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101.
Oslob JD Romanowski MJ Allen DA Baskaran S Bui M Elling RA Flanagan WM Fung AD Hanan EJ Harris S Heumann SA Hoch U Jacobs JW Lam J Lawrence CE McDowell RS Nannini MA Shen W Silverman JA Sopko MM Tangonan BT Teague J Yoburn JC Yu CH Zhong M Zimmerman KM O'Brien T Lew W 《Bioorganic & medicinal chemistry letters》2008,18(17):4880-4884
This communication describes the discovery of a novel series of Aurora kinase inhibitors. Key SAR and critical binding elements are discussed. Some of the more advanced analogues potently inhibit cellular proliferation and induce phenotypes consistent with Aurora kinase inhibition. In particular, compound 21 (SNS-314) is a potent and selective Aurora kinase inhibitor that exhibits significant activity in pre-clinical in vivo tumor models. 相似文献
102.
103.
JA Edward MK Kiesewetter H Kim JC Flanagan JL Hedrick RM Waymouth 《Biomacromolecules》2012,13(8):2483-2489
The ring-opening polymerization of substituted cyclic carbonates with 1-(3,5-bis-trifluoromethyl-phenyl)-3-cyclohexyl-thiourea (TU)/1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) organocatalysts afford highly functionalized oligocarbonates. The fluorescent alkaloid quinine can be readily incorporated into the oligocarbonates either by initiation from quinine or by ring-opening polymerization of a quinine-functionalized cyclic carbonate (MTC-Q). Copolymerization of MTC-Q with a boc-protected guanidinium cyclic carbonate affords, after deprotection, highly water-soluble cationic copolymers functionalized with both quinine and pendant guanidinium groups. When multiple quinine groups are attached to the oligomers, they exhibit minimal fluorescence due to self-quenching. Upon hydrolysis, the fluorescence intensity increases, providing a potential strategy for monitoring the hydrolysis rates in real time. 相似文献
104.
The Epstein-Barr and Kaposi's sarcoma gamma-herpesviruses (KSHVs) are associated with certain cancers, and encode B-cell leukemia/lymphoma 2 (BCL-2) homologs, BHRF-1 and KSHV BCL-2, respectively. Little is known, however, about the molecular interactions allowing viral BCL-2 homologs to mediate their anti-apoptotic function. Cellular anti-apoptotic proteins, such as BCL-2 and MCL-1, prevent death via selective interactions with pro-death BH3-only proteins. To investigate whether BHRF-1 and KSHV BCL-2 function similarly, we made recombinant BHRF-1 and KSHV BCL-2 proteins. We identified the individual binding patterns for BHRF-1 and KSHV BCL-2 to BH3 domains. These studies surprisingly showed that KSHV BCL-2 is more closely related to MCL-1 than to BCL-2, a result confirmed by sequence analysis. GST-BHRF-1 and GST-KSHV BCL-2 bound BH3-only family proteins from human cells. BHRF-1 protected mammalian cells from growth factor withdrawal, etoposide and adriamycin. We found that both BCL-2 and BHRF-1 sequestered pro-death BH3-only proteins under growth factor-deficient conditions. Finally, we tested the ability of a panel of BH3 peptides to inhibit BHRF-1 and KSHV BCL-2 function in a mitochondrial model of apoptosis. We found that each could be inhibited by the select group of BH3 peptides identified in our binding assay. Our studies define the biochemical interactions underlying BHRF-1 and KSHV BCL-2 anti-apoptotic function, and identify peptides that are prototypic inhibitors of this function. 相似文献
105.
Kitanovic S Yuen T Flanagan CA Ebersole BJ Sealfon SC 《Molecular endocrinology (Baltimore, Md.)》2001,15(3):390-397
The pattern of side-chain conservation at the cytoplasmic side of the third transmembrane domain of rhodopsin family G protein-coupled receptors, Asp/Glu-Arg-Tyr/X-X-X-Ile/Val, defines a structural "arginine cage" domain. Previous computational and mutagenesis studies of the GnRH receptor indicated an important contribution of local interactions to the function of this domain. We have investigated the functional importance of the intrahelical position and orientation of the arginine cage using insertional mutagenesis. Introduction of a single Ala proximal to the conserved Asp-Arg of this domain caused loss of detectable ligand binding. Inserting a second Ala, however, restored high-affinity agonist binding. Further insertion of three or four Ala residues at this site generated receptors that bound agonist with an affinity 3- to 10-fold higher than that of the wild-type receptor. Loss of detectable coupling to inositol phosphate turnover in all these mutant receptors confirms that the structure required in this region for efficient signaling is highly constrained. In contrast, the recovery of agonist binding with the progressive insertion of two to four Ala residues indicates that specific orientations of this segment can stabilize high-affinity receptor conformations that are uncoupled from signal transduction. 相似文献
106.
