Mapping the fluorophilicity of a hydrophobic pocket: synthesis and biological evaluation of tricyclic thrombin inhibitors directing fluorinated alkyl groups into the p pocket

In the completion of our fluorine scan of tricyclic inhibitors to map the fluorophilicity/fluorophobicity of the thrombin active site, a series of 11 new ligands featuring alkyl, alkenyl, and fluoroalkyl groups was prepared to explore fluorine effects on binding into the hydrophobic proximal (P) pocket, lined by Tyr 60A and Trp 60D, His 57, and Leu 99. The synthesis of the tricyclic scaffolds was based on the 1,3-dipolar cycloaddition of azomethine ylides, derived from L-proline and 4-bromobenzaldehyde, with N-(4-fluorobenzyl)maleimide. Introduction of alkyl, alkenyl, and partially fluorinated alkyl residues was achieved upon substitution of a sulfonyl group by mixed Mg/Zn organometallics followed by oxidation/deoxyfluorination, as well as oxidation/reduction/deoxyfluorination sequences. In contrast, the incorporation of perfluoroalkyl groups required a stereoselective nucleophilic addition reaction at the "upper" carbonyl group of the tricycles, thereby yielding scaffolds with an additional OH, F, or OMe group, respectively. All newly prepared inhibitors showed potent biological activity, with inhibitory constants (K(i) values) in the range of 0.008-0.163 microM. The X-ray crystal structure of a protein-ligand complex revealed the exact positioning of a difluoromethyl substituent in the tight P pocket. Fluorophilic characteristics are attributed to this hydrophobic pocket, although the potency of the inhibitors was found to be modulated by steric rather than electronic factors.     

DNA-protein noncovalent cross-linking: ruthenium dipyridophenazine biotin complex for the assembly of proteins and gold nanoparticles on DNA templates

We report the first example of a small molecule that can noncovalently cross-link DNA with streptavidin and streptavidin-labeled materials. Molecule 1 possesses a ruthenium dipyridophenazine DNA-intercalating moiety and a biotin unit; these two units are adequately separated to ensure efficient cross-linking of DNA with protein. Complex 1 is essentially nonemissive in aqueous solution and when bound to streptavidin, however, its luminescence is turned "on" when it binds to DNA. We have used these properties to establish that this complex can simultaneously bind to DNA and streptavidin, and can thus bring these two biomolecules together. We also synthesized a related molecule, 3, in which the biotin and DNA-intercalating moieties are covalently bound. While complex 3 can intercalate into DNA through a threading mechanism, luminescence experiments show that it cannot simultaneously bind DNA and streptavidin, most likely due to the proximity of its two molecular-recognition units. The cross-linking ability of molecule 1 was used to template the assembly of streptavidin molecules on circular plasmid DNA, as visualized by atomic force microscopy. In addition, using 1, we show the organization of discrete groups of gold nanoparticles labeled with streptavidin on a linear DNA template of finite size, with transmission electron microscopy. In these experiments the DNA template acted as a "molecular ruler" that dictated the number of particles in the assembly.     

Fluorine Scan of Inhibitors of the Cysteine Protease Human Cathepsin L: Dipolar and Quadrupolar Effects in the π‐Stacking of Fluorinated Phenyl Rings on Peptide Amide Bonds

The π‐stacking of fluorinated benzene rings on protein backbone amide groups was investigated, using a dual approach comprising enzyme–ligand binding studies complemented by high‐level quantum chemical calculations. In the experimental study, the phenyl substituent of triazine nitrile inhibitors of human cathepsin L (hCatL), which stacks onto the peptide amide bond Gly67?Gly68 at the entrance of the S3 pocket, was systematically fluorinated, and differences in inhibitory potency were measured in a fluorimetric assay. Binding affinity is influenced by lipophilicity (clog P), the dipole and quadrupole moments of the fluorinated rings, but also by additional interactions of the introduced fluorine atoms with the local environment of the pocket. Generally, the higher the degree of fluorination, the better the binding affinities. Gas phase calculations strongly support the contributions of the molecular quadrupole moments of the fluorinated phenyl rings to the π‐stacking interaction with the peptide bond. These findings provide useful guidelines for enhancing π‐stacking on protein amide fragments.     

