Russian Journal of Bioorganic Chemistry最新文献

Objective: Despite a large number of works focused on the search for the mechanisms of formation of IgE-producing B-cells, the question of the relative contribution of germinal centers and extrafollicular foci B-cells in this process still remains controversial. Of particular interest is the study of the mechanisms of stimulation of the allergic immune response under the influence of air pollutants. The aim of the work was to study the connection between the adjuvant effect of benzo(a)pyrene (BaP) on the production of specific IgE in a novel low-dose allergy model with changes in the subpopulation composition of B-cells in the tissue of the immunization site and secondary lymphoid organs. Methods: Antigen without any stimuli was administrated to one group of BALB/c mice for 9 weeks in a low (0.3 μg) dose. BaP was administrated to another group of mice along with antigens at a dose of 4 ng. B-cell subpopulations were analyzed by flow cytometry. Results and discussion: BaP significantly stimulated the production of allergen-specific IgG₁ at early (3 weeks) time point, and allergen-specific IgE at late (9 weeks) time point. The aeropollutant increased the content of CD19⁺CD38^–CD95⁺B220⁺ germinal center B-cells with the phenotype and their precursors (CD19⁺CD38⁺CD95⁺B220⁺) with the phenotype in the spleen at early and late time points, but not in the lungs or regional lymph nodes. Under its influence, the content of CD19⁺CD38^–CD95⁺B220^– and CD19⁺CD38⁺CD95⁺B220⁺ extrafollicular plasmablasts in the spleen at an early time point and in lung tissue at a later time point also increases. In the spleen, BaP increased the content of CD138⁺CD19^–B220⁺ and CD138⁺CD19^–B220^– mature plasma cells, and in regional lymph nodes the content of CD138⁺CD19⁺B220^– immature plasma cells at a later time point. Conclusions: The adjuvant effect of BaP on the production of specific IgE was largely associated with stimulation of the formation of germinal centers in the spleen and with extrafollicular activation of B-cells in lung tissue.

Objective: The current study aimed to develop novel 1,2,3-triazole-piperzine-quinazolines and test their anticancer potential against MCF-7, HeLa, A-549, and HEK-293. Methods: Initially, we combined 4-chloro-2-methylquinazoline with 1-(prop-2-yn-1-yl)piperazine to produce the key intermediate alkyne. Following this, various aryl azides reacted with alkyne to produce the final 1,2,3-triazoles. We evaluated the anticancer activity of the newly synthesized derivatives using the MTT microcultured tetrazolium assay, which measures cell viability. Results and discussion: ESI-MS, ¹H, and ¹³C NMR spectroscopy show the verification of all the prepared derivatives. Compounds (IVe) and (IVk) are demonstrated more potent activity against MCF-7 with IC₅₀ values of 3.03 ± 0.34 and 3.18 ± 0.42 μM. And also compounds (IVd) and (IVl) have shown good activity against MCF-7, with IC₅₀ values of 4.23 ± 0.54 and 6.32 ± 0.61 μM. These results are compared to the standard doxorubicin. Conclusions: A novel series of 1,2,3-triazole-piperzine-quinazoline conjugates were synthesized and tested for in vitro anticancer activity. Some of the compounds had strong activity against MCF-7 and good activity against the A-549 cell lines. More powerful compounds did not harm the normal cell line, HEK-293. Finally, by making a modest alteration to powerful compounds, it has the potential to be a future therapeutic candidate for cancer treatment.

Natural products and their main substances are used to treat various health disorders. Flavonoids, a significant group of natural compounds with considerable pharmacological effects, are underutilized due to their rapid metabolism, restricted absorption, and low solubility in water. The development of novel technologies such as nanocarriers is crucial for addressing this issue and enhancing bioavailability. Hesperetin (Hst) and hesperidin (Hes) are flavanones that have promising antimicrobial, antituberculosis, anti-inflammatory, antioxidant, and anticancer activities. This paper discusses numerous approaches to the delivery of Hst and Hes-loaded nanoformulations (liposomes, polymeric nanoparticles, lipid nanoparticles, hybrid nanoparticles, nanocrystals, ethosomes, and nanogels) along with the many pharmacological properties that these nanoparticles possess primarily anticancer and antibacterial capabilities.

