Russian Journal of Bioorganic Chemistry最新文献

Microorganisms are able to produce a wide range of biological surfactants, also known as biosurfactants. The potential for using biosurfactants in various areas of human life requires the development and improvement of methods to find producer strains and to determine the content of biosurfactants in different natural samples, as well as to upgrade the approaches to these substances isolation and purification. This review focuses on the structure, properties, applications, and methods of synthesis of surfactin, which is one of the most interesting lipopeptide biosurfactants, and of its derivatives. Information regarding the instrumental approaches to detecting and measuring surfactin in bacterial cultures, including those based on various types of chromatography (TLC, HPLC, and HPLC-MS), Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry (MS), were summarized and analyzed. The accessibility, sensitivity, selectivity, and overall effectiveness of these techniques were discussed.

Objective: Despite significant advances in drug discovery, effective treatments for diseases such as cancer, bacterial infections, diabetes, and chronic inflammatory conditions remain an urgent challenge for humanity. Methods: In this study, four novel 3,3′-bihalocoumarins (denoted as (BH1–BH4)) were synthesized via the coupling of their corresponding precursors, 7-halocoumarin-3-acetic acids (B1–B4), with various 4-halosalicylaldehydes. The molecular structures of the synthesized compounds were confirmed using spectroscopic techniques, including IR, ¹H, and ¹³C NMR. The bioactive potential of the precursors and their derivatives was assessed based on six selected pharmacological properties. The dual inhibitory effect on 5-LOX and COX enzymes was evaluated against three interrelated targets, while antioxidant activity was assessed using two radical scavenging assays. The cytotoxic effects were examined using four cancer cell lines, while cytocompatibility was evaluated on a normal cell line. The antidiabetic potential was tested against two relevant enzymatic targets, and antibacterial activity was assessed against four pathogenic bacterial strains. Results and Discussion: The findings suggest that these synthesized compounds hold promise as bioactive agents. They demonstrated varying degrees of antioxidant activity, no significant toxicity toward normal or cancerous cells, minimal influence on glucose metabolism, and limited antibacterial activity. Notably, precursor (B1) exhibited potent COX-1 inhibitory activity, making it a promising scaffold for developing selective COX-1 inhibitors. The 3,3′-bihalocoumarins, particularly (BH1), showed strong selective COX-2 inhibition, suggesting their potential as lead compounds for COX-2-targeted drug development. Furthermore, precursor (B1) selectively inhibited Salmonella typhi proliferation, highlighting its potential as an antibacterial agent against this pathogen. In silico pharmacokinetic analysis indicated that these compounds have favorable oral bioavailability. Conclusions: The synthesized compounds present a promising basis for the development of biosafe and pharmacologically active scaffolds for novel therapeutics.

Objective: Chimeric oligonucleotides are an important modern tool for various molecular biological problems. The aim of this work is to study a new type of synthetic analogues of oligonucleotides containing two types of modifications – phosphoryl guanidine (PG) internucleotide group and 2′,4′-locked ribose fragments (LNA)—in one nucleotide unit. Methods: All oligonucleotides were synthesized via the solid phase phosphoramidite method. To investigate the physico-chemical properties of PG-LNAs, modified oligonucleotides were analysed by reversed-phase liquid chromatography, denaturing electrophoresis in polyacrylamide gel, and electrospray ionization mass spectrometry. The stability and structure of DNA-duplexes, containing PG-LNA oligonucleotides, were studied using thermal denaturation and circular dichroism spectropolarimetry. Results and Discussion: It has been shown the presence of PG-LNA linkages decreases the electrophoretic mobility of the oligonucleotides, primarily due to the electroneutrality of the PG group. Additionally, the PG-LNA modifications increase the hydrophobicity of the oligonucleotides, resulting in longer retention times during reversed-phase chromatography. The thermal stability of complementary duplexes containing PG-LNA oligonucleotides has been investigated. It was found the melting temperature increases by 1.5–4.0°C per modification, depending on the position of the modified unit and the ionic strength of the solution. Furthermore, circular dichroism spectropolarimetry revealed the secondary structure of the complexes formed by PG-LNA differs from the B-form, which may be attributed to the presence of LNA fragments exhibiting a 3′-endo conformation of the ribose ring. Thus, PG-LNA oligonucleotides can be considered as a new structural analogue of RNA with a partially uncharged backbone. Conclusions: Based on the data obtained, it can be concluded that PG-LNA oligonucleotides can be considered a promising tool for various methods of isolation and analysis of nucleic acids.