Volatilisation and catalytic effects of alkali and alkaline earth metallic species during the pyrolysis and gasification of Victorian brown coal. Part IX. Effects of volatile-char interactions on char-H2O and char-O2 reactivities

Volatile-char interactions are an important consideration in the design and operation of a gasifier. This study aims to investigate the effects of volatile-char interactions on the in situ char-steam reactivity at 800 °C and the ex-situ char-O₂ reactivity at 400 °C. A Victorian brown coal was gasified in 15% steam at 800 °C in a one-stage novel fluidised-bed/fixed-bed quartz reactor, in which the extent of volatile-char interactions could be controlled. The chars after varying extents of volatile-char interactions and/or varying extents of char conversion in steam were also collected for the measurement of their reactivity with air at 400 °C in a thermogravimetric analyser. Our results show that the char-steam gasification reactions were greatly inhibited by the volatile-char interactions. It is believed that the H radicals generated from the thermal cracking/reforming of volatiles slowed the char gasification in three ways: occupying the char reactive sites, causing the char structure to re-arrange/condense and enhancing the release of catalytic species inherently present in the brown coal. The importance of volatile-char interactions to char-steam reactivity was further confirmed by the char-air reactivity.     

Electrochemistry of anodic fluorine gas evolution at carbon electrodes: Part II studies on the ‘CF’ film by the current-interruption,AC impedance,ESCA and auger techniques

The CF films that are formed on the surface of carbon anodes used for the fluorine evolution reaction (FER) in KF·2HF melts at 358 K have been studied by bothin situ electrochemical current-interruption and a.c. impedance methods, and byex situ surface spectroscopy [ESCA (XPS) and Auger] techniques. The surface analysis measurements indicate that a thin CF (CF₂) film, 1.7 nm in thickness is formed on the carbon anodesurface. Results from depth profiling analyses of the film indicate that it is not uniform, higher levels of CF and F components being found towards the carbon anode surface. Thein situ electrochemical measurements demonstrate that an abnormally small interfacial capacitance, (1.6–2.7)×10^–7 F cm^–2, arises in the course of the FER at carbon anodes; this was attributed to the presence of a passive dielectric CF film on the carbon electrodes. The determined interfacial capacitance does not change significantly with potential in the potential range studied, which implies that the thickness of the CF film on the fluorine-evolving carbon anodes may be independent of potential.     

Chemoenzymatic synthesis of HIV-1 gp41 glycopeptides: effects of glycosylation on the anti-HIV activity and alpha-helix bundle-forming ability of peptide C34

C34 is a 34-mer peptide derived from the C-terminal ectodomain of HIV-1 envelope glycoprotein, gp41. The C34 region in native gp41 carries a conserved N-glycan at Asn637 and the sequence is directly involved in the virus-host membrane fusion, an essential step for HIV-1 infection. This paper describes the synthesis of glycoforms of C34 which carry a monosaccharide, a disaccharide, and a native oligosaccharide moiety. The synthesis of the glycopeptide which carries a native high-mannose type N-glycan was achieved by a chemoenzymatic approach by using an endoglycosidase-catalyzed oligosaccharide transfer as the key step. The effects of glycosylation on the inhibitory activity and the helix-bundle forming ability of C34 were investigated. It was found that glycosylation moderately decreases the anti-HIV activity of C34 and, in comparison with C34, glyco-C34 forms less compact six-helix bundles with the corresponding N-terminal peptide, N36. This study suggests that conserved glycosylation modulates the anti-HIV activity and conformations of the gp41 C-peptide, C34.     

Influence of the Electronic Structure of the Metal at the Polymer/Metal Interface: A Tentative Interpretation on the Basis of Lewis Acid-Base Reactions

In the present paper, we examine the link between theoretical qualitative predictions made on the grounds of the Lewis acid-base concept and the actual interface built between polyamide-6,6 (PA-6,6) and copper, and PA-6,6 and platinum. By using a combination of very-surface-sensitive photoemission spectroscopies and model polymers, it becomes possible to obtain important information about the chemical nature of the polymer/metal interface. Our experiments show a complete dissociative chemisorption of the polymer on Pt, while PA-6,6 retains its chemical integrity on copper.     

