Russian Journal of Bioorganic Chemistry最新文献

Proteins belonging to the pathogenesis-related class 10 (PR-10), especially the main birch pollen allergen Bet v 1, are members of one of the most clinically significant groups of plant panallergens. Their highly conserved spatial structure provides the molecular basis for a high IgE cross-reactivity, leading to the pollen-food allergy syndrome (PFAS) that affects millions of people worldwide. This comprehensive overview of PR-10 allergens integrates their structural biology with the latest advances and future directions in immunotherapy. Here, we analyze molecular determinants of cross-reactivity, discuss mechanisms of allergen-specific immunotherapy (AIT), and critically evaluate its current state for the birch pollen and related food allergies, highlighting limitations of conventional extract-based vaccines in treating PFAS. Finally, we review the most promising strategies that have entered clinical trials, including T-cell epitope-based peptide vaccines, recombinant hypoallergenic derivatives, and innovative hapten-carrier vaccines, designed to induce polyclonal IgG responses against multiple clinically relevant IgE epitopes of several PR-10 allergens. All data collected in this review not only represents current understanding of PR-10 allergic properties but also highlights the need for further research into molecular mechanisms of the PR-10-related allergy and development of next-generation immunotherapy strategies.

The therapeutic potential of various nitrogen-containing heterocyclic compounds has significantly contributed to the development of cardiotonic drugs. This article explores pyridazine-based cardiotonic agents—such as sulmazole, pimobendan, and levosimendan—which are noted for their ability to reduce both preload and afterload while exhibiting positive inotropic and vasodilatory properties. Particular emphasis is placed on the pyridazine and pyridazinone families due to their broad pharmacological activity and promising applications in the treatment of cardiovascular disorders. Beyond their cardiac effects, these compounds demonstrate a wide range of biological activities, including antibacterial, antithrombotic, antihypertensive, anti-allergic, antidiabetic, anticancer, and anti-ulcer effects. Pyridazine and pyridazinone derivatives are frequently employed in pharmaceutical development due to their versatile pharmacological profiles. While existing studies underscore their clinical importance, further laboratory research is essential to expand their therapeutic applications.

The development of CAR-T cells has become an important step in the treatment of hematological malignancies and solid tumors. However, the application of CAR-T cells is limited by the complex mechanisms of immunosuppression in the tumor microenvironment, including changes in the metabolic environment. Adenosine plays a key role in the functioning of the immune system, exerting an inhibitory effect on the immune response in the tumor microenvironment. It reduces the activity of T lymphocytes involved in antitumor immunity and inhibits phagocytosis, which allows the tumor to evade immune control. In tumor cells, adenosine stimulates epithelial-mesenchymal transition, inhibits apoptosis and promotes tumor cell proliferation. Various molecular genetic strategies are being developed to overcome the immunosuppressive effect of adenosine. Currently, clinical trials are underway aimed at suppressing the adenosine pathway using antibodies against CD39 and CD73, A2A receptor inhibitors, and overexpression of adenosine deaminase. In this review, we examine the latest advances in the regulation of the adenosine pathway in the regulation of CAR-T cell metabolism to improve the functioning of these cells in the treatment of various forms of cancer. At present, a promising strategy for increasing the effectiveness of CAR-T cells in the treatment of solid cancers is combined CAR-T cells with overexpression of the ADA enzyme and genetic suppression of adenosine pathway receptors and immunosuppressive factors (IL-10, FOXP3) using CRISPR/Cas9 or epigenetic editing.

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-Stein reactions should be primarily determined by the peculiarities of their 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. The conclusions drawn are, in our opinion, of great importance for understanding the factors that determine the behavior of reacting particles in the classical pair of diene/dienophile in a reaction mixture. Also discussed are methods for synthesizing artificial (–)-shikimic acid (hereafter referred to as “acid”) as a replacement for its costly extraction from plant raw materials, as well as the features of using this acid and similar compounds for the development of new pharmaceuticals.

Photoimmunotherapy has recently emerged as a promising method of treating cancer. It is based on selective tumor delivery of light-activated cytotoxic agents, or photosensitizers, by conjugating them to antibodies against tumor-associated antigens, creating photoimmunoconjugates. Despite the promising preclinical performance of several such conjugates, only those based on IR700DX (also known as IR700), a hydrophilic silicon phthalocyanine, have entered clinical trials. Thus far, this has resulted in one clinical approval. However, not all of the numerous reported IR700DX-based immunoconjugates demonstrate impressive activity in vivo, even when the antigen is a validated target for antibody–drug conjugates (ADCs). Importantly, the principal mechanism of action of these conjugates is unique among photosensitizers, which impacts their activity profile. This review surveys all IR700-based conjugates disclosed to date, seeking to elucidate the factors underpinning their therapeutic efficacy. The review also offers a perspective on possible future avenues of research concerning these promising targeted phototherapeutics.

