Application of Phosphoramidate ProTide Technology for the Synthesis of 5’-mRNA Cap Analogs Modified on the Exocyclic Amine Group

Aryloxy triester phosphoramidate methodology, commonly known as ProTide technology, is one of the most widely used prodrug approaches applied to therapeutic nucleosides. This approach has been used extensively by the pharmaceutical industry and researchers in medicinal chemistry. Herein we report our adaptation of this effective method for the synthesis of bioactive 5’-mRNA cap analogues as inhibitors for targeting cap-dependent translation. The synthesis was performed in two main stages: preparation of N2-modified guanosine analogues and their subsequent transformation into prodrugs using phenylethoxy-l -alaninyl phosphorochloridate. The prepared pro-nucleotide cap analogues were tested for their capacity in enzymatic activation, inhibitory properties in a rabbit reticulocyte lysate system, and passive membrane translocation properties.     

5’-Phosphorylation Increases the Efficacy of Nucleoside Inhibitors of the DNA Repair Enzyme SNM1A

Certain cancers exhibit upregulation of DNA interstrand crosslink repair pathways, which contributes to resistance to crosslinking chemotherapy drugs and poor prognoses. Inhibition of enzymes implicated in interstrand crosslink repair is therefore a promising strategy for improving the efficacy of cancer treatment. One such target enzyme is SNM1A, a zinc co-ordinating 5’–3’ exonuclease. Previous studies have demonstrated the feasibility of inhibiting SNM1A using modified nucleosides appended with zinc-binding groups. In this work, we sought to develop more effective SNM1A inhibitors by exploiting interactions with the phosphate-binding pocket adjacent to the enzyme's active site, in addition to the catalytic zinc ions. A series of nucleoside derivatives bearing phosphate moieties at the 5’-position, as well as zinc-binding groups at the 3’-position, were prepared and tested in gel-electrophoresis and real-time fluorescence assays. As well as investigating novel zinc-binding groups, we found that incorporation of a 5’-phosphate dramatically increased the potency of the inhibitors.     

PEG Modification Effect of Silica on the Suzuki–Miyaura Coupling Reaction Using Silica-immobilized Palladium Catalysts

Abstract  

The Pd phosphine complex catalysts immobilized onto polyethylene glycol (PEG)-modified silica were prepared in order to clarify the effect of the PEG modification on the Suzuki–Miyaura coupling reaction in organic solvents. For the reaction of ethyl p-bromobenzoate and phenylboronic acid in the presence of potassium carbonate in toluene, the PEG-modified silica-immobilized Pd catalysts exhibited much higher activities than the catalysts without PEG modification.     

Calculation of Viscosities of Liquid Mixtures Using Eyring’s Theory in Combination with Cubic Equations of State

1 INTRODUCTON The viscosity, particularly that of liquid mixtures is very important in engineering calculations involved in the process design for petroleum and other chemica industries. Since the successful development of a one-parameter equation for correlating the liquid vis cosity of nonpolar mixtures by Grunberg and Nissan[1] many other models have been proposed. Most of them are based on the corresponding state principle, the absolute rate theory of Eyring[2], or the free volume the…     

Phase Equilibria of the SiO2–V2O5 system

The SiO₂–V₂O₅ system is one of the key systems for vanadium extraction and applications of vanadium oxides in the ceramic industries. However, only limited data in this system and contradictive results were reported from preceding studies. In the present study, high-temperature phase equilibrium experiments were conducted to construct the phase diagram of SiO₂–V₂O₅ system at temperature range of 660–1100 °C. Electron probe X-ray micro-analyzer (EPMA) was used to analyze the microstructure and composition of the phases presented in quenched samples. The liquidus temperatures in both SiO₂ and V₂O₅ primary phase field were determined. The eutectic temperature is confirmed to be within 670–680 °C and the eutectic composition comprises 1.9 wt% SiO₂. SiO₂ phase contains up to 1.4 wt% V₂O₅ in the temperature range investigated.     

