1,2,6-thiadiazinones as novel narrow spectrum calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) inhibitors

We demonstrate for the first time that 4H-1,2,6-thiadiazin-4-one (TDZ) can function as a chemotype for the design of ATP-competitive kinase inhibitors. Using insights from a co-crystal structure of a 3,5-bis(arylamino)-4H-1,2,6-thiadiazin-4-one bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), several analogues were identified with micromolar activity through targeted displacement of bound water molecules in the active site. Since the TDZ analogues showed reduced promiscuity compared to their 2,4-dianilinopyrimidine counter parts, they represent starting points for development of highly selective kinase inhibitors

Diffractive Contribution to the Elasticity and the Nucleonic Flux in the Atmosphere

We calculate the average elasticity considering non-diffractive and single diffractive interactions and perform an analysis of the cosmic-ray flux by means of an analytical solution for the nucleonic diffusion equation. We show that the diffractive contribution is important for the adequate description of the nucleonic and hadronic fluxes in the atmosphere.Comment: 10 pages, latex, 2 figures (uuencoded PostScript

Ensino de Soluções em uma Sala de Alunos Surdos

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Polycyclic Aromatic Hydrocarbons (PAHs) and nitrated analogs associated to particulate matter emission from a Euro V-SCR engine fuelled with diesel/biodiesel blends

© 2018 Among the new technologies developed for the heavy-duty fleet, the use of Selective Catalytic Reduction (SCR) aftertreatment system in standard Diesel engines associated with biodiesel/diesel mixtures is an alternative in use to control the legislated pollutants emission. Nevertheless, there is an absence of knowledge about the synergic behaviour of these devices and biodiesel blends regarding the emissions of unregulated substances as the Polycyclic Aromatic Hydrocarbons (PAHs) and Nitro-PAHs, both recognized for their carcinogenic and mutagenic effects on humans. Therefore, the goal of this study is the quantification of PAHs and Nitro-PAHs present to total particulate matter (PM) emitted from the Euro V engine fuelled with ultra-low sulphur diesel and soybean biodiesel in different percentages, B5 and B20. PM sampling was performed using a Euro V – SCR engine operating in European Stationary Cycle (ESC). The PAHs and Nitro-PAHs were extracted from PM using an Accelerated Solvent Extractor and quantified by GC–MS. The results indicated that the use of SCR and the largest fraction of biodiesel studied may suppress the emission of total PAHs. The Toxic Equivalent (TEQ) was lower when using 20% biodiesel, in comparison with 5% biodiesel on the SCR system, reaffirming the low toxicity emission using higher percentage biodiesel. The data also reveal that use of SCR, on its own, suppress the Nitro-PAHs compounds. In general, the use of larger fractions of biodiesel (B20) coupled with the SCR aftertreatment showed the lowest PAHs and Nitro-PAHs emissions, meaning lower toxicity and, consequently, a potential lower risk to human health. From the emission point of view, the results of this work also demonstrated the viability of the Biodiesel programs, in combination with the SCR systems, which does not require any engine adaptation and is an economical alternative for the countries (Brazil, China, Russia, India) that have not adopted Euro VI emission standards

Renewable resources are the future: The role of sustainable raw materials and the potential of biopolymers in Brazil.

This article discusses the emergence of a global biopolymer market and the potential for economic use in the Brazilian case. The aim is to identify and discuss the potential of access to biopolymers, their uses, and transformations in Brazilian industrial production. It is considered that Brazil has a high production potential for biopolymers. However, it is known that these new materials are still in the initial phase of production and replacement of conventional plastic products. We present global data from regions that stand out in the production process of these raw materials, as well as data on countries that already use these sources to convert more sustainable products. After presenting data, an analysis of Porter's diamond was carried out to know and understand how the biopolymer chain is currently organized, its potential, and its challenges in Brazil

Imidazo[1,2-b]pyridazines as inhibitors of DYRK kinases

Selective inhibitors of DYRK1A are of interest for the treatment of cancer, Type 2 diabetes and neurological disorders. Optimization of imidazo [1,2-b]pyridazine fragment 1 through structure−activity relationship exploration and in silico drug design efforts led to the discovery of compound 17 as a potent cellular inhibitor of DYRK1A with selectivity over much of the kinome. The binding mode of compound 17 was elucidated with X-ray crystallography, facilitating the rational design of compound 29, an imidazo [1,2-b]pyridazine with improved kinase selectivity with respect to closely related CLK kinases.</p

Imidazo[1,2-b]pyridazines as inhibitors of DYRK kinases

Selective inhibitors of DYRK1A are of interest for the treatment of cancer, Type 2 diabetes and neurological disorders. Optimization of imidazo [1,2-b]pyridazine fragment 1 through structure−activity relationship exploration and in silico drug design efforts led to the discovery of compound 17 as a potent cellular inhibitor of DYRK1A with selectivity over much of the kinome. The binding mode of compound 17 was elucidated with X-ray crystallography, facilitating the rational design of compound 29, an imidazo [1,2-b]pyridazine with improved kinase selectivity with respect to closely related CLK kinases.</p

Structural characterization of human Vaccinia-Related Kinases (VRK) bound to small-molecule inhibitors identifies different P-loop conformations

The human genome encodes two active Vaccinia-related protein kinases (VRK), VRK1 and VRK2. These proteins have been implicated in a number of cellular processes and linked to a variety of tumors. However, understanding the cellular role of VRKs and establishing their potential use as targets for therapeutic intervention has been limited by the lack of tool compounds that can specifically modulate the activity of these kinases in cells. Here we identified BI-D1870, a dihydropteridine inhibitor of RSK kinases, as a promising starting point for the development of chemical probes targeting the active VRKs. We solved co-crystal structures of both VRK1 and VRK2 bound to BI-D1870 and of VRK1 bound to two broad-spectrum inhibitors. These structures revealed that both VRKs can adopt a P-loop folded conformation, which is stabilized by different mechanisms on each protein. Based on these structures, we suggest modifications to the dihydropteridine scaffold that can be explored to produce potent and specific inhibitors towards VRK1 and VRK2

Discovery and Characterization of Selective and Ligand-Efficient DYRK Inhibitors

Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) regulates the proliferation and differentiation of neuronal progenitor cells during brain development. Consequently, DYRK1A has attracted interest as a target for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD) and Down's syndrome. Recently, the inhibition of DYRK1A has been investigated as a potential treatment for diabetes, while DYRK1A's role as a mediator in the cell cycle has garnered interest in oncologic indications. Structure-activity relationship (SAR) analysis in combination with high-resolution X-ray crystallography leads to a series of pyrazolo[1,5-b]pyridazine inhibitors with excellent ligand efficiencies, good physicochemical properties, and a high degree of selectivity over the kinome. Compound 11 exhibited good permeability and cellular activity without P-glycoprotein liability, extending the utility of 11 in an in vivo setting. These pyrazolo[1,5-b]pyridazines are a viable lead series in the discovery of new therapies for the treatment of diseases linked to DYRK1A function