The effects of nitrogen fertilizer form on the plant availability of phosphate from soil,phosphate rock and mono-calcium phosphate

A glasshouse trial using lettuce as the test crop, and laboratory incubations were used to evaluate the influence of various nitrogen fertilizers on the availability of phosphate from an unfertilized loamy sand soil and from the same soil fertilized with Sechura phosphate rock or monocalcium phosphate. The order in which nitrogen fertilizer form increased plant yield and P uptake from soil alone and from soil fertilized with the rock was ammonium sulphate > sulphurised urea > ammonium nitrate > urea > potassium nitrate. For each rock application (both 30 and 60 mg/pot) and for soil alone, increased P uptake by the plant correlated well with decreased soil pH. In soil fertilized with the soluble P form, monocalcium phosphate, the form of the nitrogen fertilizer had little effect on plant P uptake. Subsequent laboratory incubation studies showed that increased dissolution of soil-P or Sechura phosphate rock did not occur until acidity, generated by nitrification or sulphur oxidation of the fertilizer materials, had lowered soil pH to below 5.5. A sequential phosphate fractionation procedure was used to show that in soils treated with the acidifying nitrogen fertilizers, ammonium sulphate and urea, there was considerable release of Sechura phosphate rock P to the soil, amounting to 42% and 27% of the original rock P added, respectively.     

Inhibitory effect of umbelliferone aminoalkyl derivatives on oxidosqualene cyclases from S. cerevisiae, T. cruzi, P. carinii, H. sapiens, and A. thaliana: a structure-activity study

Eighteen coumarin derivatives were tested as inhibitors of oxidosqualene cyclases (OSCs) from Saccharomyces cerevisiae, Trypanosoma cruzi, Pneumocystis carinii, Homo sapiens, and Arabidopsis thaliana, all expressed in an OSC-defective strain of S. cerevisiae.35 All the compounds have an aminoalkyl chain bound to an aromatic nucleus; unconventional synthetic procedures (microwave- and ultrasound-promoted reactions) were successfully used to prepare some of them. The most interesting structure-dependent difference in inhibitory activities was observed with an N-oxide group replacement of the tertiary amino group at the end of the side chain. An interesting species specificity also emerged: T. cruzi OSC was the least sensitive enzyme; P. carinii and A. thaliana OSCs were the most sensitive. The remarkable activities of three compounds on the T. cruzi enzyme and of five of them on the P. carinii enzyme suggest the present series as a promising compound family for the development of novel antiparasitic agents.     

Catalytic decomposition of N2O on supported Pd catalysts: Support and thermal ageing effects on the catalytic performances

This study is devoted to the catalytic decomposition of N₂O over noble metal-based catalysts under lean conditions in the presence of O₂, NO and water. A particular attention has been paid toward the influence of the support and the thermal ageing-induced effects on the catalytic properties of palladium species. In those operating conditions, the deposition of palladium on reducible supports, such as LaCoO₃, leads to higher activity in comparison with conventional supports such as alumina. Surface reconstructions take place during thermal ageing under reactive conditions on pre-reduced perovskite-based catalysts which lead to a significant rate enhancement in the decomposition of N₂O. On the other hand, it was found that oxygen and water strongly inhibit the surface reconstructions associated with changes in the selectivity towards the production of NO₂.     

Mass Transfer in the Celery Slice: Effects of Temperature,Moisture Content,and Density on Water Diffusivity

Abstract

Statistical tests were applied to determine the effects of temperature, moisture content, density, and porosity of material on the effective moisture diffusion coefficient during convective drying of root celery. In biological materials with colloidal capillary-porous structure (like root celery), which shrink considerably during drying and show high heterogeneity, the effective water diffusion coefficient depends not only on material temperature and moisture content, but also on its density. It was found that statistical tests can be applied to predict which independent variables should describe the water diffusivity in colloidal capillary-porous materials. A mathematical model of the effective water diffusion coefficient in root celery was formulated as Arhenius-type equation with moisture content of the raw material, its temperature and density as independent variables.     

Mass Transfer in the Celery Slice: Effects of Temperature, Moisture Content, and Density on Water Diffusivity

Statistical tests were applied to determine the effects of temperature, moisture content, density, and porosity of material on the effective moisture diffusion coefficient during convective drying of root celery. In biological materials with colloidal capillary-porous structure (like root celery), which shrink considerably during drying and show high heterogeneity, the effective water diffusion coefficient depends not only on material temperature and moisture content, but also on its density. It was found that statistical tests can be applied to predict which independent variables should describe the water diffusivity in colloidal capillary-porous materials. A mathematical model of the effective water diffusion coefficient in root celery was formulated as Arhenius-type equation with moisture content of the raw material, its temperature and density as independent variables.     