A Study of the γ-Radiolysis of N,N-Didodecyl-N′,N′-Dioctyldiglycolamide Using UHPLC-ESI-MS Analysis

Solutions of N,N-didodecyl-N′,N′-dioctyldiglycolamide in n-dodecane were subjected to γ-irradiation in the presence and absence of both an aqueous nitric acid phase and air sparging. The solutions were analyzed using ultra-high-performance liquid chromatography-electrospray ionization-mass spectrometry (UHPLC-ESI-MS) to determine the rates of radiolytic decay of the extractant as well as to identify radiolysis products. The DGA concentration decreased exponentially with increasing dose, and the measured degradation rate constants were uninfluenced by the presence or absence of acidic aqueous phase, or by air sparging. The identified radiolysis products suggest that the bonds most vulnerable to radiolytic attack are those in the diglycolamide center of these molecules and not in the side chains.     

A Comparison of the γ-Radiolysis of TODGA and T(EH)DGA Using UHPLC-ESI-MS Analysis

Solutions of TODGA and T(EH)DGA in n-dodecane were subjected to γ-irradiation in the presence and absence of an aqueous nitric acid phase and analyzed using UHPLC-ESI-MS to determine the rates of radiolytic decay of the two extractants, as well as to identify radiolysis products. The DGA concentrations decreased exponentially with increasing dose, and the measured degradation rate constants were uninfluenced by the presence or absence of an acidic aqueous phase, or by chemical variations in the alkyl side-chains. The DGA degradation was attributed to reactions of the dodecane radical cation, whose kinetics were measured for TODGA using picosecond electron pulse radiolysis to be k₂ = (9.72 ± 1.10) × 10⁹ M^?1 s^?1. The identified radiolysis products suggest that the bonds most vulnerable to radiolytic attack are those in the diglycolamide center of these molecules and not on the side-chains.     

areviewof: A Comprehensive Review of the Book DRYING’85

This work studied the effects of drying temperature on the quality and drying kinetics of betel leaves (Piper betle L.). As the drying process applies heat on the product, this might lead to the degradation and decomposition of valuable phytochemicals within the herbs. In this study, the effect of drying temperature on the quality of dried leaves was studied by analyzing the change of major phytochemicals found in the leaves, which are hydroxychavicol and eugenol. The results indicate that the content of major compounds increased with temperature from 40 to 70°C but underwent decomposition when the leaves dried at 80°C. Besides that, the drying kinetics for different drying temperatures also studied. The kinetics results show that the increase of drying temperature shortened the total drying time. Five thin-layer models were selected in describing the drying process of betel leaves. The logarithmic model was found to be the most suitable one.     

Biochemical Investigation of the Interaction of pICln,RioK1 and COPR5 with the PRMT5–MEP50 Complex

The PRMT5–MEP50 methyltransferase complex plays a key role in various cancers and is regulated by different protein–protein interactions. Several proteins have been reported to act as adaptor proteins that recruit substrate proteins to the active site of PRMT5 for the methylation of arginine residues. To define the interaction between these adaptor proteins and PRMT5, we employed peptide truncation and mutation studies and prepared truncated protein constructs. We report the characterisation of the interface between the TIM barrel of PRMT5 and the adaptor proteins pICln, RioK1 and COPR5, and identify the consensus amino acid sequence GQF[D/E]DA[E/D] involved in binding. Protein crystallography revealed that the RioK1 derived peptide interacts with a novel PPI site.     

A 2D metal–organic framework with dual-acidic sites for the valorization of saccharides to 5-hydroxymethylfurfural

The conversion of macromolecular saccharides (fructose, glucose, sucrose, and inulin) to 5-hydroxymethylfurfural (HMF) is often limited by the mass transfer resistance of existing catalysts. Herein, a two-dimensional metal–organic framework (NUS-8-PhSO₃H) containing high densities of dual acidic sites (Lewis and Brønsted acid sites) was developed for the first time by diazo grafting. Characterization results and reaction kinetics showed that the rapid molecular diffusion leads to an unusual pseudozeroth reaction order and a considerably lower apparent activation energy for the fructose reaction over NUS-8-PhSO₃H in contrast to the first order and higher activation energy over three-dimensional counterpart (NUS-16-PhSO₃H) and reported catalysts. In addition, NUS-8-PhSO₃H can also produce substantially high HMF yields and has a low activation energy for other saccharides (glucose, sucrose, and inulin) by powerful tandem steps, including polysaccharide hydrolysis, glucose isomerization, and fructose dehydration. The preparation of hydrophobic acidic NUS-8-PhSO₃H provides an efficient means of synthesizing HMF from various saccharides.     

