Quinazoline Antifolate Thymidylate Synthase Inhibitors: Replacement of Glutamic Acid by Aminophosphonic Acids

The synthesis of six analogues of the potent thymidylate synthase (TS) inhibitor N -[4-[ N -[(3,4-dihydro-2-methyl-4-oxo-6-quinazolinoyl)-methyl]- N -prop-2-ynylamino]benzoyl]- L -glutamic acid 2 is described in which the glutamic acid residue has been replaced by DL -aminophosphonic acids. New antifolates were tested as inhibitors of TS isolated from mouse L1210 leukemic cells as well as inhibitors of growth mouse leukemic L5178Y cells. In general these modifications result in compounds that are considerably less potent than 2 as TS inhibitors with K i 's 0.17-1.10 w M. Very poor solubility in water limited their proper assay of growth cells inhibition.     

Usefulness of chaotropic salt additive in RP‐HPLC of organic nonionized compounds

New synthesized 1,4‐disubstituted thiosemicarbazide derivatives were analyzed in the RP system, modified with the addition of salts; chaotropic (sodium hexafluorophosphate – Na PF₆), cosmotropic (sodium phosphate – NaH₂PO₄), and neutral (NaCl) on Zorbax XDB C18 column. The effect of the eluent composition on the analytes retention (k), system efficiency (N), peak symmetry (A_s), and LOD values were all examined and compared to unmodified organic‐aqueous mobile phase system. It was established that eluent modified with chaotropic salts addition was also the most advantageous according to other peak parameters such as the theoretical plates numbers and asymmetry factors. The lower LOD values were achieved in comparison to unmodified organic‐aqueous eluent system. Compatibility of lipophilicity parameters calculated by the use of computer software with experimental ones measured by RP‐HPLC was also the best for chaotropic modified mobile phase. To explain the observed phenomena, molecular modeling was performed for chosen representative compound in different environment representing examined mobile phase composition.     

Adsorption of tert-butanol at the electrode from concentrated NaClO4 solutions

The parameters of the double layer for tert-butanol adsorption determined in the supporting electrolytes: 2 mol dm^?3, 3 mol dm^?3 and 4 mol dm^?3 NaClO₄, show an increase of tert-butanol adsorption on the mercury electrode together with the increase of NaClO₄ concentration. The adsorption of tert-butanol on the electrode takes place via the ?CH₃ group which is shown by the changes in the values of zero charge potentials, E _z. On the basis of the analysis of the changes of relative surface excess values, Γ′, and the parameters determining the maximum adsorption, the process of adsorption in the discussed systems can be recognized as a physical process. Besides, it can be said that a major drawback in the process of adsorption of the organic substance on the electrode is to remove water from the electrode surface.     

Application of hot platinum microelectrodes for determination of flavonoids in flow injection analysis and capillary electrophoresis

The determination of quercetin and rutin by flow injection analysis (FIA) and capillary electrophoresis (CE) using electrochemical detection was described. These flavonoids were determined at normal (unheated) and hot platinum microelectrodes using cyclic voltammetry. When quercetin or rutin is reaching the platinum electrode, a change of the current in the region of the platinum oxide formation is observed. Integration of the current changes in this in this region creates analytical signals in the form of peaks. An increase of temperature to about 76 ?C in a small zone adjacent to the microelectrode causes an increase of the analytical signal by more than 6 times under FIA conditions. This method enables the use of hot microelectrodes as detectors in HPLC or CE. In CE the improvement of the analytical signal at hot microelectrodes is smaller than in FIA and increase only 1.3–3.4 times. Heated microelectrodes were used for analysis of the flavonoids in natural samples of the plant (extract of sea buckthorn) and a pharmaceutical preparation (Cerutin).     

Role of Gut Microbiota,Probiotics and Prebiotics in the Cardiovascular Diseases

In recent years, there has been a growing interest in identifying and applying new, naturally occurring molecules that promote health. Probiotics are defined as “live microorganisms which, when administered in adequate amounts, confer health benefits on the host”. Quite a few fermented products serve as the source of probiotic strains, with many factors influencing the effectiveness of probiotics, including interactions of probiotic bacteria with the host’s microbiome. Prebiotics contain no microorganisms, only substances which stimulate their growth. Prebiotics can be obtained from various sources, including breast milk, soybeans, and raw oats, however, the most popular prebiotics are the oligosaccharides contained in plants. Recent research increasingly claims that probiotics and prebiotics alleviate many disorders related to the immune system, cancer metastasis, type 2 diabetes, and obesity. However, little is known about the role of these supplements as important dietary components in preventing or treating cardiovascular disease. Still, some reports and clinical studies were conducted, offering new ways of treatment. Therefore, the aim of this review is to discuss the roles of gut microbiota, probiotics, and prebiotics interventions in the prevention and treatment of cardiovascular disease.     

Selective Detection of Carbohydrates and Their Peptide Conjugates by ESI-MS Using Synthetic Quaternary Ammonium Salt Derivatives of Phenylboronic Acids

We present new tags based on the derivatives of phenylboronic acid and apply them for the selective detection of sugars and peptide-sugar conjugates in mass spectrometry. We investigated the binding of phenylboronic acid and its quaternary ammonium salt (QAS) derivatives to carbohydrates and peptide-derived Amadori products by HR-MS and MS/MS experiments. The formation of complexes between sugar or sugar-peptide conjugates and synthetic tags was confirmed on the basis of the unique isotopic distribution resulting from the presence of boron atom. Moreover, incorporation of a quaternary ammonium salt dramatically improved the efficiency of ionization in mass spectrometry. It was found that the formation of a complex with phenylboronic acid stabilizes the sugar moiety in glycated peptides, resulting in simplification of the fragmentation pattern of peptide-derived Amadori products. The obtained results suggest that derivatization of phenylboronic acid as QAS is a promising method for sensitive ESI-MS detection of carbohydrates and their conjugates formed by non-enzymatic glycation or glycosylation.

