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81.
82.
Cowart M Pratt JK Stewart AO Bennani YL Esbenshade TA Hancock AA 《Bioorganic & medicinal chemistry letters》2004,14(3):689-693
2-aminoethylbenzofurans constitute a new class of H(3) antagonists that are more rotationally constrained than most previously reported H(3) antagonists. They retain high potency at human and rat receptors, with efficient CNS penetration observed in 35. The SAR of the basic amine moiety was compared in three different series of analogues. The greatest potency was found in analogues bearing a 2-methylpyrrolidine, a 2,5-dimethylpyrrolidine, or a 2,6-dimethylpiperidine. 相似文献
83.
A new role of apolipophorin III (apoLp-III) as an immune activator has emerged recently. To gain insight into this novel function, the interaction of apoLp-III with lipopoly-saccharide (LPS) was investigated. ApoLp-III from Galleria mellonella was incubated with LPS from Escherichia coli O55:B5, and analyzed by non-denaturing polyacrylamide gel electrophoresis (PAGE). Protein staining showed that apoLp-III mobility was significantly reduced. In addition, silver and LPS fluorescent staining demonstrated that LPS mobility was increased upon incubation with apoLp-III. This result suggests association of apoLp-III with LPS. Sodium dodecyl sulfate (SDS) PAGE analysis showed decreased apoLp-III mobility upon LPS addition, indicative of LPS apoLp-III interaction in the presence of SDS. The unique tyrosine residue that resides in apoLp-III was used to provide additional evidence for LPS binding interaction. In the absence of LPS, apoLp-III tyrosine fluorescence was relatively low. However, LPS addition resulted in a progressive increase in the fluorescence intensity, indicating tertiary rearrangement in the environment of tyrosine 142 upon LPS interaction. Other well-characterized apoLp-IIIs were also examined for LPS binding. Manduca sexta , Bombyx mori and Locusta migratoria apoLp-III were all able to interact with LPS. The ability of apoLp-III to form complexes with LPS supports the proposed role of apoLp-III in innate immunity. 相似文献
84.
The class C beta-lactamase of Enterobacter cloacae P99 is known to catalyze the hydrolysis of certain acyclic (thio)esters. Previous experiments have employed thioglycolate, m-hydroxybenzoate, and phenylphosphate leaving groups. The relative effectiveness of these leaving groups has now been quantitatively assessed by employment of a series of compounds with common acyl groups, and found to rank in the order phenylphosphate >m-hydroxybenzoate >thioglycolate. Structural models suggest that these leaving groups interact during acylation principally with Tyr 150, Lys 315, and Thr 316 of the beta-lactamase active site. The positions of the leaving group carboxylates in these models is compared with those in published crystal structures of complexes of class C beta-lactamases with beta-lactams. The particular effectiveness of the acyl phosphate indicates the positions of two oxyanions that strongly interact with the active site. This information should be useful in the design of inhibitors of class C beta-lactamases. 相似文献
85.
Aryl malonamates are demonstrated to be novel substrates of a broad range of beta-lactam-recognizing enzymes. These compounds are isomers of the aryl phenaceturates, which are well-known substrates of these enzymes, but the new compounds contain a retro-amide side chain. Several lines of evidence, including comparisons of steady-state kinetic parameters between enzymes and a detailed investigation of the methanolysis kinetics, solvent deuterium isotope effects, and pH-rate profile for turnover of a retro substrate by the Enterobacter cloacae P99 beta-lactamase, suggested that the new substrates are likely to be hydrolyzed by the same chemical mechanisms as "normal" substrates. Molecular modeling indicated that the retro-amide group fits snugly into the active site of the P99 beta-lactamase by hydrogen bonding to the conserved lysine-67 residue. The retro-amide side chain may represent a lead to novel mechanism-based and transition state analogue inhibitors. 相似文献
86.
87.
