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971.
Brian C. Shook Stefanie Rassnick Daniel Hall Kenneth C. Rupert Geoffrey R. Heintzelman Kristen Hansen Devraj Chakravarty James L. Bullington Robert H. Scannevin Brian Magliaro Lori Westover Karen Carroll Lisa Lampron Ronald Russell Shawn Branum Kenneth Wells Sandra Damon Scott Youells Xun Li Mel Osbourne Paul F. Jackson 《Bioorganic & medicinal chemistry letters》2010,20(9):2864-2867
A novel series of arylindenopyrimidines were identified as A2A and A1 receptor antagonists. The series was optimized for in vitro activity by substituting the 8- and 9-positions with methylene amine substituents. The compounds show excellent activity in mouse models of Parkinson’s disease when dosed orally. 相似文献
972.
Jiaqiang Cai D. Jonathan Bennett Zoran Rankovic Maureen Dempster Xavier Fradera Jonathan Gillespie Iain Cumming William Finlay Mark Baugh Sylviane Boucharens John Bruin Kenneth S. Cameron William Hamilton Jennifer Kerr Emma Kinghorn George McGarry John Robinson Paul Scullion Joost C.M. Uitdehaag Mario van Zeeland Eric Nicolai 《Bioorganic & medicinal chemistry letters》2010,20(15):4447-4450
Starting from previously disclosed equally potent cathepsin K and S inhibitor 4-propyl-6-(3-trifluoromethylphenyl)pyrimidine-2-carbonitrile 1, a novel 2-phenyl-9H-purine-6-carbonitrile scaffold was identified to provide potent and selective cathepsin S inhibitors. 相似文献
973.
Tricyclic dihydroquinazolinones as novel 5-HT2C selective and orally efficacious anti-obesity agents
Saleem Ahmad Khehyong Ngu Keith J. Miller Ginger Wu Chen-pin Hung Sarah Malmstrom Ge Zhang Eva O’Tanyi William J. Keim Mary Jane Cullen Kenneth W. Rohrbach Michael Thomas Thao Ung Qinling Qu Jinping Gan Rangaraj Narayanan Mary Ann Pelleymounter Jeffrey A. Robl 《Bioorganic & medicinal chemistry letters》2010,20(3):1128-1133
Agonists of the 5-HT2C receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT2B receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and highly selective dihydroquinazolinone-derived 5-HT2C agonists with no detectable agonism of the 5-HT2B receptor is described. Among these, compounds (+)-2a and (+)-3c were identified as potent and highly selective agonists which exhibited weight loss in a rat model upon oral dosing. 相似文献
974.
Chiao-Ting Yen Kyoko Nakagawa-Goto Tsong-Long Hwang Pei-Chi Wu Susan L. Morris-Natschke Wan-Chun Lai Kenneth F. Bastow Fang-Rong Chang Yang-Chang Wu Kuo-Hsiung Lee 《Bioorganic & medicinal chemistry letters》2010,20(3):1037-1039
The first total synthesis of the naturally occurring tetracyclic homoisoflavonoid brazilein (1) and 14 new analogs (1a–n) is reported. Target compounds and intermediates were assayed for anti-inflammatory effects on superoxide anion generation and elastase release by human neutrophils in response to fMLP/CB, and for cytotoxic activity against nasopharyngeal (KB), vincristine-resistant nasopharyngeal (KBvin), lung (A549) and prostate (DU-145) human cancer cell lines. The most active compound 1b showed potent effects on superoxide anion generation and elastase release with IC50 values of 1.2 and 1.9 μM, respectively, and was 65 times more potent than phenylmethylsulfonyl fluoride (PMSF), the positive control, in the latter assay. Additionally, 1b exhibited broad spectrum in vitro anticancer activity with IC50 values of 6–11 μM against the four tested cancer cell lines. 相似文献
975.
