PROTAC-attractive site as a new target for suppressing P-glycoprotein activity.

P-glycoprotein (P-gp) plays an important role in the rapid release of various small molecule substances from the cell. In turn, inhibition of this efflux transporter is an attractive strategy for both overcoming chemoresistance and facilitating oral absorption of drugs or CNS drug delivery. In this work, we adopt an approach typical for PROteolysis Targeting Chimera (PROTAC), which is based on the artificial drawing together of the target protein to E3 ubiquitin ligase, to P-gp.

Temperature dependence of the electron and hole Landé -factors in CsPbI nanocrystals embedded in a glass matrix.

The coherent spin dynamics of electrons and holes in CsPbI perovskite nanocrystals in a glass matrix are studied by the time-resolved Faraday ellipticity technique in magnetic fields up to 430 mT across a temperature range from 6 K to 120 K. The Landé -factors and spin dephasing times are evaluated from the observed Larmor precession of electron and hole spins. The nanocrystal size in the three studied samples varies from about 8 to 16 nm, resulting in exciton transition varying from 1.

Synthesis and optical properties of perovskite nanocrystals in glass with cationic substitution.

The effect of cadmium ions introduced into fluorophosphate glass on the growth and photoluminescence (PL) of the CsPb1-xCdxBr3 perovskite nanocrystals (NCs) is systematically studied. The x-ray diffraction patterns have shown that cadmium ions are really incorporated into the NCs that results in a decrease in the lattice constant from 5.85 (x = 0) to 5.

Thermodynamics of gaseous strontium and calcium cerates studied by Knudsen effusion mass spectrometry and estimation of relative electron ionization cross-section for CeO(g).

Rationale: Ceria-based systems are of great interest because of their unique properties. Such systems may be used as anode materials for SOFCs or in oxygen sensors. The exploitation of these materials often requires high temperatures.

Rational Design Problematics of Peptide Nucleic Acids as SARS-CoV-2 Inhibitors.

The use of viral protein inhibitors has shown to be insufficiently effective in the case of highly variable SARS-CoV-2. In this work, we examined the possibility of designing agents that bind to a highly conserved region of coronavirus (+)RNA. We demonstrated that while the design of antisense RNAs is based on the complementary interaction of nitrogenous bases, it is possible to use semirigid docking methods in the case of unnatural peptide nucleic acids.

A Visual Compendium of Principal Modifications within the Nucleic Acid Sugar Phosphate Backbone.

Nucleic acid chemistry is a huge research area that has received new impetus due to the recent explosive success of oligonucleotide therapy. In order for an oligonucleotide to become clinically effective, its monomeric parts are subjected to modifications. Although a large number of redesigned natural nucleic acids have been proposed in recent years, the vast majority of them are combinations of simple modifications proposed over the past 50 years.

Ubiquitin recruiting chimera: more than just a PROTAC.

Ubiquitinylation of protein substrates results in various but distinct biological consequences, among which ubiquitin-mediated degradation is most well studied for its therapeutic application. Accordingly, artificially targeted ubiquitin-dependent degradation of various proteins has evolved into the therapeutically relevant PROTAC technology. This tethered ubiquitinylation of various targets coupled with a broad assortment of modifying E3 ubiquitin ligases has been made possible by rational design of bi-specific chimeric molecules that bring these proteins in proximity.

Fullerene C Conjugate with Folic Acid and Polyvinylpyrrolidone for Targeted Delivery to Tumor Cells.

The use of targeted drug delivery systems, including those based on selective absorption by certain receptors on the surface of the target cell, can lead to a decrease in the minimum effective dose and the accompanying toxicity of the drug, as well as an increase in therapeutic efficacy. A fullerene C conjugate (FA-PVP-C) with polyvinylpyrrolidone (PVP) as a biocompatible spacer and folic acid (FA) as a targeting ligand for tumor cells with increased expression of folate receptors (FR) was obtained. Using C NMR spectroscopy, FT-IR, UV-Vis spectrometry, fluorometry and thermal analysis, the formation of the conjugate was confirmed and the nature of the binding of its components was established.

New Insights into Chemoresistance Mediated by Mdm2 Inhibitors: The Benefits of Targeted Therapy over Common Cytostatics.

The inhibition of the Mdm2-p53 protein-protein interaction is a promising strategy for anticancer therapy. However, the problem of developing secondary chemoresistance in tumors treated with such drugs has not yet been sufficiently studied. In this work, we compared the properties of a drug-resistant cell line obtained during long-term cultivation in the presence of an Mdm2 inhibitor, Nutlin-3a, with a similarly obtained line insensitive to the cytostatic drug paclitaxel.

