Russian Journal of Bioorganic Chemistry最新文献

This review discusses the significance of 1,3,4-oxadiazole (OXD) derivatives in medicinal chemistry, focusing on their diverse biological activities and the importance of eco-friendly production methods. The primary objective is to explore green synthetic routes that minimize environmental impact while preserving the pharmacological potential of OXD derivatives. Traditional methods, which typically involve acid hydrazides and dehydrating agents like phosphorus oxychloride, often yield low amounts of product and generate hazardous byproducts, and are also addressed. In contrast, green chemistry techniques, such as solvent-free processes, microwave-assisted synthesis, and the use of non-toxic catalysts, have been shown to improve reaction efficiency, reduce energy consumption, and produce higher yields with fewer environmental risks. The review also emphasizes the structural flexibility of the 1,3,4-oxadiazole core moiety and its ability to be tailored into various derivatives with promising biological activities, including antibacterial, antitubercular, antifungal, anticancer, and antioxidant properties. Green synthetic approaches not only enhance the yield and purity of OXD derivatives but also improve their biological efficacy against cancers and drug-resistant bacteria. Future considerations are discussed, emphasizing the dual benefits of these approaches in supporting environmentally sustainable practices and enhancing the pharmacological profiles of OXD derivatives, which offer a promising strategy for the development of novel therapeutic agents in the pharmaceutical industry.

Objective: Nanocarriers are promising for theranostics, enabling the combination of diagnostics and therapy. The objective of this work was to develop an amphiphilic derivative of the BODIPY-FL fluorescent dye, encapsulate it in cationic liposomes made from lipopeptides, and evaluate the potential of these liposomes as a drug delivery system for anticancer therapy. Methods: An amphiphilic derivative of the BODIPY-FL fluorescent dye was developed and encapsulated into cationic liposomes made from lipopeptides. The liposomes were loaded with the lipophilic anticancer drug sunitinib. Their physicochemical properties, accumulation, localization, and cytotoxicity in human osteosarcoma (HOS) cells were analyzed. Results and Discussion: The fluorescent liposomes successfully penetrated the cells after 15 min of incubation. The cytotoxicity studies revealed that the liposomes induced cell death after 48 h, with an IC₅₀ value of 106.0 ± 10.2 μM. These results suggest that the BODIPY-FL/L-carnitine liposomes hold promise for both diagnostic and therapeutic applications, offering a potential platform for theranostic drug delivery systems. Conclusions: The developed fluorescent liposomes encapsulating sunitinib show promising potential as a novel anticancer drug delivery system, with applications in theranostics for cancer treatment.

Objective: Currently, various drugs have been developed and are being used in practice for the treatment of HIV infection, however, the emergence of multidrug resistance to the drugs used is still a serious problem in anti-HIV therapy. Limitations in the use of existing nucleoside reverse transcriptase inhibitors (NRTIs) have led to the development of strategies for creating prodrugs based on them. The development of prodrugs of antiviral nucleosides with isosteric derivatives of natural lipids makes it possible to increase the bioavailability of these drugs and modulate their efficiency. Methods: In this work, new lipophilic prodrugs of 3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxy-3′-thiacytidine (3TC) based on 1,3-(dipalmitoylamino)propan-2-ol were synthesized using the H-phosphonate method. Phosphoramidate derivatives with various esters of L-α-alanine have also been obtained. Results and Discussion: The anti-HIV activity of the synthesized compounds against various HIV strains (HIV-1 MVP-899; HIV-1 RF) and cytotoxicity in relation to MT-4 cells were studied.The H-phosphonatediester and phosphodiester conjugates showed anti-HIV activity inferior to the parent nucleosides, and their advantages include low cytotoxicity (CC₅₀ >100 µM). The phosphodiester conjugate 3TC was inactive in this virus cell system. The antiviral activity of phosphoamidates with L-α-alanine esters decreased in the range (^tBu) >Me > (ⁱPr) > Et. Thus, compounds with methyl, ethyl and isopropyl ether residues showed a similar level of anti-HIV activity (IC₅₀ = 4.60­–12.55 µM), the derivative containing the residue of tert-butyl ether of L-α-alanine (IC₅₀ = 0.46 µM) showed the greatest activity. These compounds showed cytotoxicity similar to AZT (CC₅₀ >50 µM). Conclusions: The new lipophilic derivatives of AZT and 3TC synthesized in the work have low toxicity and exhibit antiviral activity against various clinical isolates of HIV-1. Although they are inferior in effectiveness to the parent anti-HIV nucleosides in cellular models, their cytotoxicity is lower, the advantages of such conjugates include the possibility of increasing the bioavailability of drugs due to enterocyte-mediated lymphatic transport, potential intracellular release of nucleoside monophosphate, which additionally bypasses the limiting stage of primary phosphorylation of nucleosides. Therefore, the design of such prodrugs can serve as the basis for the search for drugs with high efficacy.

