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91.
Eva-Maria Herrlinger Mirjam Hau Dr. Desiree Melanie Redhaber Dr. Gabriele Greve Dr. Dominica Willmann Simon Steimle Prof. Dr. Michael Müller Prof. Michael Lübbert Dr. Christoph Cornelius Miething Prof. Roland Schüle Prof. Manfred Jung 《Chembiochem : a European journal of chemical biology》2020,21(16):2329-2347
Lysine-specific demethylase 1 (LSD1) has evolved as a promising therapeutic target for cancer treatment, especially in acute myeloid leukaemia (AML). To approach the challenge of site-specific LSD1 inhibition, we developed an enzyme-prodrug system with the bacterial nitroreductase NfsB (NTR) that was expressed in the virally transfected AML cell line THP1-NTR+. The cellular activity of the NTR was proven with a new luminescent NTR probe. We synthesised a diverse set of nitroaromatic prodrugs that by design do not affect LSD1 and are reduced by the NTR to release an active LSD1 inhibitor. The emerging side products were differentially analysed using negative controls, thereby revealing cytotoxic effects. The 2-nitroimidazolyl prodrug of a potent LSD1 inhibitor emerged as one of the best prodrug candidates with a pronounced selectivity window between wild-type and transfected THP1 cells. Our prodrugs are selectively activated and release the LSD1 inhibitor locally, proving their suitability for future targeting approaches. 相似文献
92.
Jiale Feng Lupeng Yang Alexander S. Romanov Jirawit Ratanapreechachai Antti‐Pekka M. Reponen Saul T. E. Jones Mikko Linnolahti Timothy J. H. Hele Anna Khler Heinz Bssler Manfred Bochmann Dan Credgington 《Advanced functional materials》2020,30(9)
Carbene‐metal‐amides (CMAs) are a promising family of donor–bridge–acceptor molecular charge‐transfer (CT) emitters for organic light‐emitting diodes. A universal approach is demonstrated to tune the energy of their CT emission. A blueshift of up to 210 meV is achievable in solid state via dilution in a polar host matrix. The origin of this shift has two components: constraint of thermally‐activated triplet diffusion, and electrostatic interactions between guest and polar host. This allows the emission of mid‐green CMA archetypes to be tuned to sky blue without chemical modifications. Monte‐Carlo simulations based on a Marcus‐type transfer integral successfully reproduce the concentration‐ and temperature‐dependent triplet diffusion process, revealing a substantial shift in the ensemble density of states in polar hosts. In gold‐bridged CMAs, this shift does not lead to a significant change in luminescence lifetime, thermal activation energy, reorganization energy, or intersystem crossing rate. These discoveries offer new insight into coupling between the singlet and triplet manifolds in CMA materials, revealing a dominant interaction between states of CT character. The same approach is employed using materials which have been chemically modified to alter the energy of their CT state directly, shifting the emission of sky‐blue chromophores into the practical blue range. 相似文献
93.
A low‐carbon electricity supply for Australia was simulated, and the installed capacity of the electrical grid was optimized by shifting the electricity demand of residential electric water heaters (EWHs). The load‐shifting potential of Australia was estimated for each hour of the simulation period using a nationwide aggregate EWH load model on a 90 × 110 raster grid. The electricity demand of water heaters was shifted from periods of low renewable resource and high demand to periods of high renewable resource and low demand, enabling us to effectively reduce the installed capacity requirements of a 100%‐renewable electricity grid. It was found that by shifting the EWH load by just 1 hour, the electricity demand of Australia could be met using purely renewable electricity at an installed capacity of 145 GW with a capacity factor of 30%, an electricity spillage of 20%, and a generation cost of 15.2 ¢/kWh. A breakdown of the primary energy sources used in our scenario is as follows: 43% wind, 29% concentrated solar thermal power, and 20% utility photovoltaic. Sensitivity analysis suggested that further reduction in installed capacity is possible by increasing the load‐shifting duration as well as the volume and insulation level of the EWH tank. 相似文献
94.
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97.
This article debates the production of mouldings made of keratin. It is demonstrated that the properties of keratin allow
for being processed with heat and pressure to manufacture tough mouldings without chemical preprocessing of the used wool.
This material thus has a high potential as a bioplastic, because it potentially can be used with conventional plastic manufacturing
techniques. Additionally, it might also serve as an adhesive in various applications. The biobased material might become a
sustainable source for mouldings.
相似文献
Manfred DrackEmail: |
98.
The Alternaria toxins alternariol (AOH; 3,7,9-trihydroxy-1-methyl-6H-benzo[c]chromen-6-one) and alternariol methyl ether (AME, 3,7-dihydroxy-9-methoxy-1-methyl-6H-benzo[c]chromen-6-one) are common contaminants of food and feed, but their oxidative metabolism in mammals is as yet unknown. We have therefore incubated AME and AOH with microsomes from rat, human, and porcine liver and analyzed the microsomal metabolites with HPLC and GC-MS/MS. Seven oxidative metabolites of AME and five of AOH were detected. Their chemical structures were derived from their mass spectra using deuterated trimethylsilyl (TMS) derivatives, and from the information obtained from enzymatic methylation. Several of the metabolites were identified by comparison with synthetic reference compounds. AME as well as AOH were monohydroxylated at each of the four possible aromatic carbon atoms and also at the methyl group. In addition, AME was demethylated to AOH and dihydroxylated to a small extent. As the four metabolites arising through aromatic hydroxylation of AME and AOH are either catechols or hydroquinones, the oxidative metabolism of these mycotoxins may be of toxicological significance. 相似文献
99.
Lebedkin S Blum C Stürzl N Hennrich F Kappes MM 《The Review of scientific instruments》2011,82(1):013705
We describe the simple modification of a confocal Raman imaging microscope to incorporate two ultra-narrow holographic notch filters. The modified microscope rejects the laser excitation line (Rayleigh peak) by a discrimination factor of ~10(11) and allows simultaneous measurements of Stokes/anti-Stokes Raman shifts as close as ~10/20 cm(-1) to the Rayleigh line. The extremely high rejection ratio of the Rayleigh peak results in its intensity becoming comparable to typical Raman scattering signals. This is essential for micro-Raman spectroscopy and imaging in the low-wavenumber region. We illustrate the resulting performance with measurements on silicon/silica, sapphire, sulfur, L-cystine, as well as on single-walled carbon nanotubes (SWNTs). We find that both aggregated (bulk) and individual (deposited on substrate) SWNTs demonstrate strong and broad characteristic Raman features below ~100 cm(-1)-in a region which has remained essentially unexplored in measurements of bulk SWNT samples and which has so far been inaccessible for Raman spectroscopy of individual SWNTs. 相似文献
100.
Dr. Li Di Prof. Per Artursson Dr. Alex Avdeef Prof. Leslie Z. Benet Prof. J. Brian Houston Dr. Manfred Kansy Edward H. Kerns Prof. Hans Lennernäs Dr. Dennis A. Smith Prof. Kiyohiko Sugano 《ChemMedChem》2020,15(20):1862-1874
Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients. 相似文献