NMR-Verified Dearomatization of 5,7-Substituted Pyrazolo[1,5-a]pyrimidines.

Tetrahydropyrazolo[1,5-a]pyrimidine (THPP) is an attractive scaffold for designing biologically active compounds. The most obvious way to obtain such compounds is to reduce pyrazolopyrimidines with complex hydrides, because the pyrimidine ring is reduced in the preference over the pyrazole ring. The presence of substituents at positions five and seven of pyrazolo[1,5-a]pyrimidines complicates the set of reaction products but makes it more attractive for medicinal chemistry because four possible stereoisomers can be formed during reduction.

Tailoring the Electron and Hole Landé Factors in Lead Halide Perovskite Nanocrystals by Quantum Confinement and Halide Exchange.

The tunability of the optical properties of lead halide perovskite nanocrystals makes them highly appealing for applications. Halide anion exchange and quantum confinement enable tailoring of the band gap. For spintronics, the Landé -factors of electrons and holes are essential.

Deposition of Nanostructured Tungsten Oxide Layers by a New Method: Periodic Modulation of the Deposition Angle.

Periodic modulation of the deposition angle (PMDA) is a new method to deposit nanostructured and continuous layers with controllable periodic density fluctuation. The method is used for the magnetron sputtering of a WO layer for an electrochromic device (ECD). An experimental study indicates that the electrochromic coloration-bleaching rate nearly doubles and the electrochromic efficiency grows by about 25% in comparison with the traditional method.

Is It Possible to Obtain a Product of the Desired Configuration from a Single Knoevenagel Condensation? Isomerization vs. Stereodefined Synthesis.

The biological activity of compounds directly depends on the three-dimensional arrangement of affinity fragments since a high degree of pharmacophore compliance with the binding site is required. 3-Benzylidene oxindoles are privileged structures due to their wide spectrum of biological activity, synthetic availability, and ease of modification. In particular, both kinase inhibitors and kinase activators can be found among 3-benzylidene oxindoles.

Mode locking of hole spin coherences in CsPb(Cl, Br) perovskite nanocrystals.

The spin physics of perovskite nanocrystals with confined electrons or holes is attracting increasing attention, both for fundamental studies and spintronic applications. Here, stable [Formula: see text] lead halide perovskite nanocrystals embedded in a fluorophosphate glass matrix are studied by time-resolved optical spectroscopy to unravel the coherent spin dynamics of holes and their interaction with nuclear spins of the Pb isotope. We demonstrate the spin mode locking effect provided by the synchronization of the Larmor precession of single hole spins in each nanocrystal in the ensemble that are excited periodically by a laser in an external magnetic field.

Luminescent polyelectrolytes with antiviral activity.

Radical polymerization was used to synthesize and characterize (co)polymers with sodium styrenesulfonate (NaSS), 4-methacryloylamidosalicylic acid (MASA), and -vinylpyrrolidone, which have a low cytotoxicity and a high antiviral activity against the human respiratory syncytial virus. The interaction of copolymers with Tb ions was studied. The complexes formed in dilute aqueous solutions at a concentration of MASA units ⩽ 1 · 10 mol L demonstrate a strong luminescence.

Rapid Assessment of Neutralizing Antibodies Using Influenza Viruses with a Luciferase Reporter.

Unlabelled: Influenza viruses cause acute respiratory infections, especially in the autumn-winter period. They are characterized by a high mutation frequency and cause annual seasonal epidemics. The detection of antibodies that neutralize the virus is an important criterion in the assessment of population immunity and the influenza vaccine effectiveness.

ATP Mimetic Attack on the Nucleotide-Binding Domain to Overcome ABC Transporter Mediated Chemoresistance.

Since the problem of transporter-mediated multidrug resistance of tumor cells is becoming increasingly important in cancer therapy, it is necessary to modulate the activity of efflux transporters of the ABC family, among which P-glycoprotein is the best known. We consider the nucleotide binding domain, a universal fragment of these transporters, as a target for the rational design of small molecule compounds capable of preventing ATP-dependent drug efflux. Using various ATP mimetics, we showed that they suppress the efflux of fluorescent substrates and paclitaxel from the cells due to suppressing the ATPase activity of the transporters.

