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排序方式: 共有236条查询结果,搜索用时 31 毫秒
141.
Hing L. Sham Herman Stein Cheryl A. Rempel Jerome Cohen Jacob J. Plattner 《FEBS letters》1987,220(2):299-301
We have designed and synthesized a series of small peptides containing a perfluoroalkyl ketone group at the C-terminal position of the angiotensin I sequence as inhibitors of human renin. From this series of compounds, 8 and 10 showed strong inhibition of human renin (IC50 = 3 × 10−9, 7 × 10−9 M, respectively). Compound 10 did not inhibit pepsin and cathepsin D at 10−4 M. Comparison of the IC50 of compound 8 and compound 11 (8.7 × 10−7 M) demonstrated the marked effect of the perfluoropropyl group on the potency of inhibition on renin, presumably due to the strong electron-withdrawing effect causing the ketone in 8 to exist predominantly as the hydrate — thus mimicking the tetrahedral transition state during hydrolysis of the scissile Leu10—Val11 amide bond. 相似文献
142.
AIMS: To study the effect of smoking, passive smoking, alcohol drinking, and occupational exposure to low level of benzene on DNA strand breaks in elevator manufacturing workers in Guangzhou, China. METHODS: Three hundred and fifty-nine workers (252 men and 107 women) of a modern elevator manufacturing factory, 205 were from production departments and 154 from managerial department. Information on the workers' health conditions, smoking, passive smoking, alcohol consumption and occupational exposure history was collected by personal interview. Lymphocyte DNA damage was measured by the Comet assay. RESULTS: None of the women smoked and 20.6% of the men were daily smokers. In non-smokers, the prevalence of passive smoking at work was 25% for men and 11.2% for women, and at home, 37.8 and 48.6%, respectively. Smoking significantly increased tail moment (P<0.001). Daily smokers had the largest tail moment (geometric mean, 95% CI) (0.93 microm (0.81-0.94)), followed by occasional smokers (0.76 microm (0.59-0.95)), ex-smokers (0.70 microm (0.58-0.85)), and never smokers (0.56 microm (0.53-0.60)). Tail moment increased significantly with daily tobacco consumption (cigarettes per day) (r=0.26, P<0.001) after adjusting for age, gender, occupational exposure, passive smoking, and drinking. Analysis of covariance (ANCOVA) showed that smoking (P<0.001), passive smoking at home (P=0.026), occupational exposure (P<0.001), male gender (P<0.001), and age (P=0.001) had independent effects on tail moment, whereas passive smoking at work and alcohol drinking had no significant effect. CONCLUSIONS: Smoking, passive smoking at home, male gender, age and occupational exposure independently increased lymphocyte DNA strand breaks. The presence of excess DNA damage under low level of occupational exposure to benzene or other solvents suggest that the current allowance concentrations may not be safe to prevent genotoxicity. 相似文献
143.
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
144.
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
145.
Wnt proteins are secreted proteins involved in a number of developmental processes including neural development and synaptogenesis. We sought to determine the role of the Drosophila Wnt7b ortholog, Wnt2, using the neuromuscular junction (NMJ). Mutations in wnt2 produce an increase in the number of presynaptic branches and a reduction in immunolabeling of the active zone proteins, Bruchpilot and synaptobrevin, at the NMJ. There was no change, however, in immunolabeling for the presynaptic proteins cysteine-string protein (CSP) and synaptotagmin, nor the postsynaptic proteins GluRIIA and DLG at the NMJ. Consistent with the presynaptic defects, wnt2 mutants exhibit approximately a 50% reduction in evoked excitatory junctional currents. Rescue, RNAi, and tissue-specific qRT-PCR experiments indicate that Wnt2 is expressed by the postsynaptic cell where it may serve as a retrograde signal that regulates presynaptic morphology and the localization of presynaptic proteins. 相似文献
146.
Ang LH Chen W Yao Y Ozawa R Tao E Yonekura J Uemura T Keshishian H Hing H 《Developmental biology》2006,293(1):178-190
Lim Kinase (Limk) belongs to a phylogenetically conserved family of serine/threonine kinases, which have been shown to be potent regulators of the actin cytoskeleton. Despite accumulating evidence of its biochemical actions, its in vivo function has remained poorly understood. The association of the Limk1 gene with Williams Syndrome indicates that proteins of this family play a role in the nervous system. To unravel the cellular and molecular functions of Limk, we have either knocked out or activated the Limk gene in Drosophila. At the neuromuscular junction, loss of Limk leads to enlarged terminals, while increasing the activity of Limk leads to stunted terminals with fewer synaptic boutons. In the antennal lobe, loss of Limk abolishes the ability of p21-activated kinase (Pak) to alter glomerular development. In contrast, increase in Limk function leads to ectopic glomeruli, a phenotype suppressible by the coexpression of a hyperactive Cofilin gene. These results establish Limk as a critical regulator of Cofilin function and synapse development, and a downstream effector of Pak in vivo. 相似文献
147.
Yeh VS Kurukulasuriya R Madar D Patel JR Fung S Monzon K Chiou W Wang J Jacobson P Sham HL Link JT 《Bioorganic & medicinal chemistry letters》2006,16(20):5408-5413
A series of structurally novel and metabolically stable bridged bicyclic carbocycle and heterocycle adamantane replacements have been synthesized and biologically evaluated. Several of these compounds exhibit excellent human and mouse 11beta-HSD1 potency and 11beta-HSD2 selectivity. 相似文献
148.
Li G Hasvold LA Tao ZF Wang GT Gwaltney SL Patel J Kovar P Credo RB Chen Z Zhang H Park C Sham HL Sowin T Rosenberg SH Lin NH 《Bioorganic & medicinal chemistry letters》2006,16(8):2293-2298
Based on the X-ray crystallography of our lead compound 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-cyanopyrazin-2-yl)urea in the checkpoint kinase 1 (Chk1) enzyme, we modified R4, and to a lesser extent, R2, and R5 of the phenyl ring, and made a variety of N-aryl-N'-pyrazinylurea Chk1 inhibitors. Enzymatic activity less than 20 nM was observed in 15 of 41 compounds. Compound 8i provided the best overall results in the cellular assays as it abrogated doxorubicin-induced cell cycle arrest (IC50=1.7 microM) and enhanced doxorubicin cytotoxicity (IC50=0.44 microM) while displaying no single agent activity. 相似文献
149.
150.
Mark J. Rieder Glenn E. Green Sarah S. Park Brendan D. Stamper Christopher T. Gordon Jason M. Johnson Christopher M. Cunniff Joshua D. Smith Sarah B. Emery Stanislas Lyonnet Jeanne Amiel Muriel Holder Andrew A. Heggie Michael J. Bamshad Deborah A. Nickerson Timothy C. Cox Anne V. Hing Jeremy A. Horst Michael L. Cunningham 《American journal of human genetics》2012,90(6):1116-1117