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Bjoern Moosmann Laura M. Huppertz Melanie Hutter Armin Buchwald Sascha Ferlaino Volker Auwärter 《Journal of mass spectrometry : JMS》2013,48(11):1150-1159
The appearance of pyrazolam in Internet shops selling ‘research chemicals’ in 2012 marked the beginning of designer benzodiazepines being sold as recreational drugs or ‘self medication’. With recent changes in national narcotics laws in many countries, where two uncontrolled benzodiazepines (phenazepam and etizolam), which were marketed by pharmaceutical companies in some countries, were scheduled, clandestine laboratories seem to turn to poorly characterized research drug candidates as legal substitutes. Following the appearance of pyrazolam, it comes with no surprise that recently, flubromazepam (7‐bromo‐5‐(2‐fluorophenyl)‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one), a second designer benzodiazepine, was offered on the market. In this article, this new compound was characterized using nuclear magnetic resonance, gas chromatography‐mass spectrometry (GC–MS), liquid chromatography–mass spectrometry (LC–MS/MS) and liquid chromatography quadrupole time‐of‐flight MS (LC–Q–ToF–MS). Additionally, a study was carried out, in which one of the authors consumed 4 mg of flubromazepam to gain preliminary data on the pharmacokinetic properties and the metabolism of this compound. For this purpose, serum as well as urine samples were collected for up to 31 days post‐ingestion and analyzed applying LC–MS/MS and LC–Q‐ToF‐MS techniques. On the basis of this study, flubromazepam appears to have an extremely long elimination half‐life of more than 100 h. One monohydroxylated compound and the debrominated compound could be identified as the predominant metabolites, the first allowing a detection of a consumption for up to 28 days post‐ingestion when analyzing urine samples in our case. Additionally, various immunochemical assays were evaluated, showing that the cross‐reactivity of the used assay seems not to be sufficient for safe detection of the applied dose in urine samples, bearing the risk that it could be misused in drug‐withdrawal settings or in other circumstances requiring regular drug testing. Furthermore, it may be used in drug‐facilitated crimes without being detected. Copyright © 2013 John Wiley & Sons, Ltd. 相似文献
34.
Grace Mugumbate Ana S. Newton Philip J. Rosenthal Jiri Gut Rui Moreira Kelly Chibale Rita C. Guedes 《Journal of computer-aided molecular design》2013,27(10):859-871
Increased resistance of Plasmodium falciparum to most available drugs challenges the control of malaria. Studies with protease inhibitors have suggested important roles for the falcipain family of cysteine proteases. These enzymes act in concert with other proteases to hydrolyze host erythrocyte hemoglobin in the parasite food vacuole. In order to find potential new antimalarial drugs, we screened in silico the ZINC database using two different protocols involving structure- and ligand-based methodologies. Our search identified 19 novel low micromolar inhibitors of cultured chloroquine resistant P. falciparum. The most active compound presented an IC50 value of 0.5 μM against cultured parasites and it also inhibited the cysteine protease falcipain-2 (IC50 = 25.5 μM). These results identify novel classes of antimalarials that are structurally different from those currently in use and which can be further derivatized to deliver leads suitable for optimisation. 相似文献
35.
Peter Fechner Oliver Bleher Melanie Ewald Kathrin Freudenberger Dominik Furin Urs Hilbig Felix Kolarov Katrin Krieg Lothar Leidner Goran Markovic Günther Proll Florian Pröll Sabrina Rau Johannes Riedt Barbara Schwarz Patricia Weber Julia Widmaier 《Analytical and bioanalytical chemistry》2014,406(17):4033-4051
This review is focused on methods for detecting small molecules and, in particular, the characterisation of their interaction with natural proteins (e.g. receptors, ion channels). Because there are intrinsic advantages to using label-free methods over labelled methods (e.g. fluorescence, radioactivity), this review only covers label-free techniques. We briefly discuss available techniques and their advantages and disadvantages, especially as related to investigating the interaction between small molecules and proteins. The reviewed techniques include well-known and widely used standard analytical methods (e.g. HPLC-MS, NMR, calorimetry, and X-ray diffraction), newer and more specialised analytical methods (e.g. biosensors), biological systems (e.g. cell lines and animal models), and in-silico approaches. 相似文献
36.
Melanie Platzer Sandra Kiese Thomas Herfellner Ute Schweiggert-Weisz Oliver Miesbauer Peter Eisner 《Molecules (Basel, Switzerland)》2021,26(5)
Numerous assays were developed to measure the antioxidant activity, but each has limitations and the results obtained by different methods are not always comparable. Popular examples are the DPPH and ABTS assay. Our aim was to study similarities and differences of these two assay regarding the measured antioxidant potentials of 24 phenolic compounds using the same measurement and evaluation methods. This should allow conclusions to be drawn as to whether one of the assays is more suitable for measuring specific subgroups like phenolic acids, flavonols, flavanones, dihydrochalcones or flavanols. The assays showed common trends for the mean values of most of the subgroups. Some dihydrochalcones and flavanones did not react with the DPPH radical in contrast to the ABTS radical, leading to significant differences. Therefore, to determine the antioxidant potential of dihydrochalcone or flavanone-rich extracts, the ABTS assay should be preferred. We found that the results of the flavonoids in the DPPH assay were dependent on the Bors criteria, whereas the structure–activity relationship in the ABTS assay was not clear. For the phenolic acids, the results in the ABTS assay were only high for pyrogallol structures, while the DPPH assay was mainly determined by the number of OH groups. 相似文献
37.