Haifeng Tang Yan Yan Zhe Feng Reynalda K. de Jesus Lihu Yang Dorothy A. Levorse Karen A. Owens Taro E. Akiyama Raynald Bergeron Gino A. Castriota Thomas W. Doebber Kenneth P. Ellsworth Michael E. Lassman Cai Li Margaret S. Wu Bei B. Zhang Kevin T. Chapman Sander G. Mills Joel P. Berger Alexander Pasternak 《Bioorganic & medicinal chemistry letters》2010,20(20):6088-6092
A new series of thiazole-substituted 1,1,1,3,3,3-hexafluoro-2-propanols were prepared and evaluated as malonyl-CoA decarboxylase (MCD) inhibitors. Key analogs caused dose-dependent decreases in food intake and body weight in obese mice. Acute treatment with these compounds also led to a drop in elevated blood glucose in a murine model of type II diabetes. 相似文献
976.
Feng V. Yang William D. Shipe Jaime L. Bunda M. Brad Nolt David D. Wisnoski Zhijian Zhao James C. Barrow William J. Ray Lei Ma Marion Wittmann Matthew A. Seager Kenneth A. Koeplinger George D. Hartman Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2010,20(2):531-536
An iterative analog library synthesis approach was employed in the exploration of a quinolone carboxylic acid series of selective M1 positive allosteric modulators, and strategies for improving potency and plasma free fraction were identified. 相似文献
977.
Xiang-Yang Ye Stephanie Chen Hao Zhang Kenneth T. Locke Kevin O’Malley Litao Zhang Raijit Srivastava Bowman Miao Daniel Meyers Hossain Monshizadegan Debra Search Denise Grimm Rongan Zhang Jonathan Lippy Celeste Twamley Jodi K. Muckelbauer Chiehying Chang Yongmi An Vinayak Hosagrahara Lisa Zhang Joseph A. Tino 《Bioorganic & medicinal chemistry letters》2010,20(9):2933-2937
The synthesis and follow-up SAR studies of our development candidate 1 by incorporating 2-aryl-4-oxazolylmethoxy and 2-aryl-4-thiazolylmethoxy moieties into the oxybenzylglycine framework of the PPARα/γ dual agonist muraglitazar is described. SAR studies indicate that different substituents on the aryloxazole/thiazole moieties as well as the choice of carbamate substituent on the glycine moiety can significantly modulate the selectivity of PPARα versus PPARγ. Potent, highly selective PPARα activators 2a and 2l, as well as PPARα activators with significant PPARγ activity, such as 2s, were identified. The in vivo pharmacology of these compounds in preclinical animal models as well as their ADME profiles are discussed. 相似文献
978.
Min Zhong Wang Shen Kenneth J. Barr Jennifer P. Arbitrario Michelle R. Arkin Minna Bui Teresa Chen Brian C. Cunningham Marc J. Evanchik Emily J. Hanan Ute Hoch Karen Huen Jennifer Hyde Jeffery L. Kumer Teresa Lac Chris E. Lawrence Jose R. Martell Johan D. Oslob Kumar Paulvannan Saileta Prabhu W. Mike Flanagan 《Bioorganic & medicinal chemistry letters》2010,20(17):5269-5273
This letter describes the discovery of a novel series of tetrahydroisoquinoline (THIQ)-derived small molecules that potently inhibit both human T-cell migration and super-antigen induced T-cell activation through disruption of the binding of integrin LFA-1 to its receptor, ICAM-1. In addition to excellent in vitro potency, 6q shows good pharmacokinetic properties and its ethyl ester (6t) demonstrates good oral bioavailability in both mouse and rat. Either intravenous administration of 6q or oral administration of its ethyl ester (6t) produced a significant reduction of neutrophil migration in a thioglycollate-induced murine peritonitis model. 相似文献
979.