Lung hypoplasia and neonatal death in Fgf9-null mice identify this gene as an essential regulator of lung mesenchyme 总被引:6,自引:0,他引:6
Mammalian lung develops as an evagination of ventral gut endoderm into the underlying mesenchyme. Iterative epithelial branching, regulated by the surrounding mesenchyme, generates an elaborate network of airways from the initial lung bud. Fibroblast growth factors (FGFs) often mediate epithelial-mesenchymal interactions and mesenchymal Fgf10 is essential for epithelial branching in the developing lung. However, no FGF has been shown to regulate lung mesenchyme. In embryonic lung, Fgf9 is detected in airway epithelium and visceral pleura at E10.5, but is restricted to the pleura by E12.5. We report that mice homozygous for a targeted disruption of Fgf9 exhibit lung hypoplasia and early postnatal death. Fgf9(-/-) lungs exhibit reduced mesenchyme and decreased branching of airways, but show significant distal airspace formation and pneumocyte differentiation. Our results suggest that Fgf9 affects lung size by stimulating mesenchymal proliferation. The reduction in the amount of mesenchyme in Fgf9(-/-) lungs limits expression of mesenchymal Fgf10. We suggest a model whereby FGF9 signaling from the epithelium and reciprocal FGF10 signaling from the mesenchyme coordinately regulate epithelial airway branching and organ size during lung embryogenesis. 相似文献
88.
89.
The class C beta-lactamase of Enterobacter cloacae P99 is competitively inhibited by low concentrations of 1:1 complexes of vanadate and hydroxamic acids. Structure-activity studies indicated that the hydroxamic acid functional group was essential to this inhibition. Both aryl and alkyl hydroxamic acids form inhibitory ternary complexes with vanadate and the enzyme, although, in certain cases of the latter, the inhibition may not be seen because of the low formation constants of the vanadate-hydroxamic acid complex. After all of the vanadate species present in solution had been taken into account, "real" K(i) values for the vanadate complexes could be determined. The K(i) value of the best of the inhibitors that were investigated, the 1:1 complex of vanadate with 4-nitrobenzohydroxamic acid, was 0.48 microM. Kinetics studies showed that the association and dissociation rate constants of this complex with the enzyme were 1.48 x 10(6) s(-1) M(-1) and 0.73 s(-1), respectively; the magnitude of the latter indicates covalent interaction of the complex with the enzyme. (51)V NMR and UV-vis spectra suggest that the structure of the vanadate complex bound to the enzyme may be very similar to that in solution. A (13)C NMR spectrum of the enzyme complex with 4-nitrobenzo[(13)C]hydroxamic acid and vanadate yields a coordination-induced shift (CIS) of 7.74 ppm. This is significantly larger than that of the vanadate complex in free solution (3.62 ppm), suggesting either, somewhat contrary to the (51)V and UV-vis spectra, greater interaction between vanadium and the hydroxamate carbonyl oxygen in the enzyme complex than in free solution or, more likely, polarization of the hydroxamate by interaction, e.g., hydrogen bonding, with the enzyme. Molecular modeling indicates that a pentacoordinated vanadate complex may well be able to snugly occupy the enzyme active site; Asn 152 is suitably placed to hydrogen bond to the hydroxamic acid oxygen atom. The experimental results are in accord with a model whereby the vanadate-hydroxamate-enzyme complex is a moderately good analogue of the transition state of the reaction of the beta-lactamase with phosphonate inhibitors. 相似文献
90.
The predatory mite Neoseiulus fallacis (Garman) was evaluated as a biological control agent of herbivorous mites on outdoor-grown ornamental landscape plants. To elucidate factors that may affect predator efficiency, replicated tests were conducted on 30 ornamental plant cultivars that varied in relationship to their generalized morphology (e.g., conifers, shade trees, evergreen shrubs, deciduous shrubs, and herbaceous perennials), production method (potted or field grown), canopy density, and the prey species present on each. Plant morphological grouping and foliar density appeared to be the most influential factors in predicting successful biological control. Among plant morphological groups, N. fallacis was most effective on shrubs and herbaceous perennials and less effective on conifers and shade trees. N. fallacis was equally effective at controlling spider mites on containerized (potted) and field grown plants, and there was no difference in control of mites on plants with Tetranychus spp. versus those with Oligonychus or Schizotetranychus spp. Moderate to unsuccessful control of spider mites by N. fallacis occurred mostly on tall, vertical plants with sparse canopies. Acceptable spider mite control occurred in four large-scale releases of N. fallacis into production plantings of Abies procera, Thuja occidentalis 'Emerald', Malus rootstock, and Viburnum plicatum 'Newport'. These data suggest that N. fallacis can be an effective biological control agent of multiple spider mite species in a range of low-growing and selected higher growing ornamental plants. 相似文献