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201.
Mederski WW Dorsch D Anzali S Gleitz J Cezanne B Tsaklakidis C 《Bioorganic & medicinal chemistry letters》2004,14(14):3763-3769
Neutral weak halothiophene benzimidazole inhibitors of the serine protease factor Xa were identified via screening of a compound library. The X-ray crystal structure of representative 3a bound to human fXa confirmed the S1 binding mode. Starting from 3a a series of halothiophene benzimidazoles was synthesized and investigated for their factor Xa inhibitory activity. This led to potent and selective achiral inhibitors against fXa such as compounds 9k and 9w. 相似文献
202.
Scholz D Baumann K Grassberger M Wolff-Winiski B Rihs G Walter H Meingassner JG 《Bioorganic & medicinal chemistry letters》2004,14(11):2983-2986
The 17-alpha-substituted triterpene 1 [(17alpha)-23-(E)-dammara-20,23-diene-3beta,25-diol] showed promising activity in animal models of immunosuppression and inflammation. Using a mouse model for inflammatory skin diseases (oxazolone-induced allergic contact dermatitis, ACD) as the directing in vivo test system, Structure-activity-relationship studies with the aim to understand the necessary structural requirements for the biological activity of 1 were conducted. Furthermore, we anticipated to identify biologically active compounds with the 17beta configuration, which are thermodynamically more stable and much easier to synthesize. This was achieved by identifying the 17-beta substituted dammarane 5B and its analogues. 相似文献
203.
Adhesion and invasion of pathogenic bacteria represent the important initial step of infection. Pathogens utilize surface-located adhesins/invasins for specific interaction with host cell receptors. The three-dimensional structures of a number of adhesins/invasins show that many are elongated molecules containing domains commonly found in eukaryotic proteins. Similar folds are employed repeatedly to target different receptors. 相似文献
204.
Minimal cut sets in biochemical reaction networks 总被引:3,自引:0,他引:3
MOTIVATION: Structural studies of metabolic networks yield deeper insight into topology, functionality and capabilities of the metabolisms of different organisms. Here, we address the analysis of potential failure modes in metabolic networks whose occurrence will render the network structurally incapable of performing certain functions. Such studies will help to identify crucial parts in the network structure and to find suitable targets for repressing undesired metabolic functions. RESULTS: We introduce the concept of minimal cut sets for biochemical networks. A minimal cut set (MCS) is a minimal (irreducible) set of reactions in the network whose inactivation will definitely lead to a failure in certain network functions. We present an algorithm which enables the computation of the MCSs in a given network related to user-defined objective reactions. This algorithm operates on elementary modes. A number of potential applications are outlined, including network verifications, phenotype predictions, assessing structural robustness and fragility, metabolic flux analysis and target identification in drug discovery. Applications are illustrated by the MCSs in the central metabolism of Escherichia coli for growth on different substrates. AVAILABILITY: Computation and analysis of MCSs is an additional feature of the FluxAnalyzer (freely available for academic users upon request, special contracts for industrial companies; see web page below). Supplementary information: http://www.mpi-magdeburg.mpg.de/projects/fluxanalyzer 相似文献
205.
Wiegand H Wirz B Schweitzer A Gross G Perez MI Andres H Kimmerlin T Rueping M Seebach D 《化学与生物多样性》2004,1(11):1812-1828
The solid-phase synthesis and an ADME investigation with albino and pigmented male rats of the doubly 14C-labelled beta/alpha-tetrapeptide derivative Ac-beta3 hTyr-(D)Trp-beta3 hLys-beta3 hThr-lactone (3; Fig. 3) are described. After intravenous (i.v.) and peroral (p.o.) administration of the peptide, its concentration in blood and plasma, its tissue distribution, and the metabolism and the excretion of the peptide were analyzed over a period of up to 7 days post dose. The tetrapeptide in its ring opened form, 5, has a bioavailability of ca. 25%; radioactivity is distributed in the animals in an organ-specific way, and the compound appears to pass the blood-brain barrier to a very small extent, if at all (Tables 1-3 and Figs. 2-6). Excretion (37% renal, 44% fecal, including biliary) of the tetrapeptide 4 days after i.v. administration is almost complete, with only 4.3% remaining in the carcass; 4 days after p.o. administration 97% of the dose has been excreted in the feces. Radiochromatograms taken of plasma (0.5 and 24 h after i.v. dosing) and of urine and feces extracts (0-48 h collected) reveal the presence of lactone 3 and/or the corresponding hydroxy acid 5 with essentially no or very minor other peaks, respectively, representing possible metabolites (Tables 4-6, and Fig. 7 and 8). A comparison with a previous ADME investigation of a beta-nonapeptide show that--except for the lack of metabolism--all aspects of exposure, distribution, and elimination are different (structure-specific properties). The investigated tetrapeptide 3 is a potent and highly specific agonist of the somatostatin receptor hsst4, rendering the results described herein promising for diagnostic and therapeutic applications of beta-peptides. 相似文献
206.