Diversity and temporal stability of bacterial communities in a model passerine bird, the zebra finch
The composition and dynamics of the gastrointestinal bacterial communities in birds is determined by both host-specific and environmental exposure factors yet these are poorly understood. We selected the zebra finch, Taeniopygia guttata, as the host species to examine the diversity and temporal stability of the faecal microflora in a bird, owing to its importance as a model organism in avian ecology, neuroscience and evolution studies. The stability of the gut bacterial community of individual male and female zebra finches was assessed through repeat faecal sampling via culture and temperature gradient gel electrophoresis and partial sequencing of PCR-amplified eubacterial 16S rRNA gene products. Nineteen bacterial genera were detected across all samples (n = 99), with each bird carrying on average six operational taxonomic units. Using a novel statistical approach, we showed that bacterial assemblages and community richness varied between individual birds but remained stable over time within individuals. Neither the composition nor richness of bacterial communities differed significantly between the sexes. Our results show that zebra finches housed together under controlled conditions show consistent variation between individuals in their gut microflora that is not attributable to differences in host exposure to environmental microbial sources. Future studies could usefully explore the origin of this individual-specific variation and its consequences for host fitness and sexual selection. 相似文献
980.
Ari Jumpponen Karen Keating Gary Gadbury Kenneth L Jones J David Mattox 《Plant signaling & behavior》2010,5(9):1157-1161
Diverse fungal mutualists, pathogens and saprobes colonize plant leaves. These fungi face a complex environment, in which stochastic dispersal interplays with abiotic and biotic filters. However, identification of the specific factors that drive the community assembly seems unattainable. We mined two broad data sets and identified chemical elements, to which dominant molecular operational taxonomic units (OTUs) in the foliage of a native tree respond most extremely. While many associations could be identified, potential complicating issues emerged. Those were related to unevenly distributed OTU frequency data, a large number of potentially explanatory variables and the disproportionate effects of outlier observations.Key words: community assembly, environmental filter, fungi, heavy metal enrichment, nutrient enrichment, oak, Quercus macrocarpaHyperdiverse fungal communities inhabit the foliage of most plants1,2 and these fungal communities have been reported for virtually every plant that has been examined.3 Baas-Becking hypothesis states that environment selects microbial communities from the abundant and possibly globally distributed propagule pools.4 Although the foliage-associated communities—like other microbial communities—are suspected to be sensitive to environmental drivers, determination of the mechanisms that control the assembly of these foliar communities has remained difficult and elusive. Some of the proposed mechanisms include distance limitations to propagule dispersal,5–7 volume limitations to propagule loads,7 or limitations set by the environmental conditions either on the scale of the site of fungal colonization8 or more broadly on a landscape level.6,9 The forces that may control the fungal community assembly are overlaid by additional biotic controls that include compatibilities between the fungi and host species10,11 or genotypes6,12 and the competitive or facilitative interactions among the component fungal genotypes.6,10–13 Although a variety of potential controls for the foliage-associated fungal communities have been speculated, very little consensus exists on the relative importance of the different drivers. For example, while macronutrient and heavy metal enrichment may have an influence on the composition fungal communities14 and populations,15 relative importance of various chemical elements in the foliage remains yet to be investigated.To evaluate the use of multi-element fingerprinting data produced by Inductively Coupled Plasma Mass Spectrometry (ICP-MS) in combination with high throughput 454-pyrosequencing for determining influential chemical elements in structuring of the leaf-associated fungal communities, we mined a recent dataset16 that explored the effects of urbanization on the diversity and composition of the fungal communities associated with a native tree Quercus macrocarpa. From a total list of more than 700 non-singleton fungal OTUs, we selected fifty with highest overall frequency to provide an observationrich dataset