Objective: Spirooxindole derivatives are emerging as key building blocks in drug discovery due to their diverse biological activities, including antineoplastic, antibiotic, cytostatic, monoamine transporter inhibition, bradykinin antagonism, and cell cycle inhibition. Methods: Given the broad spectrum of biological activities associated with spiroindoles, pyrimidopyrimidines, and thiazolopyrimidines, we aimed to design and synthesize a novel system integrating these bioactive rings within a single molecular framework to assess their potential additive biological effects. Results and Discussion: Among the synthesized novel spiro-1,4-dihydropyridine (DHP) derivatives (IVa–IVf), compounds (IVc), (IVe), and (IVf) exhibited excellent activity against Staphylococcus aureus and Klebsiella pneumoniae. Additionally, compounds (IVb), (IVc), (IVe), and (IVf) demonstrated significant antifungal activity against Aspergillus niger. Of all tested compounds, spiro-1,4-DHP derivative (IVf) showed the highest cytotoxic activity against the HepG2 cell line, with an IC₅₀ value of 13.6 and 2.39 µg/mL, respectively, indicating strong anticancer potential. Conclusions: These findings suggest that the designed compounds exhibit excellent antibacterial, antifungal, and anticancer activities, making them promising candidates for the development of novel pharmaceutical agents for the treatment of bacterial and fungal infections as well as cancer.

Objective: As part of our ongoing research in organic and medicinal chemistry, we have been investigating the chemical and biological properties of compounds that incorporate different heterocycles, such as fused 1,3,4-oxadiazole and 1,3,4-thiadiazole systems. In this study, we synthesized novel oxadiazolyl-thiadiazole hybrids and evaluated their antibacterial activity against several pathogenic bacteria, as well as their antitubercular efficacy against the Mycobacterium tuberculosis H37Rv strain, using moxifloxacin and rifampicin as positive controls. Methods: We synthesized a series of novel indazole-based 1,2,3-triazoles using 1-methyl-1H-indazole-3-carbohydrazide and various isothiocyanates, followed by antibacterial activity assessment using the Agar well dilution method. The structural identity of the newly synthesized compounds was confirmed through a combination of spectroscopic techniques, including ¹H and ¹³C NMR, IR, and mass spectrometry. In silico molecular docking studies were performed to assess the binding affinity of the synthesized ligands to the M. tuberculosis DNA gyrase active site (PDB ID: 5BS8). Additionally, pharmacokinetic properties, including absorption, distribution, metabolism, excretion, and toxicity (ADMET), were predicted using SwissADME and ADMETlab2.0. Results and Discussion: The synthesized compounds exhibited moderate to excellent antibacterial and antitubercular activity. Among them, the p-tolyl-substituted thiadiazole derivative demonstrated potent antibacterial activity against Bacillus subtilis, with a zone of inhibition of 36 ± 0.1 mm. Meanwhile, the m-nitrophenyl-substituted oxadiazole showed superior antitubercular activity against the H37Rv strain, with a minimum inhibitory concentration (MIC) of 4.0 ± 0.3 μM. Molecular docking studies revealed that the m-nitrophenyl-indazole derivative interacts with key amino acid residues within the active site of M. tuberculosis DNA gyrase, including Met127 (A), Arg128 (A), Ala126 (A), Ala90 (A), Ala74 (A), Tyr93 (A), Lys72 (A), Ser73 (A), and Asp89 (A). Furthermore, bioavailability, drug-likeness, and gastrointestinal absorption parameters were evaluated in detail using the BOILED-Egg method based on SMILES notations. Conclusions: These findings suggest that oxadiazole-thiadiazole conjugates represent a promising class of antimicrobial agents with potential for further development.

Objective: The aim of this study is to investigate the mechanisms underlying the intracellular transport of the mechanosensitive protein zyxin. Zyxin, a conserved LIM domain protein, plays a critical role in regulating the assembly of F-actin filaments at cellular junctions. In response to mechanical stimuli such as cell stretch, zyxin has the capacity to translocate into the nucleus to influence gene expression, or it may exit the nucleus. Importantly, zyxin is recognized as a tumor marker, making the exploration of its post-translational modifications and the dynamics of its nuclear-cytoplasmic shuttling significant for advancements in molecular diagnostics related to disease. Methods: To elucidate the nuclear entry dynamics of zyxin, we employed site-directed mutagenesis to selectively target palmitylation sites, O-GlcNAcylation sites, and specific amino acids at both the N- and C-termini. This investigation was conducted using Xenopus laevis gastrula embryos, which serve as an effective model for studying protein trafficking. Results and Discussion: Our findings reveal that the introduction of a Flag epitope at the C-terminus of the zyxin molecule results in a loss of its nuclear translocation capability. Conversely, mutating the palmitylation sites leads to a noticeable decrease in the nuclear presence of zyxin, while modifications to amino acids responsible for O-GlcNAcylation result in an increased accumulation of zyxin in the nucleus. Conclusions: The data obtained from this study highlight the significant impact of these specific post-translational modifications on the subcellular localization of zyxin. These findings contribute to the broader research knowledge regarding the mechanistic aspects of the localization dynamics of zyxin and related mechanosensitive proteins. Given that the disruption of intracellular localization can have profound implications in the development of cancer and cardiovascular diseases, this research bears both fundamental and medical importance.

