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Тек жазылушылар үшін
Том 51, № 4 (2025)
Articles
BCR-ABL Inhibitors in Targeted Therapy of Chronic Myeloid Leukemia
Аннотация
Chronic myeloid leukemia (CML) is a malignant disease of the hematopoietic system with a key pathogenic protein BCR-ABL, which seriously threatens the lives of patients. The first drug based on the inhibition of the hybrid tyrosine kinase BCR-ABL, the gene of which is located on the "Philadelphia chromosome", was imatinib. Imatinib therapy turned out to be quite successful: patients with CML achieved a complete cytogenic response 2 years after the start of treatment and a state of stable remission for a long time. However, the inevitable resistance to imatinib, which occurs in clinical settings due to mutations in the BCR-ABL kinase, gave impetus to the development of new specific drugs, such as dasatinib, nilotinib, bosutinib and ponatinib. Currently, the pharmaceutical market offers the second and third generations of BCR-ABL tyrosine kinase inhibitors designed to combat mutant BCR-ABL and possessing better selectivity. It is noteworthy that the first allosteric inhibitor that can effectively overcome mutations in the ATP binding site has appeared on the market. In recent years, chimeras aimed at proteolysis (PROTAC) based on another E3 ligand have come into use, as a result of which they are able to overcome drug resistance due to selective degradation of target proteins. Data on inhibitors that have received the status of approved drugs for the treatment of CML are presented. Promising areas for the development of new BCR-ABL inhibitors are indicated. The relevance of this area of research is confirmed by the emergence of a significant number of new publications on this topic.
Bioorganičeskaâ himiâ. 2025;51(4):547–563
547–563
Reactivity of (–)-Shikimic Acid as the Basis of Its Biological Role and a Template for the Development of Antiviral Agents: A Case Study of Oseltamivir Phosphate
Аннотация
The review is dedicated to the analysis of the current data in the field of molecular organization of unsaturated cyclic systems, using the example of the monocarboxylic unsaturated cyclic structure of (–)-shikimic acid, which exhibits the properties of both a carboxylic acid and a polyatomic vicinal alcohol, as well as cycloolefins, considering the influence of side substituents. The question of the most optimal method for the production of shikimic acid and its derivatives with a significant yield remains unresolved. The search for new synthetic routes and the potential use of compounds whose behavior follows the principles of the Diels-Alder/Alder-Steiner reactions should be primarily determined by the peculiarities of its molecular organization. The study of the static system underlying the chemical structure of this acid, its reactivity, and the comparative analysis of possible methods and approaches for obtaining cycloalkenes with heteroatoms in the molecule, electron-accepting side groups using the example of the antiviral drug (oseltamivir phosphate), allowed for the investigation of the relationship between the properties and the structural parameters of this chemical object at a new qualitative and quantitative level.
Bioorganičeskaâ himiâ. 2025;51(4):564–580
564–580
Application of 3D Visualization in Biomedical Research
Аннотация
Three-dimensional microscopy (3D microscopy) has become an important tool in cellular analysis and biomedical research, providing unique opportunities to visualize and study complex biological structures. The capabilities of different types of microscopies in studying cellular structures and macromolecular complexes span a wide range of scales, from investigating cell behavior and function in physiological environments to understanding the molecular architecture of organelles. At each scale, the challenge of 3D imaging is to extract the highest possible spatial resolution while minimizing damage to living cells. This review highlights the various applications of 3D microscopy in areas such as cancer research, viruses, bacterial properties and structure, and organ and implant microstructure analysis.
Bioorganičeskaâ himiâ. 2025;51(4):581-598
581-598
Integration of Software for 3D Tissue Reconstruction Based on Optical Probe Nanotomography Data
Аннотация
The task of three-dimensional (3D) reconstruction of tissues at the cellular and subcellular level is an integral part of modern biomedical research. Developing 3D reconstruction methods based on atomic force and optical microscopy images enables a more detailed understanding of the morphology and structure of biological specimens at the nanoscale. In the present study, we integrated dedicated software into the workflow of optically probed nanotomography (OPNT) to optimize and standardize the volumetric reconstruction process and demonstrated the capabilities of the enhanced method by reconstructing a fragment of an astrocyte in 3D. The incorporation of 3D Slicer into the OPNT protocol provides a reliable, high-precision platform for the three-dimensional reconstruction of complex biological structures. The proposed approach has practical utility for specialized tasks – such as evaluating the synaptic environment of individual neurons – as well as for a wide range of investigations in biomedical research and materials science.
