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71.
Dr. Jessica S. Kelsey Dr. Tamas Geczy Nancy E. Lewin Dr. Noemi Kedei Colin S. Hill Julia S. Selezneva Christopher J. Valle Wonhee Woo Dr. Inna Gorshkova Dr. Peter M. Blumberg 《Chembiochem : a European journal of chemical biology》2014,15(8):1131-1144
The C1 domain, which represents the recognition motif on protein kinase C for the lipophilic second messenger diacylglycerol and its ultrapotent analogues, the phorbol esters, has emerged as a promising therapeutic target for cancer and other indications. Potential target selectivity is markedly enhanced both because binding reflects ternary complex formation between the ligand, C1 domain, and phospholipid, and because binding drives membrane insertion of the C1 domain, permitting aspects of the C1 domain surface outside the binding site, per se, to influence binding energetics. Here, focusing on charged residues identified in atypical C1 domains which contribute to their loss of ligand binding activity, we showed that increasing charge along the rim of the binding cleft of the protein kinase C δ C1 b domain raises the requirement for anionic phospholipids. Correspondingly, it shifts the selectivity of C1 domain translocation to the plasma membrane, which is more negatively charged than internal membranes. This change in localization is most pronounced in the case of more hydrophilic ligands, which provide weaker membrane stabilization than do the more hydrophobic ligands and thus contributes an element to the structure–activity relations for C1 domain ligands. Coexpressing pairs of C1‐containing constructs with differing charges each expressing a distinct fluorescent tag provided a powerful tool to demonstrate the effect of increasing charge in the C1 domain. 相似文献
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Discovery of Quinoline‐Derived Trifluoromethyl Alcohols,Determination of Their in vivo Toxicity and Anticancer Activity in a Zebrafish Embryo Model 下载免费PDF全文
Prof. Dr. Vinoth Sittaramane Jihan Padgett Philip Salter Ashley Williams Shauntelle Luke Rebecca McCall Prof. Dr. Jonathan F. Arambula Vincent B. Graves Mark Blocker David Van Leuven Keturah Bowe Julia Heimberger Hannah C. Cade Supriya Immaneni Prof. Dr. Abid Shaikh 《ChemMedChem》2015,10(11):1802-1807
In this study the rational design, synthesis, and anticancer activity of quinoline‐derived trifluoromethyl alcohols were evaluated. Members of this novel class of trifluoromethyl alcohols were identified as potent growth inhibitors in a zebrafish embryo model. Synthesis of these compounds was carried out with an sp3‐C?H functionalization strategy of methyl quinolines with trifluoromethyl ketones. A zebrafish embryo model was also used to explore the toxicity of ethyl 4,4,4‐trifluoro‐3‐hydroxy‐3‐(quinolin‐2‐ylmethyl)butanoate ( 1 ), 2‐benzyl‐1,1,1‐trifluoro‐3‐(quinolin‐2‐yl)propan‐2‐ol ( 2 ), and trifluoro‐3‐(isoquinolin‐1‐yl)‐2‐(thiophen‐2‐yl)propan‐2‐ol ( 3 ). Compounds 2 and 3 were found to be more toxic than compound 1 ; apoptotic staining assays indicated that compound 3 causes increased cell death. In vitro cell proliferation assays showed that compound 2 , with an LC50 value of 14.14 μm , has more potent anticancer activity than cisplatin. This novel class of inhibitors provides a new direction in the discovery of effective anticancer agents. 相似文献
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Tiffany D. Andras Troy S. Alexander Asiri Gahlena R. Mitchell Parry Facundo M. Fernandez Julia Kubanek May D. Wang Mark E. Hay 《Journal of chemical ecology》2012,38(10):1203-1214
Coral reefs are in global decline, with seaweeds increasing as corals decrease. Although seaweeds inhibit coral growth, recruitment, and survivorship, the mechanism of these interactions is poorly understood. Here, we used field experiments to show that contact with four common seaweeds induces bleaching on natural colonies of Porites rus. Controls in contact with inert, plastic mimics of seaweeds did not bleach, suggesting seaweed effects resulted from allelopathy rather than shading, abrasion, or physical contact. Bioassay-guided fractionation of the hydrophobic extract from the red alga Phacelocarpus neurymenioides revealed a previously characterized antibacterial metabolite, neurymenolide A, as the main allelopathic agent. For allelopathy of lipid-soluble metabolites to be effective, the compounds would need to be deployed on algal surfaces where they could transfer to corals on contact. We used desorption electrospray ionization mass spectrometry (DESI-MS) to visualize and quantify neurymenolide A on the surface of P. neurymenioides, and we found the molecule on all surfaces analyzed, with highest concentrations on basal portions of blades. 相似文献
76.