for elemental effect assessment; these OTUs accounted for 84.5% of all sequences. Even so, many of these OTUs had a number of zero frequencies (Fig. 1), highlighting one of the difficulties in the use of environmental sequencing data. We omitted one OTU (OTU630 with a likely affinity to Trimmatostroma cordae [Mycosphaerellaceae]) that was strongly affected by the original land use design (urbanization; Wilcoxon rank sum test with a Bonferroni adjustment) and therefore unlikely to be representative for the present analyses of elemental drivers. This OTU was replaced with one with the next highest frequency. The frequencies of these 50 OTUs were investigated in the context of concentrations for 29 elements after the omission of five (Ag, Au, C, δ13C, δ15N) in the final analyses because of their strong association with the land use or the difficulty of finding a biological relevance. Of the remaining elements three (Fe, Cr and Ni) had pairwise correlations exceeding 0.98 between the three pairings; others showed no similar high correlations. To allow comparable evaluation across the broad array of elements, all concentrations were standardized to have a mean equal to zero and a standard deviation equal to one.Open in a separate windowFigure 1Rank-ordered distribution of observed frequencies for those OTU s whose frequency had an extreme slope when associated with the concentrations of one or more chemical elements in the mixed effects model. The asterisk denotes one extreme frequency for OTU 313 with a value 0.8636. Numbers in parentheses indicate the number of observations with a frequency equal to zero. The OTU s were assigned to approximate taxa using BLAST:20 425: Alternaria alternata (Pleosporaceae); 46: Phoma glomerata (Pleosporaceae); 686: Aureobasidium pullulans (Dothioraceae); 520: Davidiella tassiana (Davidiellaceae); 567: Cladosporioum tenuissimum (Davidiellaceae); 313 Oidium heveae (mitosporic Erysiphaceae); 586: Erysiphe hypogena (Erysiphaceae); 671: Mycosphaerella microsora (Mycosphaerellaceae); 555: Pestalotiopsis sp. (Amphisphaeriaceae); 607: Pleiochaeta setosa (incertae sedis).To rank elements according to their magnitude of association with the abundance of each OTU, a total of 1,450 models (50 OTUs times 29 elements) relating element concentration to OTU abundance were fit to the data. For each model, OTU frequency was the dependent variable, element concentration and time (a factor with three levels) were fixed effects, and—to account for the spatial arrangement of the experimental units—random effects associated with tree nested within site were included in the error structure. Time by element interactions were also investigated and tested using a likelihood ratio test. These mixed effect models were fit using R and the package lme4 (www.rproject.org).Statistical “tests of significance” that produce p-values can be sensitive to assumptions or outliers. Because of this and the fact that our analyses evaluated a total of 1,450 models, p-values themselves were not considered a reliable measure of importance when associating elements with OTU frequency. Instead, we emphasized metrics that highlight extraordinary findings rather than rely on tests of statistical significance. This approach facilitates finding few elements that have the strongest effect on OTU frequency. Note that the use of standardized element concentrations (above) provided slope coefficients that are comparable across all models. “Extreme slopes”, i.e., models where the OTU response to element concentration was strongest, were identified as those with estimated slope coefficients in the lower or upper 2.5 percentile, i.e., those farther than 1.8 standard deviations from the mean across all estimated slopes (Fig. 2). Using this approach, we identified a total of 69 models with extreme slopes (Open in a separate windowFigure 2Distribution of estimated slopes (i.e., the slope for element concentration) for a model relating OTU frequency to element concentration, time and a concentration by time interaction, including a tree-nested-within-site random effect. The mean across all 1,450 OTU s is approximately zero; the two vertical lines identify upper and lower 2.5 percentiles, beyond which the slopes were considered extreme (large black symbols). The horizontal line identifies the cut off maximum leverage (0.24), above which the slopes were considered to have observations with high leverage. Models with observations with a high leverage were tested for extreme slopes by refitting without those observations. Models are ranked from bottom to top in order of increasing leverage and the element for which the high-leverage observations and extreme slopes were recorded are identified on the right y-axis.
