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71.
Prof. Dr. Bernhard Kräutler 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(67):15438-15445
The recently delineated structure- and reactivity-based concept of antivitamins B12 has begun to bear fruit by the generation, and study, of a range of such B12-dummies, either vitamin B12-derived, or transition metal analogues that also represent potential antivitamins B12 or specific B12-antimetabolites. As reviewed here, this has opened up new research avenues in organometallic B12-chemistry and bioinorganic coordination chemistry. Exploratory studies with antivitamins B12 have, furthermore, revealed some of their potential, as pharmacologically interesting compounds, for inducing B12-deficiency in a range of organisms, from hospital resistant bacteria to laboratory mice. The derived capacity of antivitamins B12 to induce functional B12-deficiency in mammalian cells and organs also suggest their valuable potential as growth inhibitors of cancerous human and animal cells. 相似文献
72.
Caleb J. Hiller Dr. Chi Chung Lee Dr. Martin T. Stiebritz Lee A. Rettberg Prof. Dr. Yilin Hu 《Chemistry (Weinheim an der Bergstrasse, Germany)》2019,25(10):2389-2395
Nitrogenase utilizes an ATP-dependent reductase to deliver electrons to its catalytic component to enable two important reactions: the reduction of N2 to NH4+, and the reduction of CO to hydrocarbons. The two nitrogenase-based reactions parallel the industrial Haber–Bosch and Fischer–Tropsch processes, yet they occur under ambient conditions. As such, understanding the enzymatic mechanism of nitrogenase is crucial for the future development of biomimetic strategies for energy-efficient production of valuable chemical commodities. Mechanistic investigations of nitrogenase has long been hampered by the difficulty to trap substrates and intermediates relevant to the nitrogenase reactions. Recently, we have successfully captured CO on the Azotobacter vinelandii V-nitrogenase via two approaches that alter the electron fluxes in a controlled manner: one approach utilizes an artificial electron donor to trap CO on the catalytic component of V-nitrogenase in the resting state; whereas the other employs a mismatched reductase component to reduce the electron flux through the system and consequently accumulate CO on the catalytic component of V-nitrogenase. Here we summarize the major outcome of these recent studies, which not only clarified the catalytic relevance of the one-CO (lo-CO) and multi-CO (hi-CO) bound states of nitrogenase, but also pointed to a potential competition between N2 and CO for binding to the same pair of reactive Fe sites across the sulfur belt of the cofactor. Together, these results highlight the utility of these strategies in poising the cofactor at a well-defined state for substrate- or intermediate-trapping via controlled alteration of electron fluxes, which could prove beneficial for further elucidation of the mechanistic details of nitrogenase-catalyzed reactions. 相似文献
73.
Yae Eun Chong Manting Chiang Kiran Deshpande Simon Haroutounian Leonid Kagan Jong Bong Lee 《Biomedical chromatography : BMC》2019,33(11)
Ondansetron, a widely used antiemetic agent, is a P‐glycoprotein (P‐gp) substrate and therefore expression of P‐gp at the blood–brain barrier limits its distribution to the central nervous system (CNS), which was observed to be reversed by coadministration with P‐gp inhibitors. Tariquidar is a potent and selective third‐generation P‐gp inhibitor, and coadministration with ondansetron has shown improved ondansetron distribution to the CNS. There is currently no reported bioanalytical method for simultaneously quantifying ondansetron with a third‐generation P‐gp inhibitor. Therefore, we aimed to develop and validate a method for ondansetron and tariquidar in rat and human plasma samples. A full validation was performed for both ondansetron and tariquidar, and sample stability was tested under various storage conditions. To demonstrate its utility, the method was applied to a preclinical pharmacokinetic study following coadministration of ondansetron and tariquidar in rats. The presented method will be valuable in pharmacokinetic studies of ondansetron and tariquidar in which simultaneous determination may be required. In addition, this is the first report of a bioanalytical method validated for quantification of tariquidar in plasma samples. 相似文献
74.
Imines can be readily allylated with samarium/allyl bromide system to afford homoallylamines in satisfactory yields in THF under mild conditions. 相似文献
75.
