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《Bioorganic & medicinal chemistry letters》2014,24(19):4714-4723
Use of the tools of SBDD including crystallography led to the discovery of novel and potent 6,5 heterobicyclic MEKi’s [J. Med. Chem. 2012, 55, 4594]. The core change from a 5,6 heterobicycle to a 6,5 heterobicycle was driven by the desire for increased structural diversity and aided by the co-crystal structure of G-925 [J. Med. Chem. 2012, 55, 4594]. The key design feature was the shift of the attachment of the five-membered heterocyclic ring towards the B ring while maintaining the key hydroxamate and anilino pharamcophoric elements in a remarkably similar position as in G-925. From modelling, changing the connection point of the five membered ring heterocycle placed the H-bond accepting nitrogen within a good distance and angle to the Ser212 [J. Med. Chem. 2012, 55, 4594]. The resulting novel 6,5 benzoisothiazole MEKi G-155 exhibited improved potency versus aza-benzofurans G-925 and G-963 but was a potent inhibitor of cytochrome P450’s 2C9 and 2C19. Lowering the log D by switching to the more polar imidazo[1,5-a] pyridine core significantly diminished 2C9/2C19 inhibition while retaining potency. The imidazo[1,5-a] pyridine G-868 exhibited increased potency versus the starting point for this work (aza-benzofuran G-925) leading to deprioritization of the azabenzofurans. The 6,5-imidazo[1,5-a] pyridine scaffold was further diversified by incorporating a nitrogen at the 7 position to give the imidazo[1,5-a] pyrazine scaffold. The introduction of the C7 nitrogen was driven by the desire to improve metabolic stability by blocking metabolism at the C7 and C8 positions (particularly the HLM stability). It was found that improving on G-868 (later renamed GDC-0623) required combining C7 nitrogen with a diol hydroxamate to give G-479. G-479 with polarity distributed throughout the molecule was improved over G-868 in many aspects. 相似文献
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Henryk Brzeskwiniewicz 《Biometrical journal. Biometrische Zeitschrift》1995,37(2):191-198
We present the idea of using multiresponse incomplete block designs when not all responses can be observed in all experimental units. For a special class of such designs, in which partial designs are PBB designs, a method for estimating natural treatment contrast is given. We also consider the problem of testing the hypotheses concerning the natural and any estimable treatment contrasts. For testing this hypothesis the Wald statistics, being asymptotically chi-square distributed, is proposed. 相似文献
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Abstract Schizosaccharomyces pombe becomes resistant to killing by high concentration of hydrogen peroxide and other severe stresses including oxidants, high temperature and high concentration of ethanol when pretreated with nonlethal levels of hydrogen peroxide. In the presence of the protein synthesis inhibitor, cycloheximide, during hydrogen peroxide pretreatment, the cell obtained partial resistance to a higher level of hydrogen peroxide. The partial resistance to hydrogen peroxide in the presence of cycloheximide was acquired within 30 min of pretreatment but complete resistance obtained with de novo protein synthesis was not attained before 45 min of pretreatment. During adaptation to hydrogen peroxide, at least 15 polypeptides are induced, as analyzed by two-dimensional gel electrophoresis. Catalase activity is induced eight-fold by treatment with a nonlethal level of hydrogen peroxide. 相似文献
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I. Siatkowski 《Biometrical journal. Biometrische Zeitschrift》1993,35(3):283-289
For some subclass of a two-way elimination of heterogeneity design, necessary and sufficient conditions are established for row-connectedness and column-connectedness of a design to imply its connectedness. 相似文献
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Field-measured grazing rates (ml/animal/d) of cladocerans (mostly daphniids) and diaptomids were assembled from various published
studies and plotted as a function of corresponding phytoplankton concentration (μg l−1 f.w.). Filtering rates of both zooplankton groups initially increased with seston concentration until maximal grazing rates
were observed at approximately 4 × 102 and 1 × 102 μg l−1 for cladocerans and copepods, respectively; at higher algal concentrations, filtering rates of both declined as a function
of food concentration. The shape of these curves are most consistent with Holling's (1966) Type 3 functional response.
We found little support for the Type 3 functional response in published laboratory studies of Daphnia; most investigators report either a Type 1 or Type 2 response. The one study in which the Type 3 response was observed involved
experiments where animals were acclimated at low food concentrations for 24 h, whereas those studies associated with response
Types 1 or 2 had acclimation periods of only 1 to 3 h. We therefore assembled relevant data from the literature to examine
the effect of acclimation period on the feeding rates of Daphnia at low food concentrations. In the absence of any acclimation, animals filtered at extremely low rates. After 2 h of acclimation,
however, filtering rates increased 4 to 5-fold but declined again with longer durations; after > 70 h of pre-conditioning,
filtering rates were almost as low as they had been with no acclimation.
We also found little support for the Type 3 functional response in published studies of copepods. The only study associated
with a Type 3 response involved a marine copepod that had been subjected to a starvation period of 48 h; however, an analysis
of the effects of acclimation period did not yield conclusive evidence that filtering rates of freshwater copepods (Diaptomus and Eudiaptomus) decrease significantly with acclimation duration.
The low filtering rates associated with long acclimation periods in laboratory experiments appears to be a direct result of
animals becoming emaciated from prolonged exposure to low food concentrations, a situation which renders them incapable of
high filtering rates. This may explain the Type 3 functional response for field cladocerans, since zooplankton in food-limiting
situations are constantly exposed to low food concentrations, and would therefore have low body carbon and consequently less
energy to filter-feed. We cannot, however, use this to explain the Type 3 response for field diaptomids, since copepods in
the laboratory did not appear to lose body carbon even after 72 h of feeding at very low food levels, and there was inconclusive
evidence that either Diaptomus or Eudiaptomus decrease their filtering rates with acclimation period.
Although Incipient Limiting Concentrations (ILC) for Daphnia ranged from 1 to 8.5 × 103 μg 1−1, more than half of these fell between 1 and 3 × 103 μg l−1, bracketing the value of 2.7 × 102 μg l−1 for field cladocerans. There was, however, a great deal of variation in reported maximum ingestion rates (MIR), maximum filtering
rates (MFR) and ILC values for Daphnia magna. ILC values from the few laboratory studies of freshwater copepods ranged between 0.5 to 2.8 × 103 μg 1−1, and was higher than the ILC value of approximately 0.2 × 103 μg l−1 calculated for field populations of D. minutus. Generally, there was considerable agreement among laboratory studies regarding the shape of grazing-rate and ingestion-rate
curves when data were converted to similar units and presented on standardized scales. 相似文献
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