Synthesis, Anti-Influenza H1N1 and Anti-Dengue Activity of A-Ring Modified Oleanonic Acid Polyamine Derivatives.

A series of sixteen A-ring modified (2,3-indolo-, 2-benzylidene) oleanonic acid derivatives, holding some cyclic amines, linear polyamines and benzylaminocarboxamides at C28, has been synthesized and screened for antiviral activity against influenza A/PuertoRico/8/34 (H1N1) and Dengue virus serotypes of DENV-1, -2, -3, -4. It was found that 28-homopiperazine and 3--phthalyl amides of oleanonic acid demonstrated high potency with selectivity index SI 27 (IC 21 μM) and 42 (IC 12 μM). Oleanonic acid aminoethylpiperazine amide and C-azepano-erythrodiol appeared to be the most effective compounds against DENV-1 (ICs 67 and 107 μM) and -2 (ICs 86 and 68 μM correspondingly) serotypes.

Analysis of P-Glycoprotein Transport Cycle Reveals a New Way to Identify Efflux Inhibitors.

P-glycoprotein (P-gp) is found to be of considerable interest for the design of drugs capable of treating chemoresistant tumors. This transporter is an interesting target for which an efficient approach has not yet been developed in terms of computer simulation. In this work, we use a combination of docking, molecular dynamics, and metadynamics to fully explore the states that occur during the capture of a ligand and subsequent efflux by P-gp.

Reaction-Diffusion Pathways for a Programmable Nanoscale Texture of the Diamond-SiC Composite.

The diamond-SiC composite has a low density and the highest possible speed of sound among existing materials except for diamond. The composite is synthesized by a complex exothermic chemical reaction between diamond powder and liquid Si. This makes it an ideal material for protection against impact loading.

CeFeO-CeO-FeO Systems: Synthesis by Solution Combustion Method and Catalytic Performance in CO Hydrogenation.

Rare-earth orthoferrites have found wide application in thermocatalytic reduction-oxidation processes. Much less attention has been paid, however, to the production of CeFeO, as well as to the study of its physicochemical and catalytic properties, in particular, in the promising process of CO utilization by hydrogenation to CO and hydrocarbons. This study presents the results of a study on the synthesis of CeFeO by solution combustion synthesis (SCS) using various fuels, fuel-to-oxidizer ratios, and additives.

Implication of ABC transporters in non-proliferative diseases.

ABC transporters play an essential role in the development of multidrug resistance and thus are of interest in the context of anticancer therapy. However, MDR1, BCRP and MRP1 are involved in a number of key processes that maintain the viability of the body as a whole, as well as individual organs and cells. These transporters support protective properties of anatomical and histohematic barriers, determining the entry of both toxins and drugs into organs and tissues, as well as facilitating their elimination.

Submillisecond Spin Relaxation in CsPb(Cl,Br) Perovskite Nanocrystals in a Glass Matrix.

Lead halide perovskite nanocrystals in a glass matrix are a promising platform for optoelectronic applications due to their excellent optical properties combined with outstanding stability against the environment. We reveal the potential of this system for spintronics by studying the electron spin properties of CsPb(Cl,Br) nanocrystals in a fluorophosphate glass matrix. Using optical spin orientation and spin depolarization with a radio frequency field, we measure longitudinal spin relaxation time, , reaching several hundreds of microseconds at low temperatures.

High-Throughput Sequencing of Circulating MicroRNAs in Plasma and Serum during Pregnancy Progression.

Although circulating microRNAs (miRNAs) in maternal blood may play an important role in regulation of pregnancy progression and serve as non-invasive biomarkers for different gestation complications, little is known about their profile in blood during normally developing pregnancy. In this study we evaluated the miRNA profiles in paired plasma and serum samples from pregnant women without health or gestational abnormalities at three time points using high-throughput sequencing technology. Sequencing revealed that the percentage of miRNA reads in plasma and serum decreased by a third compared to first and second trimesters.

Establishment of drug-resistant cell lines under the treatment with chemicals acting through different mechanisms.

The problem of chemoresistance development is an inescapable flipside of modern oncotherapy, in particular for сolorectal cancer patients. The search for or development of drugs effective against resistant tumors involves the use of model resistant cell lines in vitro. To obtain such lines, we reproduced the development of chemoresistance of human colon adenocarcinoma cells under the treatment with drugs of different mechanisms, a cytostatic (paclitaxel) and a targeted agent (Nutlin-3a, an inhibitor of p53-Mdm2 protein-protein interaction).