Methods and Approaches of the Sol–Gel Technology for the Surface Modification of Aluminum Oxide Powders

The results of studies, sol–gel synthesis, and the sedimentation stability of complex multicomponent sol–gel systems of the “silica sol modified with Co(NO₃)₂ · 6H₂O, Al(NO₃)₃ · 9H₂O with α-Al₂O₃ or γ-Al₂O₃ as highly dispersed filler” type are generalized. The physical–chemical processes accompanying the formation of modifying layers on the powder oxide particles are examined. The promising prospects of applying α-Al₂O₃ powders modified with a silicate layer of the composition (wt %) 1.2K₂O · 3Al₂O₃ · 3.2CaO · 12.5Na₂O · 28.1B₂O₃ · 52SiO₂ in the fabrication of ceramic materials with improved strength characteristics are demonstrated.     

Molecular models of coal’s organic matter and the reflectance of the macerals: A review

The mean reflectance R _o,n of vitrinite and other macerals in coal whose structure is represented by molecular chemical models may be calculated on the basis of the contributions of structural-chemical groups to the molecular refraction, if the relation between the reflection, refraction, and absorption is taken into account on the basis of the Fresnel-Beer law. The findings confirm the relation between the reflectance R _o,n and the chemical structure of the coal macerals. Consequently, reliable analysis of the possible chemical transformations in coal may be based on molecular models of the structure.     

Optimization of Enzymatic Synthesis of n-Propyl Acetate (Fruit Flavor Ester) – Effect of the Support on the Properties of Biocatalysts

The present study deals with the optimization of the enzymatic synthesis of n-propyl acetate using response surface methodology (RSM). The biocatalysts were prepared by physical adsorption of lipase from Thermomyces lanuginosus (TLL) on mesoporous hydrophobic supports – poly-hydroxybutyrate (PHB) and poly-methacrylate (PMA) particles. Their catalytic properties were also assayed in the hydrolysis of olive oil emulsion. The biocatalyst TLL–PMA presented the highest immobilization yield (IY, 90.6 ± 2.8%), immobilized protein concentration (36.5 ± 0.4 mg/g of PMA), and catalytic activity in esterification reaction. TLL–PHB was more active in the hydrolysis of olive oil emulsion by a four-fold factor (1240.5 ± 29.2 IU/g of PHB). Maximum acid consumption percentage of 84.3% was observed after 50 min of reaction catalyzed by TLL–PMA using 2000 mM of each reactant (n-propanol and acetic acid) in heptane medium. The purified ester was confirmed by gas chromatography mass spectrometry (GC–MS) analysis. After six consecutive cycles of esterification reaction, the biocatalyst retained around 50% of its initial activity. The results show that PMA may be an interesting support to prepare active biocatalysts in the synthesis of fruit flavor ester by esterification reaction.     

Modification of side chain terminals of PEGylated molecular bottle brushes—A toolbar of molecular nanoobjects

Water soluble molecular brush with poly(glycidyl methacrylate) (PGMA) as the main chain and mono-allyl terminated poly(ethylene glycol) (PEG) as the densely grafted side chains was efficiently synthesized via grafting-onto approach by copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Then highly efficient post-modification of the ends of the side chains was realized through UV light induced thiol–ene radical addition. Thus polymer brushes with various side chain terminal functional groups including hydroxyl group, carboxyl group, amino group, amino acid, sulfonic group and glucose unit were obtained.     

Wilson’s Disease: A Comprehensive Review of the Molecular Mechanisms

Wilson’s disease (WD), also known as hepatolenticular degeneration, is an autosomal recessive inherited disorder resulting from abnormal copper metabolism. Reduced copper excretion causes an excessive deposition of the copper in many organs such as the liver, central nervous system (CNS), cornea, kidney, joints, and cardiac muscle where the physiological functions of the affected organs are impaired. The underlying molecular mechanisms for WD have been extensively studied. It is now believed that a defect in P-type adenosine triphosphatase (ATP7B), the gene encoding the copper transporting P-type ATPase, is responsible for hepatic copper accumulation. Deposited copper in the liver produces toxic effects via modulating several molecular pathways. WD can be a lethal disease if left untreated. A better understanding of the molecular mechanisms causing the aberrant copper deposition and organ damage is the key to developing effective management approaches.     

