Russian Journal of Bioorganic Chemistry最新文献

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.

Objective: Quercetin, a flavonoid found in fruits and vegetables, is known for its antioxidant, anti-inflammatory, and cytotoxic properties. However, its poor water solubility limits its therapeutic potential. This study aimed to design and synthesize a nanocomposite for efficient quercetin delivery to DU-145 prostate carcinoma cells and evaluate its therapeutic effects. Methods: Ag₂O@Quercetin nanoparticles (Ag₂O@Quercetin NCs) were designed and synthesized to enhance the delivery of insoluble quercetin to DU-145 cells. The anti-tumor activities of the nanoparticles were evaluated using the MTT assay, Annexin V FITC/PI staining, scratch assay, and analysis of miR-34a and miR-181a expression patterns, along with their potential targets in cell migration and apoptosis via quantitative RT-PCR (Q-RT-PCR). Results and Discussion: Physicochemical characterization, including X-ray diffraction (XRD), transmission electron microscopy (TEM), field emission scanning electron microscopy (FE-SEM), differential thermal gravimetric (DTG) analysis, and FT-IR spectroscopy, confirmed the particle size, elemental composition, and thermal stability of the Ag₂O@Quercetin NCs. The nanoparticles exhibited antiproliferative activity, with an IC₅₀ value of 55.27 µg/mL in DU-145 cells. The scratch assay demonstrated that Ag₂O@Quercetin NCs inhibited cancer cell migration. Upregulation of miR-34a and downregulation of its potential targets, EGFR and TGF-β1, were observed in treated cells. Additionally, downregulation of oncomiR-181a and upregulation of their potential targets involved in apoptosis (Casp8 and Casp9 genes) and anti-invasion (E-cadherin) were observed in treated cells. Conclusions: The results indicate that silver oxide nanoparticles are effective carriers for quercetin delivery to cancer cells. Ag₂O@Quercetin NCs induce apoptotic pathways and inhibit cell migration and invasion in prostate cancer cells through the modulation of specific miRNAs and their associated targets.

Objective: Hyperuricemia is a major cause of gout. Over time, currently available drugs may become less effective. This study focuses on the synthesis and biological evaluation of new 3-chloro-1-phenyl-1H-pyrazolo[4,3-c]quinoline derivatives (IIIa–IIIl) as promising xanthine oxidase inhibitors for the treatment of gout. Methods: 3-chloro-1-phenyl-1H-pyrazolo[4,3-c]quinoline derivatives (IIIa–IIIl) were synthesized by reacting 4-oxo-1,4-dihydroquinoline-3-carboxylic acid with various reagents. The structures of the synthesized compounds were established using various analytical techniques. The compounds were further evaluated for their in vitro xanthine oxidase inhibitory activity. Results and Discussion: Among the tested compounds, compound IIIe exhibited significant activity with an IC₅₀ value of 4.48 ± 0.12 µg/mL, compared to the standard drug allopurinol (9.45 ± 0.08 µg/mL). A docking study was performed to understand the molecular interactions of the leading compound. Compound IIIe showed a binding energy of –7.351 kcal/mol, which was more favorable than that of the standard (–5.387 kcal/mol). This indicates that the compounds are well docked into the active site of the protein. Conclusions: The 3-chloro-1-phenyl-1H-pyrazolo[4,3-c]quinoline derivatives (IIIa–IIIl) have demonstrated significant xanthine oxidase inhibitory properties. These findings suggest that these compounds could contribute to the development of new drugs for hyperuricemia and gout treatment.

Objective: The development of drought-tolerant genotypes of Quercus robur (“English” oak) is an important task in the context of climate change. This study aimed to analyze the transcriptomes of two oak genotypes with contrasting drought tolerance under normal water availability and water deficit conditions. Methods: Transcriptome samples were collected from two oak genotypes differing in drought tolerance. The study was conducted under two conditions: normal water availability (control) and water deficit (drought). Differentially expressed genes (DEGs) were identified to compare the responses between the two genotypes under both conditions. Results and Discussion: In genotype 1 (drought-tolerant), 70 DEGs were identified, with 42 upregulated and 28 downregulated. In genotype 2 (drought-sensitive), 97 DEGs were identified, with 37 upregulated and 60 downregulated. Genotype 1 exhibited a strong overrepresentation of GO terms related to abiotic stress response and changes in photosynthesis, suggesting a better adaptation to drought conditions. Genotype 2 showed DEGs primarily related to stress-induced regulation of hormone biosynthesis and stress response in the extracellular matrix, indicating a weaker drought response. An overlap analysis revealed one common gene with increased expression in both genotypes under drought: methylsterol monooxygenase, involved in steroid biosynthesis. Conclusions: The results provide insights into the molecular mechanisms behind drought tolerance in Quercus robur. The identification of differentially expressed genes could help in early identification of drought-tolerant genotypes, aiding in the development of oak varieties more suitable for future climate conditions.

Objective: This study aimed to synthesize new artesunate-based derivatives via multicomponent reactions, including Ugi, Mannich, and Cu(I)-catalyzed azide-alkyne cycloaddition (click chemistry). Additionally, the antiviral activity of these derivatives against the SARS-CoV-2 pseudovirus was assessed. Methods: The artesunate derivatives were synthesized using Ugi reactions to form α-acetoamidocarboxamides, Mannich reactions to generate aminomethyl derivatives, and click chemistry to produce triazole-linked conjugates with sugar moieties. The antiviral activity of the resulting sugar-triazole-artesunate hybrids was evaluated in vitro using BHK-21-hACE2 cells infected with the SARS-CoV-2 pseudovirus. The half-maximal inhibitory concentration (IC₅₀) was determined through a dose-response assay. Results and Discussion: The synthesis resulted in high yields of artesunate derivatives with diverse structures. Among them, compound VIII, a sugar-triazole-artesunate hybrid, displayed promising antiviral activity against the SARS-CoV-2 pseudovirus with an IC₅₀ of 1.5 µM, approximately twice as potent as the reference drug amodiaquine. Cytotoxicity analysis further confirmed the selectivity of this compound, yielding a selectivity index (SI) of 28.28, suggesting a favorable therapeutic profile. Conclusions: The successful synthesis of novel artesunate derivatives via multicomponent reactions was achieved, with the sugar-triazole conjugate demonstrating significant antiviral activity against the SARS-CoV-2 pseudovirus. These findings highlight the potential of such conjugates as candidates for further development in antiviral therapies.

Objective: This study presents the aqueous-based synthesis of 2-aminopyrimidine derivatives (IVa–IVf) via aromatic nucleophilic substitution (S_NAr), followed by Suzuki coupling with halogenated derivatives. Methods: Characterization of the synthesized compounds was carried out using NMR spectroscopy and mass spectrometry analysis. Further computational studies, including molecular docking against the B-Raf protein, highlighted favorable binding interactions. Results and Discussion: Anticancer activity showed that certain compounds demonstrated significant potency against the A549 lung cancer cell line, with IC₅₀ values indicating moderate to high efficacy. Notably, compounds IVa, IVc, and IVf exhibited IC₅₀ values of 8.14, 9.46, and 8.6 µM, respectively. Further computational studies, including molecular docking against the B-Raf protein, highlighted favorable binding interactions, with docking scores of –8.053 for IVa and –7.617 for IVc. These findings suggest potential mechanisms of action for these compounds. Conclusions: This green synthetic approach, together with promising biological and computational results, underscores the therapeutic potential of pyrimidine derivatives as environmentally sustainable cancer treatment candidates.