Objective: A novel series of methoxyphenyl-substituted thiazole–triazole hybrid Schiff base derivatives (PB-06–PB-20) was designed, synthesized, and characterized to evaluate their potential as antitubercular agents. Methods: The compounds were obtained via a multi-step synthetic route involving Hantzsch condensation, hydrazide formation, and Schiff base condensation with various aromatic aldehydes. Their structures were confirmed by FT-IR, ¹H, ¹³C NMR, and mass spectrometry. The antitubercular activity was evaluated against Mycobacterium tuberculosis H37Rv strain using the Alamar Blue assay. Molecular docking studies supported these findings, revealing strong binding affinities of the active derivatives with the M. tuberculosis DprE1 protein. Furthermore, in silico ADME and toxicity profiling indicated favorable drug-like properties and low predicted toxicity. Results and Discussion: Compounds PB-14, PB-18, and PB-20 exhibited promising activity with MIC values of 6.25 µg/mL. Molecular docking studies supported these findings, revealing strong binding affinities of the active derivatives with the M. tuberculosis DprE1 protein. Furthermore, in silico ADME and toxicity profiling indicated favorable drug-like properties and low predicted toxicity, confirming their potential for further development. Conclusions: These results establish thiazole–triazole Schiff bases as promising leads for novel antitubercular drug discovery.

Objective: To boost surfactin (Sur) production, a novel Bacillus subtilis PY79 strain was engineered by expressing the sfp gene. The resulting PY79^sfp+ strain yielded 300 mg/L, doubling the output of the native NCIB 3610 strain. While 6S-1 and 6S-2 RNA gene deletions had no effect, the main C₁₆ surfactin isoform was consistently predominant across all strains, confirming its industrial relevance. Methods: qPCR was performed to evaluate the effect of 6S RNAs on transcription of srfA operon, colorimetric test was used for quantitative analysis of surfactin produced, HPLC, MALDI-TOF and amino acid analysis were performed for isoforms analysis. Results and Discussion: Surfactin-producing activity in B. subtilis PY79 cells was restored using the pHT01 plasmid with sfp gene, that resulted with 2-fold increase of surfactin yield using the wild-type cells. However, the transcription level was increased in cells with 6S-1 RNA knockout, there was no effect of 6S RNAs on the amount of Sur produced. All the Sur produced by mutant cells consists of the conservative amino acid sequence Glu-Leu-Leu-Val-Asp-Leu-Leu. On the other hand, the fatty acid length consists of 14-16 carbon atoms. The main isoform for all the cell lines (wild-type and knockout) is C₁₆. Conclusions: Research shows that the B. subtilis PY79 is promising for engineering a Sur superproducer. Restoring the native sfp gene sequence doubled Sur production compared to the natural NCIB 3610 strain. Deleting the 6S-1 RNA gene did not increase yield, despite raising surfactin synthetase mRNA levels. Both strains produced three Sur isoforms, with the C₁₆ variant (containing a 16-carbon fatty acid chain) being predominant. This is the most commercially and medically valuable isoform due to its beneficial properties. The obtained results can be applied to the development of a superproducing strain based on the PY79^sfp+ strain, described for the first time in this study. This can be achieved by optimizing cultivation conditions, implementing genetic engineering modifications, and utilizing other tools. Future work will focus on further increasing surfactin yield to enable its potential production for various applications.

Sulfonamides, commonly known as sulfa drugs, are well-established anticancer agents whose activity is highly dependent on their substitution pattern. The anticancer activity of sulfonamide derivatives is mediated through several mechanisms of action, including the inhibition of carbonic anhydrase (CA) enzymes, cell cycle arrest at the G1 phase, and disruption of microtubule dynamics. Sulfonamides are also utilized as ligands for the synthesis of metal complexes with ions such as Ni(II), Cu(II), Co(II), Mn(II), Pb(II), Cd(II), Cr(III), Fe(III), Sn(II), and Sr(II). These complexes exhibit diverse biological activities, including radical scavenging, enzyme inhibition, as well as antifungal, antibacterial, and anticancer properties. Numerous complexes have been identified to demonstrate favorable activity against various cancer cell lines.

