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911.
Xuan Yi Akihiro Yamazaki Eulandria Biddle Quan Zeng Ching‐Hong Yang 《Molecular microbiology》2010,77(3):787-800
Cyclic diguanylate (c‐di‐GMP) is a second messenger implicated in the regulation of various cellular properties in several bacterial species. However, its function in phytopathogenic bacteria is not yet understood. In this study we investigated a panel of GGDEF/EAL domain proteins which have the potential to regulate c‐di‐GMP levels in the phytopathogen Dickeya dadantii 3937. Two proteins, EcpB (contains GGDEF and EAL domains) and EcpC (contains an EAL domain) were shown to regulate multiple cellular behaviours and virulence gene expression. Deletion of ecpB and/or ecpC enhanced biofilm formation but repressed swimming/swarming motility. In addition, the ecpB and ecpC mutants displayed a significant reduction in pectate lyase production, a virulence factor of this bacterium. Gene expression analysis showed that deletion of ecpB and ecpC significantly reduced expression of the type III secretion system (T3SS) and its virulence effector proteins. Expression of the T3SS genes is regulated by HrpL and possibly RpoN, two alternative sigma factors. In vitro biochemical assays showed that EcpC has phosphodiesterase activity to hydrolyse c‐di‐GMP into linear pGpG. Most of the enterobacterial pathogens encode at least one T3SS, a major virulence factor which functions to subvert host defences. The current study broadens our understanding of the interplay between c‐di‐GMP, RpoN and T3SS and the potential role of c‐di‐GMP in T3SS regulation among a wide range of bacterial pathogens. 相似文献
912.
Kevin K.-C. Liu Bruce A. Lefker Mark A. Dombroski Phoebe Chiang Peter Cornelius Terrell A. Patterson Yuan Zeng Stephanie Santucci Elizabeth Tomlinson Colleen P. Gibbons Ravi Marala Janice A. Brown Jimmy X. Kong Eunsun Lee Wendy Werner Zane Wenzel Craig Giragossian Hou Chen Steven B. Coffey 《Bioorganic & medicinal chemistry letters》2010,20(7):2365-2369
Brain-penetrable proline amides were developed as 5HT2c agonists with more than 1000-fold binding selectivity against 5HT2b receptor. After medicinal chemistry optimization and SAR studies, orally active proline amides with robust efficacy in a rodent food intake inhibition model were uncovered. 相似文献
913.
Kevin K.-C. Liu Peter Cornelius Terrell A. Patterson Yuan Zeng Stephanie Santucci Elizabeth Tomlinson Colleen Gibbons Tristan S. Maurer Ravi Marala Janice Brown Jimmy X. Kong Eunsun Lee Wendy Werner Zane Wenzel Chandra Vage 《Bioorganic & medicinal chemistry letters》2010,20(1):266-271
Based on our original pyrazine hit, CP-0809101, novel conformationally-restricted 5HT2c receptor agonists with 2-piperazin-azaindane scaffold were designed. Synthesis and structure–activity relationship (SAR) studies are described with emphasis on optimization of the selectivity against 5HT2a and 5HT2b receptors with excellent 2c potency. Orally-active and selective compounds were identified with dose–responsive in vivo efficacy in our pre-clinical food intake model. 相似文献
914.
Lin He Fan He Huichang Bi Jiankang Li Su Zeng Hai-Bin Luo Min Huang 《Bioorganic & medicinal chemistry letters》2010,20(20):6008-6012
Our kinetics studies demonstrated that the nature product chrysin exhibited a high inhibitory affinity of 54 nM towards human cytochrome P450 1A2 and was comparable to α-naphthoflavone (49 nM), whereas it represented a moderate affinity of 5225 nM against human cytochrome P450 2C9. However, it remains unclear how this inhibitor selectively binds 1A2. To better understand the isoform selectivity of chrysin, molecular docking and molecular dynamics simulations were performed. Chrysin formed a strong H-bond with Asp313 of 1A2. The stacking interactions with Phe226 also contributed to its tight binding to 1A2. The larger and much more open active site architectures of 2C9 may explain the weaker inhibitory affinity of chrysin towards 2C9. The predicted binding free energies suggest that chrysin preferred 1A2 (ΔGbind, pred = ?23.11 kcal/mol) to 2C9 (?20.41 kcal/mol). Additionally, the present work revealed that 7-hydroxy-flavone bound to 1A2 in a similar pattern as chrysin and represented a slightly less negative predicted binding free energy, which was further validated by our kinetics analysis (IC50 = 240 nM). Results of the study can provide insight for designing novel isoform-selective 1A2 inhibitors. 相似文献
915.
Jacob A. Kaizerman Wade Aaron Songzhu An Richard Austin Matt Brown Angela Chong Tom Huang Randall Hungate Ben Jiang Michael G. Johnson Gary Lee Brian S. Lucas Jessica Orf Minqing Rong Maria M. Toteva Dineli Wickramasinghe Guifen Xu Qiuping Ye Wendy Zhong Dustin L. McMinn 《Bioorganic & medicinal chemistry letters》2010,20(15):4607-4610
Pyridopyridazine antagonists of the hedgehog signaling pathway are described. Designed to optimize our previously described phthalazine smoothened antagonists, a representative compound eliminates a PXR liability while retaining potency and in vitro metabolic stability. Moreover, the compound has improved efficacy in a hedgehog/smoothened signaling mouse pharmacodynamic model. 相似文献
916.