Bioorganičeskaâ himiâ. 2025;51(4):599-606
599-606
Synthesis of Reactive Pegylated Indocyanine Dyes
Аннотация
Synthesis was carried out with the selection of conditions for the isolation and purification of fluorescently labeled polyethylene glycol with a reactive carboxyl group for labeling biomolecules. Pegylated nucleotides, which are part of drugs, allow targeted delivery to the target organ, prolong the half-life, reduce immunogenicity and increase stability.
Bioorganičeskaâ himiâ. 2025;51(4):607-611
607-611
Solid-Phase PCR on Film Biochips with Brush Polymer Cells, "Lab-on-a-Chip"
Аннотация
A method of nucleic acid analysis by solid-phase PCR with immobilised primers extension (primer extension) in a closed film biochip during thermocycling, with control of Cy5-fluorescence-labelled nucleotide incorporation by digital fluorescence microscopy, by endpoint, was developed. A "film biochip", made of film polyethylene terephthalate, with an internal chamber, with brush polymer cells with immobilised primers, with channels for supply and removal of solutions into the biochip chamber, has been developed, with low heat capacity and high thermal conductivity of thin film components of the biochip, with thermocycling, with registration of results by digital fluorescence microscopy through the lid and the layer of washing liquid without disassembling the biochip, in a system isolated from the environment, "laboratory on a chip". The performance of the method and functional suitability of the "film biochip" was demonstrated by analysing samples containing DNA from pathogenic bacteria Staphylococcus auereus and Legionella pneumophila.
Bioorganičeskaâ himiâ. 2025;51(4):612-626
612-626
C-Terminal Domain of Bacillus cereus Hemolysin II is Capable of Forming Homo- and Hetero-Oligomeric Forms of Toxin on the Membrane Surface
Аннотация
Hemolysin II (HlyII) is one of the key pathogenic factors of the opportunistic gram-positive bacterium Bacillus cereus. HlyII lyses target cells by forming pores on membranes. HlyII belongs to the group of β-pore-forming toxins. A distinctive feature of HlyII is the presence of a C-terminal domain of 94 amino acid residues (HlyIICTD). It was shown that under slightly acidic conditions (pH 5.0), corresponding to the near-membrane region, the C-terminal domains, both by themselves and as part of the toxin, form stable complexes consisting of full-length and truncated toxin molecules. HlyII, HlyIILCTD (large C-terminal fragment Met225–Ile412) and HlyIICTD were obtained using recombinant producer strains Escherichia coli BL21(DE3). Biotinylation of HlyIICTD was carried out using N-hydroxysuccinimide ester of biotin. The interaction of HlyIICTD with HlyIICTD, HlyIILCTD, and HlyII, as well as the interaction of HlyIICTD with erythrocyte membranes, were studied by enzyme-linked immunosorbent assay and immunoblotting using both horseradish peroxidase-conjugated streptavidin and monoclonal antibodies against HlyII. Under slightly acidic conditions, HlyIICTD interacted with both the HlyIICTD domain within the full-length toxin and with the HlyIICTD protein. The interaction of HlyIICTD with the erythrocyte membrane increased fold in the presence of the toxin. The property of the C-terminal domain to form complexes with each other was revealed, regardless of whether it is part of the full-length toxin, the large C-terminal fragment, or the short HlyIICTD under conditions corresponding to those existing near the cell membrane (pH 5.0). The toxin in the peri membrane region exists in a partially molten globule state, in which the C-terminal domains of the monomers can bind to each other, increasing the local concentration of full-length toxins.
Bioorganičeskaâ himiâ. 2025;51(4):627-635
627-635
Synthesis of Tetraesters of Indolyl-3-acetic Acid with 24-Epibrassinosteroids and Their Influence on the Initial Growth of Wheat Plants
Аннотация
By treating 24-epibrassinosteroids with indolyl-3-acetic acid (IAA) anhydride in dioxane in the presence of dimethylaminopyridine, their 2,3,22,23-tetra-(3'-indolylacetoxy) derivatives were obtained. It has been shown that brassinosteroid tetraesters of indolyl-3-acetic acid exhibit phytogrowth-regulating activity in the early stages of wheat plant growth. It has been established that treatment with IAA tetraesters leads to a change in the steroid-hormonal balance of brassinosteroids in vegetative plants, which may indicate their participation in the processes of biosynthesis regulation. The obtained derivatives are promising for more in-depth study, primarily for investigating their effectiveness in field experiments.