The synthesis of a benzooxazol-5-yl acetic acid derivative (9) with strong heparanase and angiogenesis inhibitory activity, and thus possible commercial interest, is described in detail. 相似文献
76.
Johan F. A. Pijnenborg Eline A. Visser Dr. Marek Noga Emiel Rossing Raisa Veizaj Prof. Dirk J. Lefeber Dr. Christian Büll Dr. Thomas J. Boltje 《Chemistry (Weinheim an der Bergstrasse, Germany)》2021,27(12):4022-4027
Fucosylation of glycans impacts a myriad of physiological and pathological processes. Inhibition of fucose expression emerges as a potential therapeutic avenue for example in cancer, inflammation, and infection. In this study, we found that protected 2-fluorofucose 1-phosphate efficiently inhibits cellular fucosylation with a four to seven times higher potency than known inhibitor 2FF, independently of the anomeric stereochemistry. Nucleotide sugar analysis revealed that both the α- and β-GDP-2FF anomers are formed inside the cell. In conclusion, we developed A2FF1P and B2FF1P as potent new tools for studying the role of fucosylation in health and disease and they are potential therapeutic candidates. 相似文献
77.
《Biomedical chromatography : BMC》2017,31(3)
MLN0128, an mTOR kinase inhibitor, is currently undergoing clinical investigation for treatment of a variety of cancers. To support this work, an LC–MS/MS method has been developed for the determination of MLN0128 in human plasma. A structural analog STK040263 was used as the internal standard. Both MLN0128 and the IS were first extracted from plasma using methyl tert ‐butyl ether; then separated on a Waters XTerra® MS C18 column using a mobile phase consisting of methanol–acetonitrile–10.0 mm ammonium formate (34:6:60, v /v/v) at a flow rate of 0.300 mL min−1. Quantitation of MLN0128 was done by positive electrospray ionization tandem mass spectrometry in multiple‐reaction‐monitoring mode. This method has a total run time of <4 min with the retention times of 1.95 and 2.94 min for the IS and MLN0128, respectively. The method has been validated per the US Food and Drug Administration guidance for bioanalytical method validation. It has a calibration range of 0.100–50.0 ng mL−1 in human plasma with a correlation coefficient > 0.999. The overall assay accuracy and precision were ≤ ± 4 and ≤8%, respectively. The IS normalized recovery of MLN0128 was 98–100%. The stability studies showed that MLN0128 was stable under all tested conditions. The method developed may be useful for clinical studies of MLN0128. 相似文献
78.
《Biomedical chromatography : BMC》2017,31(11)
A rapid and highly specific assay was developed and validated for the estimation of ZYDPLA1 in rat plasma using liquid chromatography coupled to tandem mass spectrometry with positive electrospray ionization. Method validation comprised of parameters such as specificity, matrix effect, precision, accuracy, recovery, stability, etc. The assay procedure involved a simple protein precipitation of ZYDPLA1 and alprazolam (internal standard) from rat plasma using acetonitrile. Chromatographic separation was achieved with a gradient mobile phase comprising: (A) 0.2% ammonia in purified water; (B) 0.1% formic acid in isopropyl alcohol/methanol (1: 1 v /v); and (C) acetonitrile at a flow rate of 1 mL/min on an ACE‐5, C18 (4.6 × 50 mm) column with a run time of 5.5 min. The quantitation of ZYDPLA1 was achieved by the summation of four multiple reaction mode transitions (m/z 399.7 → 383.0, 399.7 → 276.10, 399.7 → 153.20 and 399.7 → 127.20), while that of the internal standard was by a single multiple reaction mode transition (m/z 309.10 → 281.00). The lower limit of quantitation achieved was 0.01 μg/mL and the method showed linearity from 0.01 to 25 μg/mL. The intra‐ and inter‐day precision (%CV) of the quality control samples was within 8.81% and accuracy was ±10% of nominal values. This novel method was applied for evaluation of toxicokinetics of ZYDLA1 in rats. 相似文献
79.
80.