The tripeptide H-Val-Ala-Leu-OH and the N-Ac-tetrapeptide amide Ac-Thr-Lys-Trp-Phe-NH2, and their beta-peptidic counterparts H-beta(3)hVal-beta(3)hAla-beta(3)hLeu-OH and Ac-beta(3)hThr-(S)beta(2)hLys-beta(3)hTrp-beta(3)hPhe-NH2, respectively, have been injected into Heliothis virescens larvae and added to cell cultures of black mexican sweet maize. The body liquids of the larvae and the supernatant of the plant cell cultures were sampled 0, 2, 3, 6, 17, and/or 24 h after application and analyzed by LC/MS. While the two alpha-peptides were degraded rapidly in these environments, the concentration of the beta-peptides was found to decrease very slowly. Thus, ca. 60% of the original amount of the beta-tetrapeptide was detected in the liquids of the insect after 24 h. The plant cells did not seem to make use of the beta-peptides at all, whereas, the alpha-tripeptide completely disappeared from the supernatant after 3 h. Thus, we have demonstrated, for the first time, the high stability of beta-peptides against degradation and metabolism in an insect and a plant. Especially remarkable is the persistence of the beta-tetrapeptide with its functionalised and, thus, 'metabolisable' side chains of Thr, Lys, Trp, and Phe in the insect larvae, which are known to have a high level of activity of oxidizing enzymes. The results described here match those of ADME investigations with radioactively labeled beta-peptides in rats, where essentially complete stability has been observed, while environmental microorganisms have been found to biodegrade beta-peptides, albeit slowly. Possible implications of these findings for biomedical and pest-control applications are proposed. 相似文献
207.
A sexually reproducing hypotrichous ciliates undergo senescence which is in general attributed to degenerative processes in the macronucleus, assuming that loss of viability is based on loss of genetic elements. It is generally accepted that the genetic elements in the macronucleus of hypotrichs segregate randomly, a process which potentially can lead to aneuploid imbalances in the distribution of gene copies. It is, however, unclear whether there are mechanisms which compensate for such imbalances such that each genetic element regains its predetermined copy number (regulatory model, conserving euploidy), or whether the genetic elements only double, so that genetic imbalances can be inherited to further generations (stochastic model, allowing aneuploidy). By means of mathematical modeling and simulations, we investigate these two models with respect to the number of generations a lineage of hypotrichs can survive under asexual conditions. Whereas the regulatory model cannot explain senescence in hypotrichs, the stochastic model provides plausible results which, however, strongly depend on the assumed distribution of copy numbers which we investigate by means of three examples. For both models, simple prediction formulae for the approximate survival time of asexually reproducing ciliates are provided. 相似文献
208.
209.
Dieter?MalchowEmail author Daniel?F?Lusche Christina?Schlatterer 《BMC developmental biology》2004,4(1):7
Background
During early differentiation of Dictyostelium the attractant cAMP is released periodically to induce aggregation of the cells. Here we pursue the question whether pulsatile cAMP signaling is coupled to a basic Ca2+-oscillation. 相似文献210.
Kienberger Ferry Zhu Rong Moser Rosita Rankl Christian Blaas Dieter Hinterdorfer Peter 《Biological procedures online》2004,6(1):120-128
Dynamic force microscopy (DFM) allows imaging of the structure and the assessment of the function of biological specimens
in their physiological environment. In DFM, the cantilever is oscillated at a given frequency and touches the sample only
at the end of its downward movement. Accordingly, the problem of lateral forces displacing or even destroying bio-molecules
is virtually inexistent as the contact time and friction forces are reduced. Here, we describe the use of DFM in studies of
human rhinovirus serotype 2 (HRV2) weakly adhering to mica surfaces. The capsid of HRV2 was reproducibly imaged without any
displacement of the virus. Release of the genomic RNA from the virions was initiated by exposure to low pH buffer and snapshots
of the extrusion process were obtained. In the following, the technical details of previous DFM investigations of HRV2 are
summarized.
Published: June 29, 2004. 相似文献