Synthesis and SAR of Tetracyclic Inhibitors of Protein Kinase CK2 Derived from Furocarbazole W16

The serine/threonine kinase CK2 modulates the activity of more than 300 proteins and thus plays a crucial role in various physiological and pathophysiological processes including neurodegenerative disorders of the central nervous system and cancer. The enzymatic activity of CK2 is controlled by the equilibrium between the heterotetrameric holoenzyme CK2α₂β₂ and its monomeric subunits CK2α and CK2β. A series of analogues of W16 ((3aR,4S,10S,10aS)-4-{[(S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-10-(3,4,5-trimethoxyphenyl)-4,5,10,10a-tetrahydrofuro[3,4-b]carbazole-1,3(3aH)-dione ((+)- 3 a )) was prepared in an one-pot, three-component Levy reaction. The stereochemistry of the tetracyclic compounds was analyzed. Additionally, the chemically labile anhydride structure of the furocarbazoles 3 was replaced by a more stable imide ( 9 ) and N-methylimide ( 10 ) substructure. The enantiomer (−)- 3 a (K_i=4.9 μM) of the lead compound (+)- 3 a (K_i=31 μM) showed a more than sixfold increased inhibition of the CK2α/CK2β interaction (protein-protein interaction inhibition, PPII) in a microscale thermophoresis (MST) assay. However, (−)- 3 a did not show an increased enzyme inhibition of the CK2α₂β₂ holoenzyme, the CK2α subunit or the mutated CK2α′ ^C336S subunit in the capillary electrophoresis assay. In the pyrrolocarbazole series, the imide (−)- 9 a (K_i=3.6 μM) and the N-methylimide (+)- 10 a (K_i=2.8 μM) represent the most promising inhibitors of the CK2α/CK2β interaction. However, neither compound could inhibit enzymatic activity. Unexpectedly, the racemic tetracyclic pyrrolocarbazole (±)- 12 , with a carboxy moiety in the 4-position, displays the highest CK2α/CK2β interaction inhibition (K_i=1.8 μM) of this series of compounds.     

Parametric study for the growth of carbon nanotubes by catalytic chemical vapor deposition in a fluidized bed reactor

Multiwalled carbon nanotubes have been produced from H₂-C₂H₄ mixtures on Fe-SiO₂ catalysts by a fluidized bed catalytic chemical vapor deposition process. Various parameters such as the catalyst preparation, the residence time, the run duration, the temperature, the H₂:C₂H₄ ratio, the amount of metal deposited on the support have been examined. The influence of these parameters on the deposited carbon yield is reported, together with observations of the produced material. This process allows an homogeneously distributed deposition of nanotubes (10-20 nm diameter), that remain anchored to the support.     

Enhanced UV- and visible-light driven photocatalytic performances and recycling properties of graphene oxide/ZnO hybrid layers

Light induced catalytic processes have attracted significant attention during the last years for wastewater treatment due to their efficiency in decomposition of organic contaminants. In this study we report the synthesis of graphene oxide (GO)/ZnO hybrid layers with high photocatalytic efficiency using laser radiation. The results show that the hybrid layers exhibit much improved photodecomposition efficiency as compared to pure GO or ZnO both under UV and visible-light irradiation. The enhanced photocatalytic efficiency of the hybrid as compared to the reference pure ZnO and GO layers was attributed to the contribution of GO to the separation and transport of the photogenerated charge carriers. Additionally, under visible light irradiation the organic molecules can act as first sensitizers in the degradation process. The recyclability of the layers was also investigated through repetitive photodegradation cycles under UV- or visible-light irradiation. After consecutive degradation runs, the hybrid photocatalyst layers were still stable and retained high degradation efficiency, ensuring reusability. The photocatalytic activity of the layers was correlated with the gradual change of their chemical structure during consecutive degradation cycles. Owing to the high photodegradation efficiency, reusability, and ease of recovery the synthesised hybrid layers consisting of easily available materials are suitable for environmental purification applications.     

Synthesis of 2‐[18F]Fluoro‐2‐deoxyisosorbide 5‐mononitrate and Assessment of Its in vivo Biodistribution as Determined by Dynamic Positron Emission Tomography (PET)

Herein we disclose the synthesis of 2‐fluoro‐2‐deoxyisosorbide 5‐mononitrate (2F‐IS‐5MN), a fluorinated analogue of the commonly prescribed vasodilator isosorbide 5‐mononitrate (IS‐5MN). X‐ray structural data for IS‐5MN and its C2‐epimeric congener IM‐5MN are presented together with structural data for 2F‐IS‐5MN. Radioisotope labeling of 2F‐IS‐5MN has, for the first time, allowed observation of the in vivo biodistribution of this organic nitrate by means of dynamic positron emission tomography (PET) in wild‐type mice.     

Studies on physico-chemical and antibacterial properties of grafted pullulans solutions

The physico-chemical properties of three grafted pullulans (P) having linked poly(3-acrylamidopropyl)trimethylammonium chloride (pAPTAC) as side chains (P-g-pAPTAC1, P-g-pAPTAC2 and P-g-pAPTAC3 with 22.53, 29.05, and 34.51 (wt.%) of pAPTAC content in polymer, respectively) and possessing polyelectrolyte character were determined by light scattering analysis. All grafted pullulan aqueous solutions were tested in the presence of 0.5 M NaCl, KCl, NaNO₃ or KNO₃. The biggest associations were recorded in 0.5 M NaCl aqueous solutions for P-g-pAPTAC1, P-g-pAPTAC2 and P-g-pAPTAC3 according to the maximum values for R_g extracted from MALLS (multiangle laser light scattering) measurements. Also, the dominant conformation in salted solution of these polyelectrolytes was random coil as Debye plot analysis revealed. Antibacterial activity was tested by Kirby–Bauer diffusion method and all grafted pullulans dissolved in aqueous solutions of 0.5 M NaCl have developed inhibition zone against Staphylococcus aureus (ATCC 25923).     