Nathan P. Oien Luong T. Nguyen Dr. Finith E. Jernigan Prof. Melanie A. Priestman Prof. David S. Lawrence 《Angewandte Chemie (International ed. in English)》2014,53(15):3975-3978
In vivo optical imaging must contend with the limitations imposed by the optical window of tissue (600–1000 nm). Although a wide array of fluorophores are available that are visualized in the red and near‐IR region of the spectrum, with the exception of proteases, there are few long wavelength probes for enzymes. This situation poses a particular challenge for studying the intracellular biochemistry of erythrocytes, the high hemoglobin content of which optically obscures subcellular monitoring at wavelengths less than 600 nm. To address this, tunable fluorescent reporters for protein kinase activity were developed. The probing wavelength is preprogrammed by using readily available fluorophores, thereby enabling detection within the optical window of tissue, specifically in the far‐red and near‐IR region. These agents were used to monitor endogenous cAMP‐dependent protein kinase activity in erythrocyte lysates and in intact erythrocytes when using a light‐activatable reporter. 相似文献
38.
Heavy‐Atom Tunneling in the Ring Opening of a Strained Cyclopropene at Very Low Temperatures 下载免费PDF全文
Melanie Ertelt Dr. David A. Hrovat Prof. Dr. Weston Thatcher Borden Prof. Dr. Wolfram Sander 《Chemistry (Weinheim an der Bergstrasse, Germany)》2014,20(16):4713-4720
The highly strained 1H‐bicyclo[3.1.0]‐hexa‐3,5‐dien‐2‐one 1 is metastable, and rearranges to 4‐oxacyclohexa‐2,5‐dienylidene 2 in inert gas matrices (neon, argon, krypton, xenon, and nitrogen) at temperatures as low as 3 K. The kinetics for this rearrangement show pronounced matrix effects, but in a given matrix, the reaction rate is independent of temperature between 3 and 20 K. This temperature independence means that the activation energy is zero in this temperature range, indicating that the reaction proceeds through quantum mechanical tunneling from the lowest vibrational level of the reactant. At temperatures above 20 K, the rate increases, resulting in curved Arrhenius plots that are also indicative of thermally activated tunneling. These experimental findings are supported by calculations performed at the CASSCF and CASPT2 levels by using the small‐curvature tunneling (SCT) approximation. 相似文献
39.
Photoionization and Pyrolysis of a 1,4‐Azaborinine: Retro‐Hydroboration in the Cation and Identification of Novel Organoboron Ring Systems 下载免费PDF全文
Fabian Holzmeier Dipl.‐Chem. Melanie Lang Dr. Patrick Hemberger Dr. Andras Bodi Dipl.‐Chem. Marius Schäfer Dr. Rian D. Dewhurst Prof. Dr. Holger Braunschweig Prof. Dr. Ingo Fischer 《Chemistry (Weinheim an der Bergstrasse, Germany)》2014,20(31):9683-9692
The photoionization and dissociative photoionization of 1,4‐di‐tert‐butyl‐1,4‐azaborinine by means of synchrotron radiation and threshold photoelectron photoion coincidence spectroscopy is reported. The ionization energy of the compound was determined to be 7.89 eV. Several low‐lying electronically excited states in the cation were identified. The various pathways for dissociative photoionization were modeled by statistical theory, and appearance energies AE0K were obtained. The loss of isobutene in a retro‐hydroboration reaction is the dominant pathway, which proceeds with a reverse barrier. Pyrolysis of the parent compound in a chemical reactor leads to the generation of several yet unobserved boron compounds. The ionization energies of the C4H6BN isomers 1,2‐ and 1,4‐dihydro‐1,4‐azaborinine and the C3H6BN isomer 1,2‐dihydro‐1,3‐azaborole were determined from threshold photoelectron spectra. 相似文献
40.
Chemical Probing of the Human Sirtuin 5 Active Site Reveals Its Substrate Acyl Specificity and Peptide‐Based Inhibitors 下载免费PDF全文
Claudia Roessler Theresa Nowak Martin Pannek Dr. Melanie Gertz Giang T. T. Nguyen Michael Scharfe Dr. Ilona Born Prof. Dr. Wolfgang Sippl Prof. Dr. Clemens Steegborn Prof. Dr. Mike Schutkowski 《Angewandte Chemie (International ed. in English)》2014,53(40):10728-10732
Sirtuins are NAD+‐dependent deacetylases acting as sensors in metabolic pathways and stress response. In mammals there are seven isoforms. The mitochondrial sirtuin 5 is a weak deacetylase but a very efficient demalonylase and desuccinylase; however, its substrate acyl specificity has not been systematically analyzed. Herein, we investigated a carbamoyl phosphate synthetase 1 derived peptide substrate and modified the lysine side chain systematically to determine the acyl specificity of Sirt5. From that point we designed six potent peptide‐based inhibitors that interact with the NAD+ binding pocket. To characterize the interaction details causing the different substrate and inhibition properties we report several X‐ray crystal structures of Sirt5 complexed with these peptides. Our results reveal the Sirt5 acyl selectivity and its molecular basis and enable the design of inhibitors for Sirt5. 相似文献