Joshua M. Unghire Ariana E. Sutton‐Grier Neal E. Flanagan Curtis J. Richardson 《Restoration Ecology》2011,19(6):738-746
Hydric soil development of riparian wetlands is primarily influenced by the hydrologic connection between the floodplains and the stream channel. Often, the goal of riparian restoration is to revitalize this connectivity through a restructuring of the stream channel and the floodplain; however, the effects of this restructuring on the physical and spatial characteristics of soil properties are rarely considered. The objective of this study was to quantify the impacts of restoration efforts on the spatial characteristics of soil properties by means of a pre‐ and post‐restoration comparison. We determined that the spatial patterns of soil organic matter (SOM) and exchangeable phosphorus (Pex) appeared less variable in the years following restoration than in the years before restoration. Mean SOM significantly decreased after restoration, whereas mean Pex significantly increased. The spatial characteristics and mean concentrations of NO2–NO3 did not differ much between sampling dates. The loss of this spatial patterning in SOM and Pex and the decrease in SOM pools may represent negative impacts of restoration on important ecosystem characteristics. This study demonstrates that soil properties and spatial patterns can be negatively affected by restoration activities potentially hindering ecosystem development and function. 相似文献
107.
108.
The structure of divalent cation-induced aggregates of PIP2 and their alteration by gelsolin and tau. 总被引:3,自引:0,他引:3 下载免费PDF全文
L A Flanagan C C Cunningham J Chen G D Prestwich K S Kosik P A Janmey 《Biophysical journal》1997,73(3):1440-1447
Phosphatidylinositol bisphosphate (PIP2) serves as a precursor for diacylglycerol and inositol trisphosphate in signal transduction cascades and regulates the activities of several actin binding proteins that influence the organization of the actin cytoskeleton. Molecules of PIP2 form 6-nm diameter micelles in water, but aggregate into larger, multilamellar structures in physiological concentrations of divalent cations. Electron microscopic analysis of these aggregates reveals that they are clusters of striated filaments, suggesting that PIP2 aggregates form stacks of discoid micelles rather than multilamellar vesicles or inverted hexagonal arrays as previously inferred from indirect observations. The distance between striations within the filaments varies from 4.2 to 5.4 nm and the diameter of the filaments depends on the dehydrated ionic radius of the divalent cation, with average diameters of 19, 12, and 10 nm for filaments formed by Mg2+, Ca2+, and Ba2+, respectively. The structure of the divalent cation-induced aggregates can be altered by PIP2 binding proteins. Gelsolin and the microtubule associated protein tau both affect the formation of aggregates, indicating that tau acts as a PIP2 binding protein in a manner similar to gelsolin. In contrast, another PIP2 binding protein, profilin, does not modify the aggregates. 相似文献
109.
J. R. Ehleringer D. R. Bowling L. B. Flanagan J. Fessenden B. Helliker L. A. Martinelli J. P. Ometto 《Plant biology (Stuttgart, Germany)》2002,4(2):181-189
Abstract: Scaling and partitioning are frequently two difficult challenges facing ecology today. With regard to ecosystem carbon balance studies, ecologists and atmospheric scientists are often interested in asking how fluxes of carbon dioxide scale across the landscape, region and continent. Yet at the same time, physiological ecologists and ecosystem ecologists are interested in dissecting the net ecosystem CO2 exchange between the biosphere and the atmosphere to achieve a better understanding of the balance between photosynthesis and respiration within a forest. In both of these multiple-scale ecological questions, stable isotope analyses of carbon dioxide can play a central role in influencing our understanding of the extent to which terrestrial ecosystems are carbon sinks. In this synthesis, we review the theory and present field evidence to address isotopic scaling of CO2 fluxes. We first show that the 13 C isotopic signal which ecosystems impart to the atmosphere does not remain constant over time at either temporal or spatial scales. The relative balances of different biological activities and plant responses to stress result in dynamic changes in the 13 C isotopic exchange between the biosphere and atmosphere, with both seasonal and stand-age factors playing major roles influencing the 13 C biosphere-atmosphere exchange. We then examine how stable isotopes are used to partition net ecosystem exchange fluxes in order to calculate shifts in the balance of photosynthesis and respiration. Lastly, we explore how fundamental differences in the 18 O isotopic gas exchange of forest and grassland ecosystems can be used to further partition terrestrial fluxes. 相似文献
110.