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11.
Substitution at the C(7) position of purine nucleotides by a potent electron-withdrawing nitro group facilitates the cleavage of glycosidic bonds under alkaline conditions. This property is useful for sequence-specific cleavage of DNA containing these analogues. Here we describe the preparation of 7-deaza-7-NO(2)-dA and 7-deaza-7-NO(2)-dG using two different approaches, starting from 2'-deoxy-adenosine and 6-chloro-7-deaza-guanine, respectively. These modified nucleosides were converted to nucleotide triphosphates, each of which can replace the corresponding, naturally occurring triphosphate to support PCR amplification. [structure: see text] 相似文献
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Das C Berezovska O Diehl TS Genet C Buldyrev I Tsai JY Hyman BT Wolfe MS 《Journal of the American Chemical Society》2003,125(39):11794-11795
gamma-Secretase cleaves the transmembrane domain of the amyloid precursor protein, a process implicated in the pathogenesis of Alzheimer's disease, and this enzyme is a founding member of an emerging class of intramembrane proteases. Modeling and mutagenesis suggest a helical conformation for the substrate transmembrane domain upon initial interaction with the protease. Moreover, biochemical evidence supports the presence of an initial docking site for substrate on gamma-secretase that is distinct from the active site, a property predicted to be generally true of intramembrane proteases. Here we show that short peptides designed to adopt a helical conformation in solution are inhibitors of gamma-secretase in both cells and enzyme preparations. Helical peptides with all d-amino acids are the most potent inhibitors and represent potential therapeutic leads. Subtle modifications that disrupt helicity also substantially reduce potency, suggesting that this conformation is critical for effective inhibition. Fluorescence lifetime imaging in intact cells demonstrates that helical peptides disrupt binding between substrate and protease, whereas an active site-directed inhibitor does not. These findings are consistent with helical peptides interacting with the initial substrate docking site of gamma-secretase, suggesting a general strategy for the development of potent and specific inhibitors of intramembrane proteases. 相似文献
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Two efficient syntheses of 3-chloro-7-[(chlorocarbonyl)methoxy]-4-methylcoumarin are described, one utilizing traditional chemistry starting from 3-chloro-7-hydroxy-4-methylcoumarin, while the other uses a novel reagent, sulfuryl chloride/thionyl chloride, in a one-pot reaction starting from 7-(carboxymethoxy)-4-methylcoumarin. 相似文献
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Water that remains unfrozen at temperatures below the equilibrium bulk freezing temperature, in the presence of ice, is sometimes called unfreezable or bound. This paper analyses the phenomenon in terms of quantitative measurements of the hydration interaction among membranes or macromolecules at freezing temperatures. These results are related to analogous measurements in which osmotic stress or mechanical compression is used to equilibrate water of hydration with a bulk phase. The analysis provides formulas to estimate, at a given sub-freezing temperature, the amount of unfrozen water due to equilibrium hydration effects. Even at tens of degrees below freezing, this hydration effect alone can explain an unfrozen water volume that considerably exceeds that of a single 'hydration shell' surrounding the hydrophilic surfaces. The formulas provided give a lower bound to the amount of unfrozen water for two reasons. First, the well-known freezing point depression due to small solutes is, to zeroth order, independent of the membrane or macromolecular hydration effect. Further, the unfrozen solution found between membranes or macromolecules at freezing temperatures has high viscosity and small dimensions. This means that dehydration of such systems, especially at freezing temperatures, takes so long that equilibrium is rarely achieved over normal experimental time scales. So, in many cases, the amount of unfrozen water exceeds that expected at equilibrium, which in turn usually exceeds that calculated for a single hydration shell. 相似文献
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Laras Y Quéléver G Garino C Pietrancosta N Sheha M Bihel F Wolfe MS Kraus JL 《Organic & biomolecular chemistry》2005,3(4):612-618
Inhibition of gamma-secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce pathogenic A beta peptides, is an attractive approach for the treatment of Alzheimer's disease. We have designed a new gamma-secretase thiazolamide inhibitor bearing a dihydronicotinoyl moiety as Redox Delivery System which allows specific delivery of the drug to the brain. Through, on the one hand, A beta peptide production measurements by specific in vitro assays (gamma-secretase Cell Free assay and Cell Based assay on HEK 293 APP transfected cells) and, on the other hand, pharmacokinetic studies on animal models, the new inhibitor shows a good pharmacokinetic profile as well as a potent gamma-secretase inhibitory activity in vitro. From the obtained results, it is expected that drug will be mainly delivered to the CNS with low diffusion in the peripheral tissues. Consequently the side effects of this gamma-secretase inhibitor on the immune cells could be reduced. 相似文献
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Wolfe SA 《Chemistry & biology》2004,11(7):889-891
In this issue of Chemistry & Biology, Weiss and colleagues use phage display to map residues in the engrailed homeodomain that influence DNA recognition. Their shotgun scanning data provides surprising new insights into the importance of regions outside the recognition helix and N-terminal arm for DNA binding. 相似文献
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[reaction: see text] A new method for the synthesis of N-tosylketimines via the palladium-catalyzed isomerization of N-tosylaziridines is described. The mild reaction conditions tolerate the presence of a variety of functional groups including ketones, esters, and acetals. The reactions are believed to proceed via the oxidative addition of the aziridine to Pd(0) and represent the first examples of transformations involving Pd(0)-mediated oxidative additions of aziridines that do not proceed through allylpalladium intermediates. 相似文献