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941.
Versatile online SPE–HPLC method for the analysis of Irinotecan and its clinically relevant metabolites in biomaterials
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Zeljko M. Prijovich Pierre‐Alain Burnouf Steve R. Roffler 《Journal of separation science》2014,37(4):360-367
Monitoring levels of Irinotecan and its metabolites during cancer therapy could help link broad interpatient variations in antitumor activity and toxicity to the patient's metabolic status. We have developed and validated a versatile and highly sensitive method for the simultaneous determination of Irinotecan and its clinically relevant metabolites 7‐ethyl‐10‐hydroxy‐camptothecin (SN‐38) and SN‐38 glucuronide. Sample clean‐up involves precipitation by acetone/methanol/0.5 M trichloroacetic acid at 4:4:2 v/v followed by extraction of the metabolites on an SPE column by 20% methanol in 25 mM KH2PO4 pH 2.9. Online transfer to an analytical μBondapak C18 column, elution with 24% acetonitrile (ACN) in 0.1 M KH2PO4 pH 2.9 and fluorescence detection with excitation at 375 nm and emission at 430 nm for SN‐38 glucuronide and Irinotecan or 540 nm for SN‐38 results in high sensitivity (1–2 pg) and short (~10 min) run times. The method was used to determine the degree of SN‐38 glucuronidation in mice after Irinotecan administration and in cultured cancer cells exposed to SN‐38. The method may be used to better understand Irinotecan metabolism, personalize therapy, and develop Irinotecan‐based tumor targeting therapies. 相似文献
942.
Correlation of Insulin‐Enhancing Properties of Vanadium‐Dipicolinate Complexes in Model Membrane Systems: Phospholipid Langmuir Monolayers and AOT Reverse Micelles
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Dr. Audra G. Sostarecz Dr. Ernestas Gaidamauskas Steve Distin Prof. Sandra J. Bonetti Prof. Nancy E. Levinger Prof. Debbie C. Crans 《Chemistry (Weinheim an der Bergstrasse, Germany)》2014,20(17):5149-5159
We explore the interactions of VIII‐, VIV‐, and VV‐2,6‐pyridinedicarboxylic acid (dipic) complexes with model membrane systems and whether these interactions correlate with the blood‐glucose‐lowering effects of these compounds on STZ‐induced diabetic rats. Two model systems, dipalmitoylphosphatidylcholine (DPPC) Langmuir monolayers and AOT (sodium bis(2‐ethylhexyl)sulfosuccinate) reverse micelles present controlled environments for the systematic study of these vanadium complexes interacting with self‐assembled lipids. Results from the Langmuir monolayer studies show that vanadium complexes in all three oxidation states interact with the DPPC monolayer; the VIII–phospholipid interactions result in a slight decrease in DPPC molecular area, whereas VIV and VV–phospholipid interactions appear to increase the DPPC molecular area, an observation consistent with penetration into the interface of this complex. Investigations also examined the interactions of VIII‐ and VIV‐dipic complexes with polar interfaces in AOT reverse micelles. Electron paramagnetic resonance spectroscopic studies of VIV complexes in reverse micelles indicate that the neutral and smaller 1:1 VIV‐dipic complex penetrates the interface, whereas the larger 1:2 VIV complex does not. UV/Vis spectroscopy studies of the anionic VIII‐dipic complex show only minor interactions. These results are in contrast to behavior of the VV‐dipic complex, [VO2(dipic)]?, which penetrates the AOT/isooctane reverse micellar interface. These model membrane studies indicate that VIII‐, VIV‐, and VV‐dipic complexes interact with and penetrate the lipid interfaces differently, an effect that agrees with the compounds’ efficacy at lowering elevated blood glucose levels in diabetic rats. 相似文献
943.
Georgia McGaughey Christopher I. Bayly Christopher D. Cox John D. Schreier Michael J. Breslin Michael Bogusky Steve Pitzenberger Richard Ball Paul J. Coleman 《Journal of computer-aided molecular design》2014,28(1):5-12
Dual Orexin Receptor Antagonists (DORA) bind to both the Orexin 1 and 2 receptors. High resolution crystal structures of the Orexin 1 and 2 receptors, both class A GPCRs, were not available at the time of this study, and thus, ligand-based analyses were invoked and successfully applied to the design of DORAs. Computational analysis, ligand based superposition, unbound small-molecule X-ray crystal structures and NMR analysis were utilized to understand the conformational preferences of key DORAs and excellent agreement between these orthogonal approaches was seen in the majority of compounds examined. The predominantly face-to-face (F2F) interaction observed between the distal aromatic rings was the core 3D shape motif in our design principle and was used in the development of compounds. A notable exception, however, was seen between computation and experiment for suvorexant where the molecule exhibits an extended conformation in the unbound small-molecule X-ray structure. Even taking into account solvation effects explicitly in our calculations, we nevertheless find support that the F2F conformation is the bioactive conformation. Using a dominant states approximation for the partition function, we made a comprehensive assessment of the free energies required to adopt both an extended and a F2F conformation of a number of DORAs. Interestingly, we find that only a F2F conformation is consistent with the activities reported. 相似文献
944.