Objective: We previously synthesized the peptide LKEKK corresponding to sequences 16–20 of human thymosin-α₁ and 131–135 of human interferon-α₂ and showed that it was capable of exerting antimicrobial and anti-inflammatory effects in vitro and in vivo. In this study, the activity of the synthetic peptide LKEKK was investigated in a mouse model of tuberculosis induced by Mycobacterium bivis-bovinus 8. Methods: CBA mice were infected by injecting a suspension of M. bovis-bovinus 8 (0.1 mg in 0.2 mL of saline, ~100 bacterial bodies, subcutaneously). Beginning on day 7 after inoculation, two mice were sacrificed every two days, and the lungs were examined. Disease severity was assessed by visual inspection and calculated as the “lung injury index.” Results and Discussion: Therapy with peptide at doses of 0.01, 0.1, and 1 μg/kg (5 daily injections) significantly reduced the lung injury index of mice compared to animals in the control groups (no treatment and isoniazid treatment). Using [³H]LKEKK, it was shown that the high sensitivity of peritoneal macrophages and splenocytes of infected mice to the peptide was maintained for at least three weeks (K_d 18.6 and 16.7 nM for macrophage and splenocyte membranes, respectively). A study of cytokine production by splenocytes of infected mice showed that, on day 24 after treatment with the peptide (doses of 1 and 10 µg/kg), the secretion of IL-2 was restored to the level observed in uninfected animals. IFN-γ production by spleen cells of infected mice also significantly increased upon peptide treatment. At the same time, IL-4 production decreased in splenocytes. In addition, the peptide treatment stimulated the phagocytic activity of peritoneal macrophages, which was reduced due to tuberculosis infection. Conclusions: The synthetic peptide LKEKK increased the effectiveness of anti-tuberculosis therapy, as well as the strength of the immune response. The peptide can be used in complex therapy of tuberculosis.

Objective: Design of a small fluorogen-activating protein picoFAST. Methods: Protein expression and purification were performed. In vitro screening with the new protein was held, the optical properties were studied. Widefield fluorescence microscopy of live cells was performed. Results and Discussion: We discovered that the N-fragment of split nanoFAST can act as a fluorogen-activating protein in complex with HBR-DOM2 in the absence of the C-fragment, and we called it picoFAST. We demonstrated that the picoFAST protein in complex with HBR-DOM2 fluorogen can be used for fluorescent labeling of individual compartments of live HeLa Kyoto cells. Conclusions: We designed the smallest fluorogen-activating protein picoFAST and showed that it can be used in pair with HBR-DOM2 as a genetically-encoded fluorescent tag in live cells.

The development of drugs which structure resembles or is completely identical to the natural components of a living organism is currently a promising area that is of great interest for scientists. Obtaining synthetic analogs of nucleic acids was made possible due to the active development of oligonucleotide synthesis in the 1980s and subsequent research in the field of chemical modification of nucleotides, which allowed to change the properties of nucleic acids and increase their stability. The accumulated worldwide experience has made it possible to create drugs based on synthetic oligonucleotides aimed at the treatment of rare genetic diseases. Since 1998, a relatively small number of drugs have been approved by regulatory authorities in different countries for use in clinical practice. Most of them are aimed at the treatment of orphan diseases. To date, there are 20 therapeutic drugs based on synthetic oligonucleotides that have been approved by medical regulatory authorities for use in clinical practice. Of this list, only one drug was developed in Russia (MIR 19^®). This review describes all drugs based on synthetic oligonucleotides approved up to 2024, and also examines and systematizes current knowledge about promising types of therapeutic oligonucleotides with different mechanisms of interaction with the target.

Objective: This research article presents a streamlined method for the synthesis of α-amino phosphonates derived from vanillin, aimed at exploring their potential antioxidant and antitubercular activities, along with in silico studies. Methods: We prepared vanillin analogs through oxidative deamination followed by the Kabachnik–Fields reaction. The procedure involves a one-pot synthesis in which various anilines are reacted with vanillin in the presence of trimethyl phosphite and dichloromethane. This methodology demonstrates a broad substrate scope and yields α-amino phosphonates in satisfactory amounts. Comprehensive characterization using ¹H, ¹³C NMR, and HRMS analysis confirms the structures of the synthesized compounds. Results and Discussion: Biological evaluation of the compounds’ potential antitubercular activity against the Mycobacterium tuberculosis H37Rv strain (ATCC no. 27294) revealed promising results, with all compounds exhibiting MICs in the range of 12–100 µg/mL. Additionally, the synthesized compounds were assessed for antioxidant activity. The lead compounds were also evaluated for binding interactions with target proteins. Compounds (IIIa) and (IIIh) showed significant docking scores of –7.2, –7.3, –7.4, and –7.6 kcal/mol, respectively, indicating their potential to interact with tuberculosis-related proteins DprE1 and Polyketide synthase. Conclusions: The observed significant antimycobacterial efficacy suggests the potential utility of these compounds as lead candidates for developing antitubercular agents, underscoring their importance in combating tuberculosis infections.