Bioorganičeskaâ himiâ. 2025;51(4):636-643
636-643
Pharmacokinetic Features of Ecdystene and Ursolic Acid in Plant Extracts After Oral Administration In Vivo
Аннотация
The determination of bioavailability during the study of the therapeutic potential of plant extracts is extremely important because it serves as an indicator of whether the original compounds will retain their biological activity or gradually lose it under the influence of multiple factors. Rosemary (Rosmarinus officinalis L.) is the source with the highest percentage of the pentacyclic triterpenoid ursolic acid, while ecdystene (20-hydroxyecdysterone) is one of the main phytoecdysteroids present in leuzea (Rhaponicum carthamoides Willd.). Both plant sources are distributed on the pharmaceutical market in the form of food and dietary supplements as metabolic therapy agents. However, there is still little information on the pharmacokinetic profile of ecdystene and ursolic acid in extracts and multicomponent compositions. In this paper, we carried out a comparative evaluation of pharmacokinetic parameters of ecdystene, ursolic acid, extracts of leuzea and rosemary, composition based on the two extracts in blood during per os administration in vivo. Methods: The investigated substances and their extracts were administered once, intragastrically to CD-1 outbred mice in doses equivalent in quantitative content of the main active substance. The content of ursolic acid and ecdystene in animal blood was determined by HPLC-MS/MS for subsequent calculation of pharmacokinetic parameters (Cmax, Tmax, AUC). Results: In both cases there was a decrease in bioavailability of ursolic acid and ecdystene in the blood of experimental animals in comparison with individual substances. In the composition, only trace amounts of ecdystene were determined, while no differences in pharmacokinetic parameters of ursolic acid in the composition and rosemary extract were found. Conclusions: This study proves that the combination of plant extracts in the form of multicomponent mixtures can lead to a decrease in bioavailability of the main active substances by many different factors. The development of products based on plant extracts should be accompanied by pharmacokinetic studies to prove the quality of the finished product.
Bioorganičeskaâ himiâ. 2025;51(4):644-653
644-653
Molecular Species of Membrane Lipids of the Sea Anemone Exaiptasia diaphana and Its Symbionts
Аннотация
The molecular types of membrane lipids of the sea anemone Exaiptasia diaphana and the molecular types of glycolipids of its symbionts were studied using the method of high-performance liquid chromatography with mass spectrometric detection. A total of 82 molecular types of E. diaphana glycerophospholipids were identified, the main ones being 16:0/22:6 cholinoglycerophospholipid (PC), 18:1e/20:4 and 18:1e/20:5 ethanolaminoglycerophospholipids (PE), 18:0/22:4 serinoglycerophospholipid (PS), 18:0/22:4 inositoglycerophospholipid (PI), 18:2b/16:0 ceramidaminoethylphosphonate (CAEP). 36 molecular types of glycolipids have been identified in symbionts. The main molecular species were 18:4/18:5 monohalactosyldiacylglycerol (MGDG), 18:3/18:5 and 18:4/18:4 digalactosyldiacylglycerols DGDG, 14:0/16:0 sulfoquinovosyldiacylglycerol (SQDG). Molecular genetic analysis revealed that all E. diaphana colonies contained the following dinoflagellates: Breviolum minutum, Cladocopium thermophilum, and Gerakladium endoclionum. The profile of the molecular types of lipids of the host organism can act as a chemotaxonomic feature, and galactolipids of symbionts indicate resistance to changes in seawater temperature. This study contributes to the development of lipidomics of marine organisms of the phylum Cnidaria.
Bioorganičeskaâ himiâ. 2025;51(4):654–666
654–666
Synthesis and Anti-Leukemia Activity N-[1-(1-Adamantile)ethyl]-3-hydroxylup-20(29)-en-28-amide
Аннотация
The paper presents the results of synthesis of a new amide derivative of betulinic acid – N-[1-(1-adamantyl)-ethyl]-3-hydroxylup-20(29)-en-28-amide containing a pharmacophoric 1-(1-adamantyl)ethylamine group in its structure and evaluation of its antiviral action in vitro and in vivo. It was found that the minimum inhibitory dose of the substance was 31.2 µg/mL. The highest antiviral activity was observed with 2–3 times the administration of the compound to guinea pigs. The obtained results allow us to recommend the studied compound for testing on cattle.