The Identification of Cotton Fibers Dyed with Reactive Dyes for Forensic Purposes

Some of the most common microtraces that are currently collected at crime scenes are fragments of single fibers. The perpetrator leaves them at a crime scene or takes them away, for example, on their clothing or body. In turn, the microscopic dimensions of such traces mean that the perpetrator does not notice them and therefore usually does not take action to remove them. Cotton and polyester fibers dyed by reactive and dispersion dyes, respectively, are very popular within clothing products, and they are hidden among microtraces at the scene of a crime. In our recently published review paper, we summarized the possibilities for the identification of disperse dyes of polyester fibers for forensic purposes. In this review, we are concerned with cotton fibers dyed with reactive dyes. Cotton fibers are natural ones that cannot easily be distinguished on the basis of morphological features. Consequently, their color and consequently the dye composition are often their only characteristics. The presented methods for the identification of reactive dyes could be very interesting not only for forensic laboratories, but also for scientists working in food, cosmetics or pharmaceutical/medical sciences.     

Barrier Dispersion-Based Coatings Containing Natural and Paraffin Waxes

Petroleum, synthetic, and natural waxes have been used as hydrophobic bases for dispersions intended for use as barrier coatings for packaging paper. Oil-in-water dispersions with alkaline pH were prepared by a two-step homogenization procedure containing paraffin wax, with various characteristics, the Fischer–Tropsch synthesis product or beeswax. The size of the dispersed particles determined by dynamic light scattering depended on the type of hydrophobic base used and was in the range of 350–440 nm. The ability of dispersion particles in aggregation driven by electrostatic attraction, evaluated by Zeta potential analysis by electrophoretic light scattering, was from −26 to −50 mV. Static multiply light scattering was used for 30 days of stability assessment and helped to select the dispersion with a Sarawax SX70 wax base as the most stable. Dispersions were further used for coating the backing of kraft paper by the Meyer rod method. Coated paper with an applied coating of 6 g/m² had very good hydrophobic properties (Cobb60 < 4 g/m²), sufficient strength properties, and air permeation, which enabled its application as a packaging material. The dispersions based on Sarawax SX70 wax were evaluated as the best coating for Mondi ProVantage Kraftliner 125 g/m² backing paper. Good hydrophobic properties and strength properties indicate the possibility of using the SX70-based wax dispersion coating as a replacement for PFAS coatings in some applications.     

Large-Scale Synthesis of a Niche Olefin Metathesis Catalyst Bearing an Unsymmetrical N-Heterocyclic Carbene (NHC) Ligand and its Application in a Green Pharmaceutical Context

A large-scale synthesis of known Ru olefin metathesis catalyst VII featuring an unsymmetrical N-heterocyclic carbene (NHC) ligand with one 2,5-diisopropylphenyl (DIPP) and one thiophenylmethylene N-substituent is reported. The optimised procedure does not require column chromatography in any step and allows for preparation of up to 0.5 kg batches of the catalyst from simple precursors. The application profile of the obtained catalyst was studied in environmentally friendly dimethyl carbonate (DMC). Although VII exhibited low efficiency in cross-metathesis (CM) with electron-deficient partners, good to excellent results were noted for substrates featuring easy to isomerise C−C double bonds. This includes polyfunctional substrates of medicinal chemistry interest, such as analogues of psychoactive 5F-PB-22 and NM-2201 and two PDE5 inhibitors—Sildenafil and Vardenafil. Finally, a larger scale ring-closing metathesis (RCM) of a Vardenafil derivative was conducted in DMC, allowing for straightforward isolation of the expected product (23 g) in high yield and with low Ru contamination level (7.7 ppm).     

Gapmer Antisense Oligonucleotides Containing 2′,3′-Dideoxy-2′-fluoro-3′-C-hydroxymethyl-β-d-lyxofuranosyl Nucleotides Display Site-Specific RNase H Cleavage and Induce Gene Silencing

Off-target effects remain a significant challenge in the therapeutic use of gapmer antisense oligonucleotides (AONs). Over the years various modifications have been synthesized and incorporated into AONs, however, precise control of RNase H-induced cleavage and target sequence selectivity has yet to be realized. Herein, the synthesis of the uracil and cytosine derivatives of a novel class of 2′-deoxy-2′-fluoro-3′-C-hydroxymethyl-β-d -lyxo-configured nucleotides has been accomplished and the target molecules have been incorporated into AONs. Experiments on exonuclease degradation showed improved nucleolytic stability relative to the unmodified control. Upon the introduction of one or two of the novel 2′-fluoro-3′-C-hydroxymethyl nucleotides as modifications in the gap region of a gapmer AON was associated with efficient RNase H-mediated cleavage of the RNA strand of the corresponding AON:RNA duplex. Notably, a tailored single cleavage event could be engineered depending on the positioning of a single modification. The effect of single mismatched base pairs was scanned along the full gap region demonstrating that the modification enables a remarkable specificity of RNase H cleavage. A cell-based model system was used to demonstrate the potential of gapmer AONs containing the novel modification to mediate gene silencing.