Adding conductive carbon fillers to electrically insulating thermoplastic polymers increases the resulting composite's electrical conductivity, which would enable them to be used in electrostatic dissipative and semiconductive applications. In this study, varying amounts of carbon black (CB: 2 to 10 wt %), multiwalled carbon nanotubes (CNT: 0.5 to 8 wt %), or exfoliated graphite nanoplatelets (GNP: 2 to 15 wt %) were added to polycarbonate (PC) and the resulting composites were tested for electrical conductivity (EC = 1/electrical resistivity). The percolation threshold was ~ 1.2 vol % CNT, ~ 2.4 vol % CB, and ~ 4.6 vol % GNP. In addition, three EC models (Mamunya, additive, and general effective media) were developed for the CB/PC, CNT/PC, and GNP/PC composites. The general effective media (GEM) model showed the best agreement with the experimental results over the entire range of filler concentrations (above and below the percolation threshold) for all three composite systems. In addition, the GEM model can be easily adapted for composites containing combinations of different conductive fillers. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012 相似文献
77.
Julia M. Hum Amanda P. Siegel Fredrick M. Pavalko Richard N. Day 《International journal of molecular sciences》2012,13(11):14385-14400
Live-cell microscopy is now routinely used to monitor the activities of the genetically encoded biosensor proteins that are designed to directly measure specific cell signaling events inside cells, tissues, or organisms. Most fluorescent biosensor proteins rely on Förster resonance energy transfer (FRET) to report conformational changes in the protein that occur in response to signaling events, and this is commonly measured with intensity-based ratiometric imaging methods. An alternative method for monitoring the activities of the FRET-based biosensor proteins is fluorescence lifetime imaging microscopy (FLIM). FLIM measurements are made in the time domain, and are not affected by factors that commonly limit intensity measurements. In this review, we describe the use of the digital frequency domain (FD) FLIM method for the analysis of FRET signals. We illustrate the methods necessary for the calibration of the FD FLIM system, and demonstrate the analysis of data obtained from cells expressing “FRET standard” fusion proteins. We then use the FLIM-FRET approach to monitor the changes in activities of two different biosensor proteins in specific regions of single living cells. Importantly, the factors required for the accurate determination and reproducibility of lifetime measurements are described in detail. 相似文献
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Ronit Freeman Julia Girsh Bilha Willner Itamar Willner 《Israel journal of chemistry》2012,52(11-12):1125-1136
Due to an internal error, the following article was added after the original publication of the special issue on Nanochemistry (11-12/2012). Semiconductor quantum dots (QDs) exhibit unique photophysical properties, turning these nanomaterials into ideal components for the development of optical or optoelectronic sensors and biosensors. Various methods and mechanisms of using QDs for sensing have been implemented, including the probing of recognition events by the luminescence of the QDs, their application in fluorescence resonance energy transfer (FRET), electron transfer (ET), chemiluminescence resonance energy transfer (CRET), and photoelectrochemical generation of photocurrents. These different mechanisms are exemplified by discussing the QD-based sensing of low-molecular-weight substrates, chiroselective sensing of amino acids, probing of the catalytic activities of enzymes (casein kinase, tyrosinase, NAD+-dependent enzymes), and analysis of DNA and of aptamer-substrate complexes. Specifically, the amplified QD-based sensing of DNA using exonuclease III as target regeneration biocatalyst and the multiplexed detection of DNAs using differently sized QDs are discussed. Also, the implementation of the CRET process for the multiplexed analysis of DNA using differently sized QDs is addressed. Finally, the use of semiconductor QDs for the photoelectrochemical detection of DNA, aptamer-substrate complexes and enzyme activities are discussed. Specifically, the use of QDs for photoelectrochemical sensors, using the CRET process as internal excitation light source, is described. The future applications of the various QD-based sensors as analytical devices and as nanotools that probe intracellular processes are discussed. 相似文献
80.
Sylwia Matysiak Julia Zabielska Józef Kula Alina Kunicka-Styczyńska 《Journal of the American Oil Chemists' Society》2020,97(1):67-79
The growing role of fatty acid amides in medicinal chemistry has recently been observed. Therefore, using simple and fast methods, a series of chiral amide derivatives (24 compounds) of ricinoleic and 3-hydroxynonanoic acid was obtained with 31–95% yields. Then, the evaluation of their antimicrobial activity against 13 microorganisms representing Gram-positive and Gram-negative bacteria, yeast, and molds was performed. The obtained compounds showed antimold potential; however, the tested species of molds were more susceptible to derivatives of 3-hydroxynonanoic acid than to amides obtained from ricinoleic acid (RA). Interestingly, hydroxamic acids derived from RA exhibited the best activity against Candida albicans and Candida tropicalis. On the other hand, hydroxamic acids derived from 3-hydroxynonanoic acid showed the best antimicrobial potential against the remaining tested microorganisms, especially against Pseudomonas cedrina. The obtained derivatives can be considered compounds of potential pharmacological significance, which is important due to the increasing problem of microbial resistance. 相似文献