Suomen on varauduttava ilmastokriisiin - 6 ohjetta sitkeän ja vähähiilisen yhteiskunnan rakentamiseen

Non peer reviewe

Towards a 300 WP p-Type HIP-MWT-Module - Simulation, Experimental Results and Costs

In this work we are aiming at the goal of fabricating a cost-effective HIP-MWT module exceeding 300W. In order to accomplish this goal HIP-MWT (high-performance metal wrap through) silicon solar cells [1, 2] are fabricated on industrial PERC (passivated emitter and rear cell) precursors. Simulation of the optimal metallization layout for MWT based on measured parameters show cell efficiencies up to 21.5%. The consequentially fabricated HIP-MWT solar cells reach maximum efficiencies of 21.4%. The in parallel processed H-pattern reference cells reach maximum efficiencies of 21.2%. The cell efficiencies show a reduced advantage for MWT than in similar experiments, which is due to the tapered busbars of the reference cells allowing nearly the same short circuit currents. Anyhow, combined with a module interconnection based on back contact foils a cell-to-module (CTM) loss of 2 % is demonstrated which allows module power over 300 WP. Due to a power advantage of about 15W in comparison to H-pattern modules the cost of ownership calculation shows a cost advantage of the HIP-MWT module of 3.2 %. Simulation, experimental results and cost calculation show an advantage for HIP-MWT technology over the H-pattern reference leading to the conclusion that MWT is a more cost-effective concept

Design and synthesis of novel fluorescently labeled analogs of vemurafenib targeting MKK4

The mitogen-activated protein kinase kinase 4 (MKK4) plays a key role in liver regeneration and is under investigation as a target for stimulating hepatocytes to increased proliferation. Therefore, new small molecules inhibiting MKK4 may represent a promising approach for treating acute and chronic liver diseases. Fluorescently labeled compounds are useful tools for high-throughput screenings of large compound libraries. Here we utilized the azaindole-based scaffold of FDA-approved BRAF inhibitor vemurafenib 1, which displays off-target activity on MKK4, as a starting point in our fluorescent compound design. Chemical variation of the scaffold and optimization led to a selection of fluorescent 5-TAMRA derivatives which possess high binding affinities on MKK4. Compound 45 represents a suitable tool compound for Fluorescence polarization assays to identify new small-molecule inhibitors of MKK4

Pyridinylimidazoles as GSK3β Inhibitors: The Impact of Tautomerism on Compound Activity via Water Networks

Glycogen synthase kinase-3β (GSK3β) is involved in many pathological conditions and represents an attractive drug target. We previously reported dual GSK3β/p38α mitogen-activated protein kinase inhibitors and identified N-(4-(4-(4-fluorophenyl)-2-methyl-1H-imidazol-5-yl)pyridin-2-yl)cyclopropanecarboxamide (1) as a potent dual inhibitor of both target kinases. In this study, we aimed to design selective GSK3β inhibitors based on our pyridinylimidazole scaffold. Our efforts resulted in several novel and potent GSK3β inhibitors with IC50 values in the low nanomolar range. 5-(2-(Cyclopropanecarboxamido)pyridin-4-yl)-4-cyclopropyl-1H-imidazole-2-carboxamide (6g) displayed very good kinase selectivity as well as metabolical stability and inhibited GSK3β activity in neuronal SH-SY5Y cells. Interestingly, we observed the importance of the 2-methylimidazole's tautomeric state for the compound activity. Finally, we reveal how this crucial tautomerism effect is surmounted by imidazole-2-carboxamides, which are able to stabilize the binding via enhanced water network interactions, regardless of their tautomeric state

Discovery and evaluation of enantiopure 9H-pyrimido[4,5\u2010b]indoles as nanomolar GSK\u20103\u3b2 inhibitors with improved metabolic stability

Glycogen synthase kinase\u20103\u3b2 (GSK\u20103\u3b2) is a potential target in the field of Alzheimer\u2019s disease drug discovery. We recently reported a new class of 9H\u2010pyrimido[4,5\u2010b]indole\u2010based GSK\u2010 3\u3b2 inhibitors, of which 3\u2010(3\u2010((7\u2010chloro\u20109H\u2010pyrimido[4,5\u2010b]indol\u20104\u2010yl)(methyl)amino)piperidin\u20101\u2010yl)propanenitrile (1) demonstrated promising inhibitory potency. However, this compound underwent rapid degradation by human liver microsomes. Starting from 1, we prepared a series of amide\u2010based derivatives and studied their structure\u2013activity relationships against GSK\u20103\u3b2 supported by 1 \u3bcs molecular dynamics simulations. The biological potency of this series was substantially enhanced by identifying the eutomer configuration at the stereocenter. Moreover, the introduction of an amide bond proved to be an effective strategy to eliminate the metabolic hotspot. The most potent compounds, (R)\u20103\u2010(3\u2010((7\u2010chloro\u20109H\u2010pyrimido[4,5\u2010b]indol\u20104\u2010 yl)(methyl)amino)piperidin\u20101\u2010yl)\u20103\u2010oxopropanenitrile ((R)\u20102) and (R)\u20101\u2010(3\u2010((7\u2010bromo\u2010 9Hpyrimido[4,5\u2010b]indol\u20104\u2010yl)(methyl)amino)piperidin\u20101\u2010yl)propan\u20101\u2010one ((R)\u201028), exhibited IC50 values of 480 nM and 360 nM, respectively, and displayed improved metabolic stability. Their favorable biological profile is complemented by minimal cytotoxicity and neuroprotective properties