Xiu-Xiu Zeng Ren-Lin Zheng Tian Zhou Hai-Yun He Ji-Yan Liu Yu Zheng Ai-Ping Tong Ming-Li Xiang Xiang-Rong Song Sheng-Yong Yang Luo-Ting Yu Yu-Quan Wei Ying-Lan Zhao Li Yang 《Bioorganic & medicinal chemistry letters》2010,20(21):6282-6285
Novel thienopyridine derivatives 1b–1r were synthesized, based on a hit compound 1a that was found in a previous cell-based screening of anticancer drugs. Compounds 1a–1r have the following features: (1) their anticancer activity in vitro was first reported by our group. (2) The most potent analog 1g possesses hepatocellular carcinoma (HCC)-specific anticancer activity. It can specifically inhibit the proliferation of the human hepatoma HepG2 cells with an IC50 value of 0.016 μM (compared with doxorubicin as a positive control, whose IC50 was 0.37 μM). It is inactive toward a panel of five different types of human cancer cell lines. (3) Compound 1g remarkably induces G0/G1 arrest and apoptosis in HepG2 cells in vitro at low micromolar concentrations. These results, especially the HCC-specific anticancer activity of 1g, suggest their potential in targeted chemotherapy for HCC. 相似文献
917.
918.
Qingping Zeng John G. Allen Matthew P. Bourbeau Xianghong Wang Guomin Yao Seifu Tadesse James T. Rider Chester C. Yuan Fang-Tsao Hong Matthew R. Lee Shiwen Zhang Julie A. Lofgren Daniel J. Freeman Suijin Yang Chun Li Elizabeth Tominey Xin Huang Douglas Hoffman Harvey K. Yamane Christopher Fotsch Xiaoling Zhang 《Bioorganic & medicinal chemistry letters》2010,20(5):1559-1564
Through a combination of screening and structure-based rational design, we have discovered a series of N1-(5-(heterocyclyl)-thiazol-2-yl)-3-(4-trifluoromethylphenyl)-1,2-propanediamines that were developed into potent ATP competitive inhibitors of AKT. Studies of linker strand-binding adenine isosteres identified SAR trends in potency and selectivity that were consistent with binding interactions observed in structures of the inhibitors bound to AKT1 and to the counter-screening target PKA. One compound was shown to have acceptable pharmacokinetic properties and to be a potent inhibitor of AKT signaling and of in vivo xenograft tumor growth in a preclinical model of glioblastoma. 相似文献
919.
Maomao Zeng Yang Xiao Yizeng Liang Bing Wang Xian Chen Dongsheng Cao Hongdong Li Mei Wang Zhiguang Zhou 《Metabolomics : Official journal of the Metabolomic Society》2010,6(2):303-311
In this paper, a new strategy for processing GC/MS based metabolic profiling data via multivariate methods was proposed, which
is applied to a small pilot study of impaired fasting glucose. The data obtained from plasma samples of impaired fasting glucose
patients and healthy controls were first treated by principal component analysis and partial least squares-discriminant analysis
to explore the differences and discriminators of the two groups. Subsequently, correlation analyses were employed to examine
the relationships between blood glucose and the discriminators or their linear combination, thus may be considered as potential
biomarkers of impaired fasting glucose. The results showed that the metabolic patterns of the two groups were different. Furthermore,
eleven metabolites were screened as discriminators. Levels of nine of the eleven discriminators, say lactate, 2-ketoisocaproic
acid, alanine, α-hydroxyisobutyric acid, urea, phosphoric acid, α-glycerophosphoric acid, palmitic acid and stearic acid,
were found to be significantly higher in impaired fasting glucose patients, while 1-monopalmitin and 1-monostearin showed
the opposite trend. Correlation analysis indicated that 2-ketoisocaproic acid, stearic acid were positively, while 1-monopalmitin
and 1-monostearin were negatively correlated with blood glucose. Moreover, blood glucose correlated well with the linear combination
of the eleven discriminators by canonical correlation analysis. The results have demonstrated that 2-ketoisocaproic acid,
stearic acid and the linear combination of the eleven discriminators may be considered as the potential biomarkers of impaired
fasting glucose and the proposed method may be useful in a larger study for exploring the metabolic alterations and biomarker
candidates of diseases. 相似文献
920.
Yun‐Jun Liu Cheng‐Hui Zeng Jun‐Hua Yao Fu‐Hai Wu Li‐Xin He Hong‐Liang Huang 《化学与生物多样性》2010,7(7):1770-1783
Many ruthenium(II) complexes show high antitumor activities, and the in vitro antitumor activities are usually related to DNA binding. We designed and synthesized two RuII polypyridyl complexes, [Ru(dmp)2(fpp)]2+ (dmp=2,9‐dimethyl‐1,10‐phenanthroline; fpp=2‐[3,4‐(difluoromethylenedioxy)phenyl]imidazo[4,5‐f] [1,10]phenanthroline and [Ru(phen)2(fpp)]2+ (phen=1,10‐phenanthroline). The DNA‐binding properties of these complexes have been investigated by spectroscopic titration, DNA melting experiments, viscosity measurements, and photoactivated cleavage. The mechanism studies of photocleavage revealed that singlet oxygen (1O2) and superoxide anion radical (O$\rm{{_{2}^{{^\cdot} -}}}$ ) may play an important role in the photocleavage. The cytotoxicity of complexes 1 and 2 have been evaluated by MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl‐2H‐tetrazolium bromide) method; complex 2 shows slightly higher anticancer potency than 1 does against all the cell lines screened. 相似文献