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891.
Changning Wang Christian K. Moseley Stephen M. Carlin Colin M. Wilson Ramesh Neelamegam Jacob M. Hooker 《Bioorganic & medicinal chemistry letters》2013,23(11):3389-3392
EMPA is a selective antagonist of orexin 2 (OX2) receptors. Previous literature with [3H]-EMPA suggest that it may be used as an imaging agent for OX2 receptors; however, brain penetration is known to be modest. To evaluate the potential of EMPA as a PET radiotracer in non-human primate (as a step to imaging in man), we radiolabeled EMPA with carbon-11. Radiosynthesis of [11C]N-ethyl-2-(N-(6-methoxypyridin-3-yl)-2-methylphenylsulfonamido)-N-(pyridin-3-ylmethyl)acetamide ([11C]EMPA), and evaluation as a potential PET tracer for OX2 receptors is described. Synthesis of an appropriate non-radioactive O-desmethyl precursor was achieved from EMPA with sodium iodide and chlorotrimethylsilane. Selective O-methylation using [11C]CH3I in the presence of cesium carbonate in DMSO at room temp afforded [11C]EMPA in 1.5–2.5% yield (non-decay corrected relative to trapped [11C]CH3I at EOS) with ?95% chemical and radiochemical purities. The total synthesis time was 34–36 min from EOB. Studies in rodent suggested that uptake in tissue was dominated by nonspecific binding. However, [11C]EMPA also showed poor uptake in both rats and baboon as measured with PET imaging. 相似文献
892.
893.
Ryosuke Misu Shinya Oishi Shohei Setsuda Taro Noguchi Masato Kaneda Hiroaki Ohno Barry Evans Jean-Marc Navenot Stephen C. Peiper Nobutaka Fujii 《Bioorganic & medicinal chemistry letters》2013,23(9):2628-2631
Kisspeptins, endogenous peptide ligands for GPR54, play an important role in GnRH secretion. Since in vivo administration of kisspeptins induces increased plasma LH levels, GPR54 agonists hold promise as therapeutic agents for the treatment of hormonal secretion diseases. To facilitate the design of novel potent GPR54 ligands, residues in kisspeptins that involve in the interaction with GPR54 were investigated by kisspeptin-based photoaffinity probes. Herein, we report the design and synthesis of novel kisspeptin-based photoaffinity probes, and the application to crosslinking experiments for GPR54-expressing cells. 相似文献
894.
Stephen P. Muench Jozef Stec Ying Zhou Gustavo A. Afanador Martin J. McPhillie Mark R. Hickman Patty J. Lee Susan E. Leed Jennifer M. Auschwitz Sean T. Prigge David W. Rice Rima McLeod 《Bioorganic & medicinal chemistry letters》2013,23(12):3551-3555
The enoyl acyl-carrier protein reductase (ENR) enzyme is harbored within the apicoplast of apicomplexan parasites providing a significant challenge for drug delivery, which may be overcome through the addition of transductive peptides, which facilitates crossing the apicoplast membranes. The binding site of triclosan, a potent ENR inhibitor, is occluded from the solvent making the attachment of these linkers challenging. Herein, we have produced 3 new triclosan analogs with bulky A- and B-ring motifs, which protrude into the solvent allowing for the future attachment of molecular transporters for delivery. 相似文献
895.
Zhe Nie Victoria Feher Srinivasa Natala Christopher McBride Andre Kiryanov Benjamin Jones Betty Lam Yan Liu Stephen Kaldor Jeffrey Stafford Kouki Hikami Noriko Uchiyama Tomohiro Kawamoto Yuichi Hikichi Shin-ichi Matsumoto Nobuyuki Amano Lilly Zhang David Hosfield Takashi Ichikawa 《Bioorganic & medicinal chemistry letters》2013,23(12):3662-3666
Using structure-based drug design, we identified and optimized a novel series of pyrimidodiazepinone PLK1 inhibitors resulting in the selection of the development candidate TAK-960. TAK-960 is currently undergoing Phase I evaluation in adult patients with advanced solid malignancies. 相似文献
896.
Soong-Hoon Kim Keith L. Constantine Gerald J. Duke Valentina Goldfarb John T. Hunt Stephen Johnson Kevin Kish Herbert E. Klei Patricia A. McDonnell William J. Metzler Luciano Mueller Michael A. Poss Craig R. Fairchild Rajeev S. Bhide 《Bioorganic & medicinal chemistry letters》2013,23(14):4107-4111
The design, synthesis and characterization of a phosphonate inhibitor of N-acetylneuraminate-9-phosphate phosphatase (HDHD4) is described. Compound 3, where the substrate C-9 oxygen was replaced with a nonlabile CH2 group, inhibits HDHD4 with a binding affinity (IC50 11 μM) in the range of the native substrate Neu5Ac-9-P (compound 1, Km 47 μM). Combined SAR, modeling and NMR studies are consistent with the phosphonate group in inhibitor 3 forming a stable complex with native Mg2+. In addition to this key interaction, the C-1 carboxylate of the sugar interacts with a cluster of basic residues, K141, R104 and R72. Comparative NMR studies of compounds 3 and 1 with Ca2+ and Mg2+ are indicative of a highly dynamic process in the active site for the HDHD4/Mg2+/3 complex. Possible explanations for this observation are discussed. 相似文献
897.