Bioorganičeskaâ himiâ. 2025;51(4):667-677
667-677
Comparison of Alternative Piperidine Deblocking Agents in Solid-Phase Synthesis of Ingramon and Methylin
Аннотация
The work is devoted to the comparison of alternative piperidine deblocking agents using the examples of solid-phase synthesis of ingramon, which has anti-inflammatory activity, and methylin, an agonist of the transmembrane API receptor. The possibility of using these peptides for the treatment of cardiovascular diseases dictates the need to develop optimized methods for their synthesis. Particular attention in the work is paid to the choice of a reagent for removing Fmoc protection in solid-phase peptide synthesis, which would ensure a high yield and purity of the target product with a minimum amount of related impurities. In the synthesis of the aspartyl peptide ingramon, the lowest content of by-products was noted when using a mixture containing 10% piperazine for cleaving the Fmoc protection. In addition, piperazine is an accessible and low-toxic reagent, which is attractive for large-scale solid-phase peptide synthesis. In the synthesis of methylin, the maximum yield of the product was obtained using a deblocking mixture based on pyrrolidine. The selected deblocking reagents can successfully replace toxic piperidine in solid-phase peptide synthesis not only in the laboratory but also in the preparative scale. These reagents can find application in obtaining peptide pharmaceutical substances.
Bioorganičeskaâ himiâ. 2025;51(4):678-687
678-687
Chimeric Amides of Substituted Allyl- and Phenylcarboxylic Acids with Pharmacophore Fragments of Aromatic and Heteroaromatic Rings – Potential Multitarget Protein Kinase Inhibitors: Design, Synthesis, Determination of Antitumor Activity, and In Silico Analysis
Аннотация
This study aims to synthesize and evaluate the antitumor efficacy of a series designed chimeric amides (10–14, 16, 19, 21, 25–27, 28, 30) containing various combinations of nitrogen-containing heterocycles, which are the key pharmacophores of many antitumor drugs with different mechanisms of action. The designed amides were synthesized and characterized using spectroscopic techniques. The antitumor activity of all these compounds against tumor cell lines K562 (chronic myeloid leukemia), HL-60 (acute promyelocytic leukemia), and HeLa (cervical carcinoma) was assessed in vitro in terms of the values of half-maximal inhibitory concentration (IC50). As a result, 5 lead compounds, amides (10, 11, 21, 27, 30), active against the above cell lines were identified followed by in silico analysis of their pharmacological properties and prediction of the most probable mechanism of action against myeloid blood cells K562. In light of the data obtained, the identified compounds were shown to form promising basic structures for the design of novel orally active antitumor agents, multi-target protein kinase inhibitors.
Bioorganičeskaâ himiâ. 2025;51(4):688-705
688-705
Enzymatic Synthesis and Molecular Docking Studies of Substituted 5-Phenyl-1,2,4-triazole-3-thione Deoxyribosides
Аннотация
Derivatives of 1,2,4-triazole are very important in the pharmaceutical industry. In this work, we synthesized new 5-phenyl-1,2,4-triazole-3-thione 2-deoxyribosides with bulky substituents using an enzymatic transglycosylation reaction. Their antiviral activity against herpes simplex virus type 1 was investigated. The results showed that both cytotoxicity and antiviral activity increase with increasing length of the substituent.
Bioorganičeskaâ himiâ. 2025;51(4):706-714
706-714
A Phenol-Free Method for the Robust Isolation of the Double-Stranded RNA Produced in the E. coli HT115 Strain
Аннотация
Obtaining a fraction of double-stranded RNA is an integral part of any RNA interference research whether it aimed at solving fundamental or applied problems. The production of dsRNA in bacterial culture is a common technique due to its comparative cheapness and scaling-up opportunities. In this article, we propose a new method for fast and effective isolation of dsRNA from bacterial culture, as an alternative to classical phenol-chloroform extraction. In our method, phenol is replaced with less toxic methanol, and the total RNA thus isolated from bacteria contains up to 25% of the target molecule lacking the DNA contamination, which enables its usage in certain further applications without additional cleanup steps. The application of this methodology will be justified in laboratories engaged in either fundamental or applied research on RNA interference. However, scaling the technology for agricultural use may require adjustments to the protocol described in this work.
Bioorganičeskaâ himiâ. 2025;51(4):715-723
715-723