排序方式: 共有40条查询结果,搜索用时 390 毫秒
21.
Gary D. Probst Simeon Bowers Jennifer M. Sealy Brian Stupi Darren Dressen Barbara M. Jagodzinska Jose Aquino Andrea Gailunas Anh P. Truong Luke Tso Ying-Zi Xu Roy K. Hom Varghese John Jay S. Tung Michael A. Pleiss John A. Tucker Andrei W. Konradi Hing L. Sham Jacek Jagodzinski Gergely Toth John-Michael Sauer 《Bioorganic & medicinal chemistry letters》2010,20(20):6034-6039
The structure–activity relationship of the prime region of hydroxyethylamine BACE inhibitors is described. Variation in the aryl linker region with 5- and 6-membered heterocycles provided compounds such as 33 with improved permeability and reduced P-gp liability compared to benzyl amine analog 1. 相似文献
22.
Xiaocong M. Ye Andrei W. Konradi Jenifer Smith Ying-Zi Xu Darren Dressen Albert W. Garofalo Jennifer Marugg Hing L. Sham Anh P. Truong Jacek Jagodzinski Michael Pleiss Hongbin Zhang Erich Goldbach John-Michael Sauer Elizabeth Brigham Michael Bova Guriqbal S. Basi 《Bioorganic & medicinal chemistry letters》2010,20(7):2195-2199
Discovery of a series of pyrazolopiperidine sulfonamide based γ-secretase inhibitors and its SAR evolution is described. Significant increases in APP potency on the pyrazolopiperidine scaffold over the original N-bicyclic sulfonamide scaffold were achieved and this potency increase translated in an improved in vivo efficacy. 相似文献
23.
Xiaocong M. Ye Andrei W. Konradi Minghua Sun Shendong Yuan Danielle L. Aubele Michael Dappen Darren Dressen Albert W. Garofalo Jacek J. Jagodzinski Lee Latimer Gary D. Probst Hing L. Sham David Wone Ying-zi Xu Daniel Ness Elizabeth Brigham Grace T. Kwong Chris Willtis Guriqbal S. Basi 《Bioorganic & medicinal chemistry letters》2013,23(4):996-1000
Structure–activity relationship (SAR) of a novel, potent and metabolically stable series of benzo [3.2.1] bicyclic sulfonamide-pyrazoles as γ-secretase inhibitors are described. Compounds that are efficacious in reducing the cortical Aβx-40 levels in FVB mice via oral dose, as well as those with high selectivity over Notch, are highlighted. 相似文献
24.
Aubele DL Truong AP Dressen DB Probst GD Bowers S Mattson MN Semko CM Sun M Garofalo AW Konradi AW Sham HL Zmolek W Wong K Goldbach E Quinn KP Sauer JM Brigham EF Wallace W Nguyen L Bova MP Hemphill SS Basi G 《Bioorganic & medicinal chemistry letters》2011,21(19):5791-5794
The structure-activity relationship (SAR) of a novel, potent and metabolically stable series of sulfonamide-pyrazoles that attenuate β-amyloid peptide synthesis via γ-secretase inhibition is detailed herein. Sulfonamide-pyrazoles that are efficacious in reducing the cortical Aβx-40 levels in FVB mice via a single PO dose, as well as sulfonamide-pyrazoles that exhibit selectivity for inhibition of APP versus Notch processing by γ-secretase, are highlighted. 相似文献
25.
Jennifer M. Sealy Anh P. Truong Luke Tso Gary D. Probst Jose Aquino Roy K. Hom Barbara M. Jagodzinska Darren Dressen David W.G. Wone Louis Brogley Varghese John Jay S. Tung Michael A. Pleiss John A. Tucker Andrei W. Konradi Michael S. Dappen Gergely Toth Hu Pan Lany Ruslim Jim Miller Michael P. Bova Sukanto Sinha Kevin P. Quinn John-Michael Sauer 《Bioorganic & medicinal chemistry letters》2009,19(22):6386-6391
Using structure-guided design, hydroxyethylamine BACE-1 inhibitors were optimized to nanomolar Aβ cellular inhibition with selectivity against cathepsin-D. X-ray crystallography illuminated the S1′ residues critical to this effort, which culminated in compounds 56 and 57 that exhibited potency and selectivity but poor permeability and high P-gp efflux. 相似文献
26.
27.