Daryl R. Trumbo Stephen F. Spear Jason Baumsteiger Andrew Storfer 《Molecular ecology》2013,22(5):1250-1266
A species' genetic structure often varies in response to ecological and landscape processes that differ throughout the species' geographic range, yet landscape genetics studies are rarely spatially replicated. The Cope's giant salamander (Dicamptodon copei) is a neotenic, dispersal‐limited amphibian with a restricted geographic range in the Pacific northwestern USA. We investigated which landscape factors affect D. copei gene flow in three regions spanning the species' range, which vary in climate, landcover and degree of anthropogenic disturbance. Least cost paths and Circuitscape resistance analyses revealed that gene flow patterns vary across the species' range, with unique combinations of landscape variables affecting gene flow in different regions. Populations in the northern coastal portions of the range had relatively high gene flow, largely facilitated by stream and river networks. Near the southeastern edge of the species' range, gene flow was more restricted overall, with relatively less facilitation by streams and more limitation by heat load index and fragmented forest cover. These results suggested that the landscape is more difficult for individuals to disperse through at the southeastern edge of the species' range, with terrestrial habitat desiccation factors becoming more limiting to gene flow. We suggest that caution be used when attempting to extrapolate landscape genetic models and conservation measures from one portion of a species' range to another. 相似文献
898.
Patterns of isolation by distance are uncommon in coral populations. Here, we depart from historical trends of large‐scale, geographical genetic analyses by scaling down to a single patch reef in Kāne‘ohe Bay, Hawai‘i, USA, and map and genotype all colonies of the coral, Pocillopora damicornis. Six polymorphic microsatellite loci were used to assess population genetic and clonal structure and to calculate individual colony pairwise relatedness values. Our results point to an inbred, highly clonal reef (between 53 and 116 clonal lineages of 2352 genotyped colonies) with a much skewed genet frequency distribution (over 70% of the reef was composed of just seven genotypes). Spatial autocorrelation analyses revealed that corals found close together on the reef were more genetically related than corals further apart. Spatial genetic structure disappears, however, as spatial scale increases and then becomes negative at the largest distances. Stratified, random sampling of three neighbouring reefs confirms that reefs are demographically open and inter‐reef genetic structuring was not detected. Attributing process to pattern in corals is complicated by their mixed reproductive strategies. Separate autocorrelation analyses, however, show that the spatial distribution of both clones and nonclones contributes to spatial genetic structure. Overall, we demonstrate genetic structure on an intrareef scale and genetic panmixia on an inter‐reef scale indicating that, for P. damicornis, the effect of small‐ and large‐scale dispersal processes on genetic diversity are not the same. By starting from an interindividual, intrareef level before scaling up to an inter‐reef level, this study demonstrates that isolation‐by‐distance patterns for the coral P. damicornis are limited to small scales and highlights the importance of investigating genetic patterns and ecological processes at multiple scales. 相似文献
899.
Bayden D. Russell Sean D. Connell Helen S. Findlay Karen Tait Stephen Widdicombe Nova Mieszkowska 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2013,368(1627)
Climate change may cause ecosystems to become trophically restructured as a result of primary producers and consumers responding differently to increasing CO2 and temperature. This study used an integrative approach using a controlled microcosm experiment to investigate the combined effects of CO2 and temperature on key components of the intertidal system in the UK, biofilms and their consumers (Littorina littorea). In addition, to identify whether pre-exposure to experimental conditions can alter experimental outcomes we explicitly tested for differential effects on L. littorea pre-exposed to experimental conditions for two weeks and five months. In contrast to predictions based on metabolic theory, the combination of elevated temperature and CO2 over a five-week period caused a decrease in the amount of primary productivity consumed by grazers, while the abundance of biofilms increased. However, long-term pre-exposure to experimental conditions (five months) altered this effect, with grazing rates in these animals being greater than in animals exposed only for two weeks. We suggest that the structure of future ecosystems may not be predictable using short-term laboratory experiments alone owing to potentially confounding effects of exposure time and effects of being held in an artificial environment over prolonged time periods. A combination of laboratory (physiology responses) and large, long-term experiments (ecosystem responses) may therefore be necessary to adequately predict the complex and interactive effects of climate change as organisms may acclimate to conditions over the longer term. 相似文献
900.
Matthew R. Evans Mike Bithell Stephen J. Cornell Sasha R. X. Dall Sandra Díaz Stephen Emmott Bruno Ernande Volker Grimm David J. Hodgson Simon L. Lewis Georgina M. Mace Michael Morecroft Aristides Moustakas Eugene Murphy Tim Newbold K. J. Norris Owen Petchey Matthew Smith Justin M. J. Travis Tim G. Benton 《Proceedings. Biological sciences / The Royal Society》2013,280(1771)
Human societies, and their well-being, depend to a significant extent on the state of the ecosystems that surround them. These ecosystems are changing rapidly usually in response to anthropogenic changes in the environment. To determine the likely impact of environmental change on ecosystems and the best ways to manage them, it would be desirable to be able to predict their future states. We present a proposal to develop the paradigm of predictive systems ecology, explicitly to understand and predict the properties and behaviour of ecological systems. We discuss the necessary and desirable features of predictive systems ecology models. There are places where predictive systems ecology is already being practised and we summarize a range of terrestrial and marine examples. Significant challenges remain but we suggest that ecology would benefit both as a scientific discipline and increase its impact in society if it were to embrace the need to become more predictive. 相似文献