Arvind K. Subbaraj Brent A. Barrett Steve A. Wakelin Karl Fraser 《Analytical and bioanalytical chemistry》2015,407(26):8047-8058
Forage seeds are a highly traded agricultural commodity, and therefore, quality control and assurance is high priority. In this study, we have used direct analysis in real time-mass spectrometry (DART-MS) as a tool to discriminate forage seeds based on their non-targeted chemical profiles. In the first experiment, two lots of perennial ryegrass (Lolium perenne L.) seed were discriminated based on exogenous residues of N-(3, 4-dichlorophenyl)-N,N-dimethylurea (DiuronTM), a herbicide. In a separate experiment, washed and unwashed seeds of the forage legumes white clover (Trifolium repens L.) and alfalfa (Medicago sativa L.) were discriminated based on the presence or absence of oxylipins, a class of endogenous antimicrobial compounds. Unwashed seeds confer toxicity towards symbiotic, nitrogen-fixing rhizobia which are routinely coated on legume seeds before planting, resulting in reduced rhizobial count. This is the first report of automatic introduction of intact seeds in the DART ion source and detecting oxylipins using DART-MS. Apart from providing scope to investigate legume-rhizobia symbiosis further in the context of oxylipins, the results presented here will enable future studies aimed at classification of seeds based on chemicals bound to the seed coat, thereby offering an efficient screening device for industry. 相似文献
945.
Dr. Joe Briscoe Adam Marinovic Dr. Marta Sevilla Dr. Steve Dunn Dr. Magdalena Titirici 《Angewandte Chemie (International ed. in English)》2015,54(15):4463-4468
New hybrid materials consisting of ZnO nanorods sensitized with three different biomass‐derived carbon quantum dots (CQDs) were synthesized, characterized, and used for the first time to build solid‐state nanostructured solar cells. The performance of the devices was dependent on the functional groups found on the CQDs. The highest efficiency was obtained using a layer‐by‐layer coating of two different types of CQDs. 相似文献
946.
CH Activation Generates Period‐Shortening Molecules That Target Cryptochrome in the Mammalian Circadian Clock
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Tsuyoshi Oshima Dr. Iori Yamanaka Dr. Anupriya Kumar Dr. Junichiro Yamaguchi Dr. Taeko Nishiwaki‐Ohkawa Kei Muto Rika Kawamura Dr. Tsuyoshi Hirota Prof. Dr. Kazuhiro Yagita Prof. Dr. Stephan Irle Prof. Dr. Steve A. Kay Prof. Dr. Takashi Yoshimura Prof. Dr. Kenichiro Itami 《Angewandte Chemie (International ed. in English)》2015,54(24):7193-7197
The synthesis and functional analysis of KL001 derivatives, which are modulators of the mammalian circadian clock, are described. By using cutting‐edge C? H activation chemistry, a focused library of KL001 derivatives was rapidly constructed, which enabled the identification of the critical sites on KL001 derivatives that induce a rhythm‐changing activity along with the components that trigger opposite modes of action. The first period‐shortening molecules that target the cryptochrome (CRY) were thus discovered. Detailed studies on the effects of these compounds on CRY stability implicate the existence of an as yet undiscovered regulatory mechanism. 相似文献
947.
Delineating the Role of Helical Intermediates in Natively Unfolded Polypeptide Amyloid Assembly and Cytotoxicity
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Carole Anne De Carufel Noé Quittot Phuong Trang Nguyen Prof. Steve Bourgault 《Angewandte Chemie (International ed. in English)》2015,54(48):14383-14387
Amyloid deposition is a hallmark of many diseases, such as the Alzheimer’s disease. Numerous amyloidogenic proteins, including the islet amyloid polypeptide (IAPP) associated with type II diabetes, are natively unfolded and need to undergo conformational rearrangements allowing the formation of locally ordered structure(s) to initiate self‐assembly. Recent studies have indicated that the formation of α‐helical intermediates accelerates fibrillization, suggesting that these species are on‐pathway to amyloid assembly. By identifying an IAPP derivative with a restricted conformational ensemble that co‐assembles with IAPP, we observed that helical species were off‐pathway in homogenous environment and in presence of lipid bilayers or glycosaminoglycans. Moreover, preventing helical folding potentiated membrane perturbation and IAPP cytotoxicity, indicating that stabilization of helical motif(s) is a promising strategy to prevent cell degeneration associated with amyloidogenesis. 相似文献
948.
949.
Yu-San Liu Yining Zeng Yonghua Luo Qi Xu Michael E. Himmel Steve J. Smith Shi-You Ding 《Cellulose (London, England)》2009,16(4):587-597
Exoglucanases are key enzymes required for the efficient hydrolysis of crystalline cellulose. It has been proposed that exoglucanases
hydrolyze cellulose chains in a processive manner to produce primarily cellobiose. Usually, two functional modules are involved
in the processive mechanism: a catalytic module and a carbohydrate-binding module (CBM). In this report, single molecule tracking
techniques were used to analyze the molecular motion of CBMs labeled with quantum dots (QDs) and bound to cellulose crystals.
By tracking the single QD, we observed that the family 2 CBM from Acidothermus cellulolyticus (AcCBM2) exhibited linear motion along the long axis of the cellulose fiber. This apparent movement was observed consistently
when different concentrations (25 μM to 25 nM) of AcCBM2 were used. Although the mechanism of AcCBM2 motion remains unknown, single-molecule spectroscopy has been demonstrated to be a promising tool for acquiring new fundamental
understanding of cellulase action. 相似文献
950.