TL Kieft EM Murphy DL Haldeman PS Amy BN Bjornstad EV McDonald DB Ringelberg DC White J Stair RP Griffiths TC Gsell WE Holben DR Boone 《Microbial ecology》1998,36(3):336-348
Abstract Two chronosequences of unsaturated, buried loess sediments, ranging in age from <10,000 years to >1 million years, were investigated to reconstruct patterns of microbial ecological succession that have occurred since sediment burial. The relative importance of microbial transport and survival to succession was inferred from sediment ages, porewater ages, patterns of abundance (measured by direct counts, counts of culturable cells, and total phospholipid fatty acids), activities (measured by radiotracer and enzyme assays), and community composition (measured by phospholipid fatty acid patterns and Biolog substrate usage). Core samples were collected at two sites 40 km apart in the Palouse region of eastern Washington State, near the towns of Washtucna and Winona. The Washtucna site was flooded multiple times during the Pleistocene by glacial outburst floods; the Winona site elevation is above flood stage. Sediments at the Washtucna site were collected from near surface to 14.9 m depth, where the sediment age was approximately 250 ka and the porewater age was 3700 years; sample intervals at the Winona site ranged from near surface to 38 m (sediment age: approximately 1 Ma; porewater age: 1200 years). Microbial abundance and activities declined with depth at both sites; however, even the deepest, oldest sediments showed evidence of viable microorganisms. Same-age sediments had equal quantities of microorganisms, but different community types. Differences in community makeup between the two sites can be attributed to differences in groundwater recharge and paleoflooding. Estimates of the microbial community age can be constrained by porewater and sediment ages. In the shallower sediments (<9 m at Washtucna, <12 m at Winona), the microbial communities are likely similar in age to the groundwater; thus, microbial succession has been influenced by recent transport of microorganisms from the surface. In the deeper sediments, the populations may be considerably older than the porewater ages, since microbial transport is severely restricted in unsaturated sediments. This is particularly true at the Winona site, which was never flooded. 相似文献
28.
Molecular characterization of transketolase (EC 2.2.1.1) active in the Calvin cycle of spinach chloroplasts 总被引:5,自引:0,他引:5
Anke Flechner Uta Dressen Peter Westhoff Katrin Henze Claus Schnarrenberger William Martin 《Plant molecular biology》1996,32(3):475-484
A cDNA encoding the Calvin cycle enzyme transketolase (TKL; EC 2.2.1.1) was isolated from Sorghum bicolor via subtractive differential hybridization, and used to isolate several full-length cDNA clones for this enzyme from spinach. Functional identity of the encoded mature subunit was shown by an 8.6-fold increase of TKL activity upon induction of Escherichia coli cells that overexpress the spinach TKL subunit under the control of the bacteriophage T7 promoter. Chloroplast localization of the cloned enzyme is shown by processing of the in vitro synthesized precursor upon uptake by isolated chloroplasts. Southern blot-analysis suggests that TKL is encoded by a single gene in the spinach genome. TKL proteins of both higher-plant chloroplasts and the cytosol of non-photosynthetic eukaryotes are found to be unexpectedly similar to eubacterial homologues, suggesting a possible eubacterial origin of these nuclear genes. Chloroplast TKL is the last of the demonstrably chloroplast-localized Calvin cycle enzymes to have been cloned and thus completes the isolation of gene probes for all enzymes of the pathway in higher plants.Abbreviations RPE
ribulose-5-phosphate 3-epimerase
- RPI
ribose-5-phosphate isomerase
- TKL
transketolase
- GAPDH
glyceraldehyde-3-phosphate dehydrogenase
- PGK
phosphoglycerate kinase
- FBP
fructose-1,6-bisphosphatase
- SBP
sedoheptulose-1,7-bisphosphatase
- OPPP
oxidative pentose phosphate pathway
- Rubisco, ribulose
1,5-bisphosphate carboxylase/oxygenase
- FBA
fructose-1,6-bisphosphate aldolase
- IPTG
isopropyl -d-thiogalactoside
- TPI
triosephosphate isomerase 相似文献
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30.
A comparison of two methods for constructing evolutionary distances from a weighted contribution of transition and transversion differences 总被引:3,自引:3,他引:0
Since the initial work of Jukes and Cantor (1969), a number of procedures
have been developed to estimate the expected number of nucleotide
substitutions corresponding to a given observed level of nucleotide
differentiation assuming particular evolutionary models. Unlike the
proportion of different sites, the expected number of substitutions that
would have occurred grows linearly with time and therefore has had great
appeal as an evolutionary distance. Recently, however, a number of authors
have tried to develop improved statistical approaches for generating and
evaluating evolutionary distances (Schoniger and von Haeseler 1993;
Goldstein and Polock 1994; Tajima and Takezaki 1994). These studies clearly
show that the estimated number of nucleotide substitutions is generally not
the best estimator for use in reconstruction of phylogenetic relationships.
The reason for this is that there is often a large error associated with
the estimation of this number. Therefore, even though its expectation is
correct (i.e., on average the expected number of substitutions is
proportional to time- -but see Tajima 1993), it is not expected to be as
useful as estimators designed to have a lower variance.
相似文献