盐对水+丙酸+环乙醇三相体系在298.2，303.2和308.2 K下液液相平衡的影响

Effects of salt and temperature on the liquid phase equilibrium of the (water + propionic acid + cyclohexanol) system were investigated. The liquid-liquid equilibrium data in the presence of KCl for various salt ionic strength of 0.5, 1.0, 1.5, 2.0, and 2.5 mol•dm3 and in absence of the salt at T (298.2, 303.2, and 308.2) K were determined. The experimental results were correlated based on the Othmer-Tobias equation and Pitzer ion-interaction model. Thermodynamic properties such as distribution coefficients and activity coefficients of propionic acid in water + cyclohexanol were determined. In addition, the separation factor, S, of the chosen solvent was obtained for the investigated system.     

The Renin–Angiotensin-Aldosterone System,Nitric Oxide,and Hydrogen Sulfide at the Crossroads of Hypertension and COVID-19: Racial Disparities and Outcomes

Coronavirus disease 2019 is caused by SARS-CoV-2 and is more severe in the elderly, racial minorities, and those with comorbidities such as hypertension and diabetes. These pathologies are often controlled with medications involving the renin–angiotensin–aldosterone system (RAAS). RAAS is an endocrine system involved in maintaining blood pressure and blood volume through components of the system. SARS-CoV-2 enters the cells through ACE2, a membrane-bound protein related to RAAS. Therefore, the use of RAAS inhibitors could worsen the severity of COVID-19’s symptoms, especially amongst those with pre-existing comorbidities. Although a vaccine is currently available to prevent and reduce the symptom severity of COVID-19, other options, such as nitric oxide and hydrogen sulfide, may also have utility to prevent and treat this virus.     

熔渗温度和熔渗相组成对三维互穿网络结构(Mo,Ti)Six-RSiC复合材料组成、微观结构、力学和热学性能的影响

以RSiC为基体,通过MoSi2-Si-Ti合金活化熔渗(AMMI)工艺来制备三维互穿网络结构的(Mo,Ti)Six-RSiC复合材料。采用XRD、SEM、力学性能、热膨胀测试等方法研究了熔渗温度和熔渗相组成对复合材料组成、微观结构,力学和热膨胀系数等性能的影响。结果表明:采用AAMI法可获得具有三维互穿网络结构的(Mo,Ti)XSi2-RSiC复合材料,材料的组成主要为SiC、Si、TiSi2和(Mo0.2Ti0.8)Si2;随预熔配方中MoSi2含量和熔渗温度的增加,复合材料的室温力学性能均先增大后减小,采用MoSiTi-2配方1700℃熔渗所得复合材料的力学性能最佳,其弯曲强度、弹性模量和断裂韧性分别为136.8MPa、217.3GPa和2.45MPa·m^1/2,相比基体分别提高约44%,158%和75%;MoSiTi-2-S2.6-1700在1200℃的热膨胀系数约为4.51×10^-6℃^-1,且基体密度对复合材料CTE的影响高于熔渗相组成;随温度升高,复合材料的弯曲强度增加,1400℃时,其弯曲强度为189.4MPa,比室温提高了约38%;随氧化时间增加,MoSiTi-2-S2.6-1700的室温力学性能先增加后降低,氧化60h时,材料的弯曲强度和弹性模量达到最大,分别为146.8MPa和212.08GPa,与未氧化试样相比提高了约16.2%和51.7%,即使氧化100h,材料的力学性能仍高于初始值。     

A new class of highly dispersed VOx catalysts on mesoporous silica: Synthesis, characterization, and catalytic activity in the partial oxidation of ethanol

The morphology of vanadium oxide supported on a titania-modified mesoporous silica (MCM-41), obtained by means of a careful grafting process through atomic layer deposition, was studied using a variety of characterization techniques. The X-ray diffraction (XRD) together with transmission electron microscopy (TEM), ⁵¹V nuclear magnetic resonance (⁵¹V-NMR), Raman, FTIR and DRS-UV/Vis results showed that the vanadia species are extremely well dispersed onto the surface of the mesoporous support; the dispersion being stable upon thermal treatments up to 400 °C. Studies of the catalytic activity of these materials were performed using the partial oxidation of ethanol as a probe reaction. The results indicate an intrinsic relationship between dispersion, the presence of a TiO₂–VO_x phase, and catalytic activity for oxidation and dehydration.     