Objective: This study evaluated a method for assessing the immunogenicity of synthetic peptides as a potential clinical diagnostic for cellular immune responses to influenza virus. Two 9-mer peptides corresponding to epitopes from the 2023-2024 Northern Hemisphere vaccine strains were used: a 432–440 aa fragment of influenza A hemagglutinin (Phe–Leu–Asp–Ile–Trp–Thr–Tyr–Asn–Ala) and a 454–462 aa fragment of influenza B neuraminidase (Leu–Leu–Trp–Asp–Thr–Val–Thr–Gly–Val). Methods: The peptides were synthesized using classical methods of peptide chemisty, employing carbodiimide condensation with activated amino acid esters. Fifty five volunteers (aged 20–26) too part in the clinical study. Gamma interferon (IFN-γ) production was measured by the ELISA assay. Results and Discussion: No statistically significant differences in IFN-γ levels were observed across any pairwise comparisons. Conclusions: The diagnostic method requires further optimization before it can be reliably used for clinical assessment of cellular immune response to influenza A virus.

Azepine is a seven-membered, nitrogen-containing heterocyclic compound. It serves as an important structural scaffold and found in many natural and synthetic compounds, including several drugs, such as antipsychotic agents and antihistamines. This review article discusses the synthesis, pharmacological activities of azepine derivatives, and the structure–activity relationships (SAR) associated with them. The future prospects of azepine derivatives as therapeutic agents appear promising, as their diverse biological activities make them attractive candidates for the development of new drugs to treat various diseases.

Objective: This research presents the synthesis of fourteen novel coumarin derivatives, each fused with one of two distinct five-membered heterocycles, with the aim that these easily accessible coumarin frameworks will have a wide range of modifiable biomedical applications. Methods: The molecular structures of the synthesized derivatives were confirmed using spectroscopic methods, namely ¹H, ¹³C NMR, and FT-IR. The biomedical potential of these derivatives as antiproliferative, antioxidant, antidiabetic, anti-inflammatory, and antimicrobial agents was evaluated in vitro. Additionally, their biosafety toward non-infective bacterial strains and non-malignant cells was assessed. To investigate the pharmacokinetic and toxicological profiles of these derivatives, computational tools were employed. Results and Discussion: The authors identified the following key outcomes from the collected data. The type of fused heterocycle significantly influences the biomedical potential of the investigated derivatives. Compound A1 showed considerable anti-inflammatory activity via the lipoxygenase-dependent pathway and outperformed Nystatin in terms of antifungal potential. Compounds A2, A3, B2, and B3 exhibited great potential as antidiabetic candidates due to their potent glucosidase and amylase inhibitory properties. Compounds A4 and B4 demonstrated strong antioxidant, antiproliferative, and biosafety profiles. In terms of antibacterial activity, A5 and B5 were comparable to Ciprofloxacin against all the aerobic bacterial strains tested. Moreover, the biosafety profiles against non-infective bacterial strains were favorable for all the synthesized derivatives, particularly for this pair. Lastly, the synthesized derivatives exhibited favorable profiles regarding oral bioavailability and toxicity. Conclusions: These derivatives may serve as valuable building blocks for the future development of novel pharmaceuticals with a broad range of bioactivities.

Objective: The 3D structure of the fluorescent protein DiB3-F53L, an orange-red fluorescent non-covalent complex of a genetically engineered variant of the bacterial protein lipocalin Blc with a synthetic GFP-like chromophore M739, was studied by the molecular dynamics (MD) computational method. The fluorescence brightness of the complex has increased by ~1.16 times compared to the parent DiB3 biomarker, which makes it a promising biomarker for cell biology for labeling biological objects, as well as a starting object for the subsequent design of new brighter biological markers. Methods: Molecular dynamics (MD). Results and discussion: The 3D structure of the fluorescent protein DiB3-F53L, an orange-red fluorescent non-covalent complex of a genetically engineered variant of the bacterial protein lipocalin Blc with a synthetic GFP-like chromophore M739, has been studied by the computational molecular dynamics method. Calculations revealed the amino acids surrounding the chromophore at the binding site that contribute most strongly to the chromophore-protein interaction energy. Conclusions: The DiB3-F53L protein complex with the M739 chromophore has an increased fluorescence brightness compared with the parent biomarker DiB3, which makes it a promising biomarker for labeling biological objects in cell biology, as well as a starting object for the subsequent design of new brighter biomarkers.