Microwave dielectric properties of BiNbO4 ceramics with CuO–V2O5 addition

BiNbO₄ ceramics were developed by using CuO–V₂O₅ as a liquid phase sintering agent. The resultant dielectric properties were analyzed in terms of the densification and the amount of CuO–V₂O₅ sintering agent. The addition of 0.8 wt.% CuO–V₂O₅ as its sintering agent was observed to perform most satisfactory. At 850 °C, uniform and enhanced microstructure was observed for the BiNbO₄ specimen with 0.8 wt.% CuO–V₂O₅ addition. Furthermore, the effect of CuO–V₂O₅ addition on the microwave dielectric properties of BiNbO₄ was also investigated. As the sintering temperature increased to 900 °C, the dielectric constant increased but nearly constant and the quality factor (QF) showed a maximum at 850 °C and then decreased for all compositions of the 900 °C sintered specimens. With an increase in CuO–V₂O₅ content, the temperature coefficient of frequency (TCF) increased in accordance with the dielectric mixing rule and microstructural behavior.     

A Potent Mimetic of the Siglec-8 Ligand 6’-Sulfo-Sialyl Lewisx

Siglecs are members of the immunoglobulin gene family containing sialic acid binding N-terminal domains. Among them, Siglec-8 is expressed on various cell types of the immune system such as eosinophils, mast cells and weakly on basophils. Cross-linking of Siglec-8 with monoclonal antibodies triggers apoptosis in eosinophils and inhibits degranulation of mast cells, making Siglec-8 a promising target for the treatment of eosinophil- and mast cell-associated diseases such as asthma. The tetrasaccharide 6’-sulfo-sialyl Lewis^x has been identified as a specific Siglec-8 ligand in glycan array screening. Here, we describe an extended study enlightening the pharmacophores of 6’-sulfo-sialyl Lewis^x and the successful development of a high-affinity mimetic. Retaining the neuraminic acid core, the introduction of a carbocyclic mimetic of the Gal moiety and a sulfonamide substituent in the 9-position gave a 20-fold improved binding affinity. Finally, the residence time, which usually is the Achilles tendon of carbohydrate/lectin interactions, could be improved.     

A Glimpse at the Size of the Fetal Liver—Is It Connected with the Evolution of Gestational Diabetes?

Gestational diabetes mellitus (GDM) is defined as an impairment of glucose tolerance, manifested by hyperglycemia, which occurs at any stage of pregnancy. GDM is more common in the third trimester of pregnancy and usually disappears after birth. It was hypothesized that the glycemic status of the mother can modulate liver development and growth early during the pregnancy. The simplest modality to monitor the evolution of GDM employs noninvasive techniques. In this category, routinely obstetrical ultrasound (OUS) examinations (simple or 2D/3D) can be employed for specific fetal measurements, such as fetal liver length (FLL) or volume (FLV). FLL and FLV may emerge as possible predictors of GDM as they positively relate to the maternal glycated hemoglobin (HbA1c) levels and to the results of the oral glucose tolerance test. The aim of this review is to offer insight into the relationship between GDM and fetal nutritional status. Risk factors for GDM and the short- and long-term outcomes of GDM pregnancies are also discussed, as well as the significance of different dietary patterns. Moreover, the review aims to fill one gap in the literature, investigating whether fetal liver growth can be used as a predictor of GDM evolution. To conclude, although studies pointed out a connection between fetal indices and GDM as useful tools in the early detection of GDM (before 23 weeks of gestation), additional research is needed to properly manage GDM and offspring health.     

Using the Sol–Gel Technology for the Treatment of Barley Seeds

Silica sols obtained by acidic or alkaline hydrolysis of tetraethoxysilane in an excess of water or ethanol in the presence of a number of salts and/or acids are used to treat the surface of barley seeds. The surface state and the elemental composition of the seeds are studied before and after their treatment in silica sols. The conditions of the sol–gel synthesis of silica sols, their effect on the state and chemical composition of the seed surface, and the sowing characteristics are analyzed. The plant’s resistance to phytopathogen, the causative agent of root rot is studied.