Studies on the catalytic dechlorination and abatement of chlorided VOC: the cases of 2-chloropropane, 1,2-dichloropropane and trichloroethylene

The conversion of monochloropropanes and dichloropropanes over acid catalysts has been investigated in the presence of oxygen. In the temperature range of 450–550 K, dehydrochlorination of monochloropropanes to propene and HCl occurs selectively over silica–alumina, while significant formation of chlorinated by-products is observed over ZSM5 zeolite catalyst even at higher temperatures. Dichloropropanes conversion over silica–alumina catalyst gives rise mainly to chloropropenes in the temperature range 500–700 K. CO_x are predominant products only at the highest reaction temperatures (just above 700 K). Water vapor in the feed only slightly affects conversions and selectivities. Deactivation processes occur upon dichloropropane conversion, mainly due to coke deposition.

The conversion of highly chlorinated compounds, such as trichloroethylene (TCE) has been tested over silica–alumina and over HY zeolite in the presence of water vapor in the so-called “steam reforming” conditions (HVOC:water=1:2). With diluted feed (1200 ppm) on HY, reaction occurs above 800 K and formation of chlorinated by-products is minimized, CO_x being the main reaction products. At higher HVOC concentrations conversion is obtained at even lower temperature (600 K), but no more negligible by-products formation has been detected. In our conditions zeolite catalyst is more effective in TCE total conversion than silica–alumina.     

A mini-review on the modeling of volatile organic compound adsorption in activated carbons: Equilibrium,dynamics, and heat effects

The research on the adsorption equilibria, kinetics, and increase in process temperature of the volatile organic compound (VOC) adsorption in porous materials ensures safe production, thereby reducing production costs and improving separation efficiency. Therefore, it is critical in predicting the entire adsorption process based on minimal or no experimental input of the adsorbate and adsorbent. We discuss, in this review, the factors that affect the adsorption performance of VOCs in activated carbons, including the adsorption equilibrium, adsorption kinetics, and exotherm during adsorption. Subsequently, the existing prediction models are summarized and compared concerning the adsorption equilibrium, adsorption kinetics, and exothermic process of adsorption. We then propose a new prediction model based on intermolecular interaction and provide an outlook toward the design and manipulation of efficient adsorbents for the VOC system.     

Monitoring the Bi/Fe ratio at different pH values in BiFeO3 nanoparticles derived by normal and reverse chemical co-precipitation: A comparative study on the purity,microstructure and magnetic properties

Co-precipitation method was utilized for multiferroic ${\mathrm{BiFeO}}_3$(BFO) nanoparticles synthesis. The influence of different pH values on BFO powders properties was investigated. Thermogravimetric-differential thermal analysis (TG-DTA) technique indicated that optimal calcination and Curie temperatures are 550 °C and 818.7 °C. The precursor samples atomic absorption spectroscopy (AAS) results illustrate Bi and Fe atoms non-homogeneous distribution in normal co-precipitated samples. The phase formation and existence of transient phases like Bi₂₅FeO₃₉ and Bi₂Fe₄O₉ were studied by X-ray diffractometry (XRD). Nanopowders morphological features were characterized using field emission scanning electron microscopy (FESEM). Presence of absorption bands at 400–3600 cm^?1 was investigated by Fourier transformed infrared (FTIR) spectroscopy; and magnetic properties of synthesized powders were measured using vibration sample magnetometery (VSM). Results revealed that BFO powders have an R3c crystal structure. FESEM micrographs showed powders with pseudo-cubic shape and average particles size of 41.3 nm and 70.4 nm for normally and reversely synthesized powders. Magnetic hysteresis loops demonstrated a weak ferromagnetic behavior of the samples at room temperature. Due to the fact that the as-prepared powders particles size was lower than that of the spiral spin cycloid (62 nm) and that the nanoparticles surface-to-volume ratio was high and, in turn, led to more uncompensated spins, the weak ferromagnetic behavior was observed. Besides, the pH value decrement improved magnetization from 0.11 emu/g for pH = 10.5–0.2 emu/g for pH = 8.5.