<Emphasis Type="Italic">In situ</Emphasis> monitoring of solid fat content by means of pulsed nuclear magnetic resonance spectrometry and ultrasonics

An ultrasonic technique was developed to study the crystallization process of edible fats on-line. A chirp wave was used instead of the conventional pulser signal, thus achieving a higher signal-to-noise ratio. This enabled measurements to be made in concentrated systems [≈20% solid fat content (SFC)] through a 8.11-cm thick sample without significant signal loss. Fat samples were crystallized at 20, 25, and 30°C at a constant agitation rate of 400 rpm for 90 min. The crystallization process was followed by ultrasonic spectroscopy and a low-resolution pulsed nuclear magnetic resonance spectrometer. Specific relationships were found between ultrasonic parameters [integrated response, time of flight (TF), and full width half maximum] and SFC. TF, which is an indirect measurement of the ultrasonic velocity (v), was highly correlated to SFC (r ²>0.9) in a linear fashion (v=2.601 SFC+1433.0).     

Lactones in the Synthesis of Prostaglandins and Prostaglandin Analogs

In the total stereo-controlled synthesis of natural prostaglandins (PGs) and their structural analogs, a vast class of compounds and drugs, known as the lactones, are encountered in a few key steps to build the final molecule, as: δ-lactones, γ-lactones, and 1,9-, 1,11-, and 1,15-macrolactones. After the synthesis of 1,9-PGF_2α and 1,15-PGF_2α lactones, many 1,15-lactones of E₂, E₃, F₂, F₃, A₂, and A₃ were found in the marine mollusc Tethys fimbria and the quest for understanding their biological role stimulated the research on their synthesis. Then 1,9-, 1,11-, and 1,15-PG lactones of the drugs were synthesized as an alternative to the corresponding esters, and the first part of the paper describes the methods used for their synthesis. The efficient Corey procedure for the synthesis of prostaglandins uses the key δ-lactone and γ-lactone intermediates with three or four stereocenters on the cyclopentane fragment to link the PG side chains. The paper describes the most used procedures for the synthesis of the milestone δ-Corey-lactones and γ-Corey-lactones, their improvements, and some new promising methods, such as interesting, new stereo-controlled and catalyzed enantioselective reactions, and methods based on the chemical/enzymatic resolution of the compounds in different steps of the sequences. The many uses of δ-lactones not only for the synthesis of γ-lactones, but also for obtaining 9β-halogen-PGs and halogen-substituted cyclopentane intermediates, as synthons for new 9β-PG analogs and future applications, are also discussed.     

Using hydroacoustics to relate fluctuations in fish abundance to river restoration efforts and environmental conditions in the Penobscot River,Maine

Quantifying change after large habitat restoration efforts is critical to assessing the effort's success. After river restoration activities, fish abundance is expected to increase and also fluctuates naturally by season and with environmental conditions. A side‐looking hydroacoustic system was used to estimate fish abundance in the Penobscot River, ME, from 2010 to 2016 during predam (2010–2013) and postdam (2014–2016) removal years during nonice periods. Automated data processing enabled continuous abundance estimates from fish tracks. A threefold increase in mean fish abundance was recorded after dam removal. A fourfold increase in median fish abundance occurred in the fall relative to spring and summer of the same year, regardless of dam presence. Interannual fish abundance in every season monitored increased at least twofold after dam removal. We related variability in fish abundance to tide, discharge, temperature, diurnal cycle, daylength, moon phase, and restoration activities (focusing on dam presence). Daylength corresponding to the fall and summer was the most important indicator for higher fish abundance. Fish abundance was generally greatest in the fall during outgoing tides at night, with lesser peaks occurring during the month of June at night. Before dam removal, fish abundance peaked when water temperature was less than 9.25°C, at night, during outgoing tides. After dam removal, fish abundance peaked when daylength was less than 11.3 hr, at night, during outgoing tides, when water temperature was above 4.56°C and no full moon was present. Peak fish abundance occurred during only 0.02–2.3% of the total time sampled. The threefold increase in fish abundance recorded after dam removal was observed despite yearly stocking efforts of adult alewife increasing 24% in postdam removal years. Finally, parallel studies of fish presence in the Penobscot River were used to compare the utility of this method as an indicator of fish abundance in response to dam removal.     

Synthesis and characterization of {Fe2CuO} clusters as precursors for nanosized catalytic system for Biginelli reaction

The novel μ₃-oxo-bridged heterotrinuclear iron(III)-copper(II) trichloroacetates of the composition [Fe₂CuO(CCl₃COO)₆(THF)₃] (1a) and [Fe₂CuO(CCl₃COO)₆(4-DMAP)₃] (1b) have been synthesized and characterized by X-ray crystallography, IR and Mossbauer spectroscopy. These clusters were used as precursors for the synthesis of the nanosized catalytic system (～5–6 nm of γ-Fe₂O₃/CuO), which works as an efficient organic phase catalyst (～0.02 mol%) in a one-pot three component Biginelli synthesis.