Open in a separate windowPositive slopes are indicated by +, negative by −. Parentheses indicate where a statistically significant (α = 0.05) interaction was observed (likelihood ratio test). Extreme slopes with observations with high leverage are identified by an asterisk (*) and those where omission of high-leverage observations lead to a non-extreme slopes are identified by two asterisks (**). Note that eight of the ten OTU s in the table had an extreme slope with at least one element concentration after accounting for high leverage and interactions in the model.Unfortunately, the models with extreme slopes were often affected by high leverage observations (outliers in the explanatory variables) that may have exerted substantial influence on the magnitudes of the slopes. We accounted for this by computing leverage values based on the fixed effect model matrix (element concentration and time) for each model. High leverage was defined as those observations with leverage approximately twice the mean leverage over all samples for a particular model as is considered conventional by some authors.17 This value was approximately 0.24 for our models. The models with high leverage and extreme slopes were re-evaluated by refitting the model to the data after omission of the influential observations. Of the 69 models with extreme slopes only 22 were void of influential observations by our metric (Fig. 1). Our analyses included the possibility of identifying those models that were affected by numerous low frequencies and a few high frequency observations. We argue that the few higher frequencies are most likely indicative of those elements that also have extreme concentrations in the same samples; we did not want to miss such findings. Second, no one element controls the occurrence of all or even majority, of the OTUs, but the OTUs appear to respond positively or negatively to different drivers. This is strongly visible even among the eight that remained through our rigorous evaluation of a vast number of models. This can be interpreted in the context of a niche. Foliage represents a complex abiotic physicochemical habitat within which organisms are sorted based by stochastic arrival parameters, but also by either environmental tolerances or nutritional preferences. Those fungi best able to colonize and invade the available substrate under any given combination of the complex physical and chemical environmental matrix will persist and be detected most frequently. Thirdly, even for one OTU, many elements may have strong and occasionally opposing effects. For example, for OTU425, B, Cd, Ce, Cu, Na, had positive effects, whereas N, P, Sc had negative effects (18,19 it is tempting to speculate on species replacement or on tolerance to nutrient enrichment as a result of changes in the abiotic chemical environment. However, one must exercise caution: as we point out above, a number of other alternative factors come to play when a correlative relationship like this is considered across two discrete and complex datasets. Several heavy metal concentrations also showed either positive or negative associations with the fungal OTU frequencies. To exemplify, the frequencies of OTUs 313 and 425 were positively associated with the concentrations of Cd and OTU 46 was positively associated with Zn, whereas OTUs 313 and 586 were negatively associated Hg and Pb concentrations, respectively. Does this mean that these species differ in their sensitivities to these particular heavy metals? Not necessarily, but these observational data provide a starting point for more explicit hypothesis-driven experiments that allow for specific elucidation of the fungal responses to these elements and may guide future experimentation.We conducted a high-dimensional exploratory analysis to evaluate potential effects of element concentration on OTU frequencies. Using a repeated measures mixed effects model, we were able to compile a brief list of chemical elements with the most likely (based on these data) strongest effects on the abundances of the dominant components of the phyllosphere-associated fungal communities. Complicating the use of usual methods of statistical inference (i.e., use of p-values) was the sparseness in the occurrence of many OTUs across samples and outlying observations in the concentration of some elements. We chose the extreme slopes approach that allowed ranking associations between OTU frequency and element concentration with no assumptions regarding normality or equivariance that may be violated using traditional tools of inference (e.g., Analysis of Variance). Still, some of the observed associations may have been affected by extreme leverage points (outliers in the explanatory variables) and these were accounted for in the present analyses by model re-evaluation after omission of the high-leverage observations. While our analyses identified a number of biologically meaningful associations between chemical elements and molecular OTUs, rigorous experimentation is mandatory to establish causative relationships. 相似文献
Table 1
Slopes identified as extreme in our analysesElement | OTU 425 | OTU 46 | OTU 686 | OTU 520 | OTU 567 | OTU 313 | OTU 586 | OTU 671 | OTU 555 | OTU 607 |
B | +* | +* | +* | |||||||
Ba | − | − | ||||||||
Ca | −* | (−)* | −* | (+)* | +** | |||||
Cd | + | + | (+) | |||||||
Ce | + | (+) | − | |||||||
Co | +** | −* | ||||||||
Cr | −* | |||||||||
Cu | +* | −** | −* | |||||||
Fe | −* | |||||||||
Hg | +** | −* | ||||||||
K | (−) | + | − | + | (−) | (+) | ||||
Li | (+)* | (+)* | −* | |||||||
Mn | +* | |||||||||
Mo | −* | |||||||||
N | −* | +* | (+)* | |||||||
Na | + | |||||||||
Ni | −* | |||||||||
P | −* | (+)* | ||||||||
Pb | +** | −* | ||||||||
Rb | +** | +* | −* | −* | ||||||
S | (−)* | +* | +* | +* | ||||||
Sc | − | (−) | − | |||||||
Se | − | |||||||||
Sn | − | − | (−) | |||||||
Sr | +* | |||||||||
Y | +* | −* | +* | (+)* | ||||||
Zn | (−)* | +* | −** | (+)* |