cure time of a 20 μm polyester coating on a galvanised steel substrate from around 30 s via conventional heating methods down to <10 s under the lamps. Previous work suggested that the ideal situation in this case is to have a topcoat which is slightly transparent to NIR and an absorbing substrate to heat the coating from the substrate outwards in a two stage process which separates solvent removal from cross linking and film formation. This can be taken further by tinting the primer layer with a pigment that absorbs in the NIR region. In this study spectroscopy was used to show that a coated steel system could appear white in the visible region because of the reflectance of TiO2 but the NIR absorption could be altered by adding absorbing pigments such as carbon black. Lamp settings could be reduced by 20% to achieve equivalent cure with tinted primer systems. The potential degradation in corrosion protection afforded by carbon-black containing pigments at various loadings was assessed for model organic coatings applied to galvanised steel specimens. In situ scanning Kelvin probe studies showed that rates of corrosion-driven coating delamination by cathodic disbondment remained unchanged by pigment loadings of up to 3.5 wt%. 相似文献
107.
Robert K. Vander Meer Catherine A. Preston Man-Yeon Choi 《Journal of chemical ecology》2010,36(2):163-170
Alarm pheromones in social insects are an essential part of a complex of pheromone interactions that contribute to the maintenance
of colony integrity and sociality. The alarm pheromones of ants were among the first examples of animal pheromones identified,
primarily because of the large amount of chemical produced and the distinctive responses of ants to the pheromone. However,
the alarm pheromone of the fire ant, Solenopsis invicta, eluded identification for over four decades. We identified 2-ethyl-3,6-dimethylpyrazine as an alarm pheromone component
of S. invicta. Worker fire ants detect the pyrazine alarm pheromone at 30 pg/ml, which is comparable to alarm pheromone sensitivities reported
for other ant species. The source of this alarm pheromone are the mandibular glands, which, in fire ants, are not well developed
and contain only about 300 pg of the compound, much less than the microgram quantities of alarm pheromones reported for several
other ant species. Female and male sexuals and workers produce the pyrazine, which suggests that it may be involved in fire
ant mating flight initiation, as well as the typical worker alarm response. This is the first report of 2-ethyl-3,6-dimethylpyrazine
from a Solenopsis species and the first example of this alkaloid functioning as an alarm pheromone. 相似文献
108.
Staffan Jacobsson Anna Bergek Dominique Finon Volkmar Lauber Catherine Mitchell David Toke Aviel Verbruggen 《Energy Policy》2009
The recent EU Commission proposal for promoting the supply of power from renewable energy sources was originally based on a pan-European, harmonised tradable green certificate (TGC) scheme. We suggest, on the basis of a multi-disciplinary analysis, that a pan-EU TGC system is not the way forward for Europe. It is vital that the Commission (and the majority of Member States) avoids implementation of such policy designs put forward by a coalition of vested interests. They should instead look at, and act upon, the available evidence from those countries that have experimented with TGCs (e.g. Flanders, UK and Sweden) and design policies that stand a better chance of meeting the criteria of effectiveness, efficiency and equity. In particular, the policies must enable EU to meet the immense innovation/industrialisation challenge by inducing the development of a capital goods industry that can, eventually, diffuse a broad range of technologies that use renewable energy sources. Only then we can acquire an ability to implement an industrial revolution in the energy system in a way that broadly meets the criteria of effectiveness and dynamic efficiency. 相似文献
109.
Bradshaw Catherine P.; Zmuda Jessika H.; Kellam Sheppard G.; Ialongo Nicholas S. 《Canadian Metallurgical Quarterly》2009,101(4):926
This study examined the longitudinal effects of 2 first-grade universal preventive interventions on academic outcomes (e.g., achievement, special education service use, graduation, postsecondary education) through age 19 in a sample of 678 urban, primarily African American children. The classroom-centered intervention combined the Good Behavior Game (H. H. Barrish, Saunders, & Wolfe, 1969) with an enhanced academic curriculum, whereas a second intervention, the Family–School Partnership, focused on promoting parental involvement in educational activities and bolstering parents’ behavior management strategies. Both programs aimed to address the proximal targets of aggressive behavior and poor academic achievement. Although the effects varied by gender, the classroom-centered intervention was associated with higher scores on standardized achievement tests, greater odds of high school graduation and college attendance, and reduced odds of special education service use. The intervention effects of the Family–School Partnership were in the expected direction; however, only 1 effect reached statistical significance. The findings of this randomized controlled trial illustrate the long-term educational impact of preventive interventions in early elementary school. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献
110.
Alison Wenham Lihui Song Malcolm Abbott Iskra Zafirovska Sisi Wang Brett Hallam Catherine Chan Allen Barnett Stuart Wenham 《Frontiers in Energy》2017,11(1):60-66
Cast-mono crystalline silicon wafers contain crystallographic defects, which can severely impact the electrical performance of solar cells. This paper demonstrates that applying hydrogenation processes at moderate temperatures to finished screen print cells can passivate dislocation clusters within the cast-mono crystalline silicon wafers far better than the hydrogenation received during standard commercial firing conditions. Efficiency enhancements of up to 2% absolute are demonstrated on wafers with high dislocation densities. The impact of illumination to manipulate the charge state of hydrogen during annealing is investigated and found to not be significant on the wafers used in this study. This finding is contrary to a previous study on similar wafers that concluded increased H– or H0 from laser illumination was responsible for the further passivation of positively charged dangling bonds within the dislocation clusters. 相似文献