Objective: Indole, a nitrogen-containing heterocyclic compound, exhibits a range of pharmacological effects, including antimicrobial, anti-inflammatory, and anticancer properties. Colorectal cancer is a leading cause of cancer-related mortality worldwide. This study aimed to evaluate the antitumor activity of a newly synthesized indole derivative, 2-((2-chloro-5-nitrophenyl)(1H-indol-3-yl)methyl)-2H-indene-1,3-dione (designated as 2Cl-5N-ind-dione), on HT-29 colorectal adenocarcinoma cells. Methods: The novel compound 2Cl-5N-ind-dione was synthesized and its structure was confirmed by ¹H, ¹³C NMR, and FT-IR spectroscopy. Its antitumor efficacy was assessed using the MTT assay, Annexin V/PI staining, and quantitative RT-PCR. Results and Discussion: Treatment with compound 2Cl-5N-ind-dione exerted cytotoxic effects on HT-29 cells with IC₅₀ values of 70.54, 23.64, and 22.18 µg/mL at 24, 48, and 72 h, respectively. The compound modulated the expression of specific microRNAs: it upregulated the tumor-suppressive miRNAs miR-200a and miR-34a, while downregulating miR-181a. Wound healing assays, flow cytometry, and qRT-PCR analysis confirmed that 2Cl-5N-ind-dione inhibited cell migration and induced apoptosis in HT-29 cells compared to untreated controls. Conclusions: Our data indicate that compound 2Cl-5N-ind-dione acts as an anti-proliferative, antimigratory, and pro-apoptotic agent. These effects are likely mediated by the observed modulation of miR-200a, miR-34a, and miR-181a, which are known to target key pathways involved in apoptosis and cell migration.

Among numerous related natural proteins of plant and animal origin, there are families that can induce cross-IgE-mediated allergic reactions. Such protein families are called panallergens. Each family of panallegens has its specific physicochemical and immunobiological characteristics, which affect their allergenic properties. This review describes the main families of panallergens, their structure, properties, and functions and the possible consequences of patients sensitizations, as well as modern methods of molecular allergy diagnostics. The review provides a summary table of panallergen protein families. The choice of appropriate therapy of allergic pathologies, especially allergen-specific immunotherapy, and elimination measures largely depends on accurate and early diagnosis of allergic diseases. As with any pathology, the therapy of allergic diseases is effective only when it is pathogenetically justified, an integrated approach is applied, and the sequence of therapeutic measures is followed. Accordingly, understanding panallergen families and their properties allows clinicians to better identify cross-reactions and select targeted therapies for allergic patients.

Objective: This study aimed to evaluate four 3-(4,5-diaryl-1H-imidazol-2-yl)quinoline-2-amine derivatives (Ia–Id) for their potential in diabetes management using in vitro and in silico analyses. Methods: The antihyperglycemic activity of the derivatives was assessed through glucose uptake and α-amylase inhibition assays. Antioxidant properties were evaluated using DPPH, ABTS, and phosphomolybdenum assays, while anti-inflammatory activity was determined via albumin denaturation inhibition. In silico docking studies were conducted to assess binding affinities with PPAR-γ and α-amylase. Additionally, ADMET analysis was performed to predict pharmacokinetics and toxicity profiles. Results and Discussion: Compound Ib exhibited the highest glucose uptake (58.01% at 160 µg/mL) and α-amylase inhibition (48.85% at 160 µg/mL), supported by strong docking affinities for PPAR-γ and α-amylase. Antioxidant assays identified compounds Ib and Ia as the most effective derivatives, with notable DPPH, ABTS, and phosphomolybdenum activity. Anti-inflammatory activity, evaluated through albumin denaturation inhibition, further supported the therapeutic potential of Ib and Ia. ADMET analysis predicted favorable pharmacokinetics and low toxicity for all derivatives, with Ib and Ia demonstrating higher bioavailability. Conclusions: Compound Ib emerged as the most promising candidate for diabetes management, demonstrating strong antihyperglycemic, antioxidant, and anti-inflammatory activities, along with favorable pharmacokinetic and safety profiles. These findings highlight the therapeutic potential of these derivatives and provide a foundation for future in vivo studies and structural optimization to enhance efficacy and safety in diabetes management.