Objective: To rationally design, synthesize, and evaluate novel N-(arylidene)-5-(pyridin-4-yl)-1,3,4thiadiazol-2-amines as potential α-amylase inhibitors and antioxidant agents for the treatment of diabetes mellitus. Methods: Molecular docking studies were performed using the Schrödinger Suite 2016-1 against the oligosaccharide-based α-amylase inhibitor target (PDB ID: 1U30). Based on the docking results, seventeen Schiff base derivatives (D1–D17) were synthesized by reacting 5-(pyridin-4-yl)-1,3,4-thiadiazol-2-amine with various substituted aldehydes. All compounds were characterized by IR, ¹H, ¹³C NMR, and mass spectrometry. The synthesized compounds were evaluated for in vitro antidiabetic activity using the α-amylase inhibition method and for antioxidant activity using the DPPH radical scavenging assay. Results and Discussion: Docking studies revealed that most compounds exhibited good binding affinity, with compounds D2, D3, and D9 showing strong interactions with key active site residues, including HIE201, GLU233, and ASP300. In the α-amylase inhibition assay, compounds D2 and D9 demonstrated the most potent antidiabetic activity, with IC₅₀ values of 26.57 and 29.07 µg/mL, respectively, which were superior to that of the standard drug acarbose (IC₅₀ = 37.41 µg/mL). In the DPPH antioxidant assay, compound D3 exhibited the highest radical scavenging activity, with an IC₅₀ of 12.72 µg/mL, outperforming ascorbic acid (IC₅₀ = 36.61 µg/mL). The strong correlation between molecular docking scores and in vitro biological activity validates the suitability of PDB ID: 1U30 for rational drug design. Compounds bearing electron-donating groups, particularly methoxy and hydroxy substituents (D2, D3, D9), demonstrated enhanced activity due to improved hydrogen bonding interactions with catalytic residues in the α-amylase active site. The ortho-hydroxy group in compound D3 facilitates radical stabilization through resonance, explaining its superior antioxidant potential. These structure–activity relationships confirm that the nature and position of substituents on the arylidene ring critically influence biological activity. Conclusions: The 1,3,4-thiadiazole derivatives D2, D3, and D9 represent promising leads for further in vivo investigation as potential therapeutic agents for managing diabetes and oxidative stress-related conditions. The presence of electron-donating substituents enhances both antidiabetic and antioxidant activities.

Objective: The growing threat of bacterial resistance to antiseptics, along with the concerning toxicity profile of conventional quaternary ammonium compounds (QACs), underscores the critical need for new, safer antimicrobial agents. Methods: The compound design was based on the “soft drug” concept, where hydrophobic fragments are linked to the cationic center via biodegradable amide, ester, and acetal bonds. Antibacterial activity was evaluated in vitro against Gram-positive and Gram-negative bacteria, including clinical isolates. Cytotoxicity was assessed on normal human cells (MSC, CHL, HSF) and tumor (PC-3, MCF-7) cell lines. The clogP values, selectivity index (SI) for tumor cells, and acute toxicity (LD₅₀) upon intragastric administration in mice were determined. Results and Discussion: Several of the synthesized methylpyridinium salts exhibited antibacterial activity comparable to commercial antiseptics (benzalkonium chloride, miramistin, and chlorhexidine) against both Gram-positive and Gram-negative bacterial strains, including clinical isolates. Methylpyridinium salts with an amide linker were found to be more active than ester derivatives. However, one ester-based compound exhibited antibacterial activity comparable to commercial antiseptics while possessing significantly lower cytotoxicity (with IC₅₀ values 15–20 times higher than those of chlorhexidine and miramistin). In vivo acute toxicity studies in mice (intragastric administration) confirmed its safety (LD₅₀ >2000 mg/kg). The study of antitumor activity showed that some methylpyridinium salts were effective against PC-3 and MCF-7 tumor cell lines. However, the antitumor effect of most compounds was determined by high cytotoxicity. An exception was one amide derivative, which exhibited both potent antitumor activity and acceptable safety toward normal cells (selectivity index, SI = 7–15). Conclusions: These findings suggest that methylpyridinium salts derived from pyridoxine represent a promising platform for developing novel antiseptic agents with high antibacterial efficacy and low toxicity. The obtained results confirm the effectiveness of the “soft drug” concept in the design of safe antimicrobial agents.