The study of the interaction of nucleic acids with ligands is relevant both in terms of scientific interest and high potential practical significance. Nucleic acid complex formation with ligands affects the biochemical functions of the most important carrier of genetic information, which opens up opportunities for treating genetic diseases and controlling the aging of both cells and the organism as a whole. Among the huge variety of potential ligands, porphyrins and related compounds occupy a special placedue to their ability to generate reactive oxygen species under irradiation with light. The photocatalytic properties of porphyrins can be used in the creation of molecular tools for genetic engineering and the treatment of viral and bacterial infections at the genetic level. Modification of porphyrin compounds allows targeting of the ligand to a specific biological target.The review summarizes the literature data describing the process of nucleic acid complex formation with aromatic ligands, mainly with porphyrins. The influence of the structure of macroheterocycles on the features of interaction with nucleic acids is analyzed. Promising directions for further research are outlined.

Objective: The main objective of this work was to develop a convenient synthesis of a new class of oxazaphosphorines, namely 6-phenoxy-4,5-dihydro-1,2,6-oxazaphosphinine 6-oxides (IVa–IVe), for antibacterial screening. Methods: Oxazaphosphorines (IVa–IVe) were obtained through a three-step approach involving the microwave-assisted conjugative addition of diphenyl phosphite to α,β-unsaturated ketones, followed by oximation and intramolecular cyclization. The newly synthesized oxazaphosphorines were screened for their in vitro antibacterial activity against Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli, Salmonella typhimurium, and Pseudomonas aeruginosa) bacteria. The obtained results were also correlated with the in silico molecular docking studies in DNA gyrase enzyme active site. Results and Discussion: Oxazaphosphorines (IVa–IVe) were obtained in 47–60% yields. The biological assays showed that these compounds exhibited appreciable antibacterial activity. Compound (IVe) was found to be the most potent antibacterial agent with an inhibition zone diameter of 9.66 ± 0.89 mm, and MIC and MBC values of 10 and 25 mg/mL respectively, when tested against S. typhimurium. We also observed a fairly good agreement between these experimental in vitro antibacterial outcomes and the in silico molecular docking results in DNA gyrase enzyme active site. Conclusions: We have successfully developed a convenient synthesis of a new class of oxazaphosphorines, namely 6-phenoxy-4,5-dihydro-1,2,6-oxazaphosphinine 6-oxides (IVa–IVe). When screened for their in vitro antibacterial activity, compound (IVe) was found to be the most potent antibacterial agent. We tried to correlate these results with those obtained in the in silico molecular docking study. The obtained results suggest that the synthesized compound (IVe) is a potential DNA gyrase inhibitor and could be used as a lead compound for developing new potent antibacterial drugs.

Objective: Prolyl endopeptidase (PEP) and dipeptidyl peptidase IV (DPP4) are serine peptidases, cleaving peptides at the carboxyl group of proline residues. These enzymes are involved in the regulation of many physiological processes, participating in the production, modification, and utilization of neuropeptides and peptide hormones. We found that compounds of the X-Y-2-S-cyanopyrrolidine general formula, where X is a protecting group and Y is any amino acid other than glycine and proline, which are PEP inhibitors, also inhibit DPP4. To explain the unexpected ability of these compounds to inhibit DPP4, we set out to develop a structurally reasoned insights of their interaction with the PEP and DPP4 active sites. Methods: To achieve this goal, we synthesized a series of N-protected amino acid derivatives of 2-S-cyanopyrrolidine, determined their inhibition constants for PEP and DPP4, and performed molecular dynamics modeling of the structures of these complexes. Results and Discussion: X-Y-2-S-pyrrolidine PEP inhibitors can inhibit DPP4, if X is a benzyloxycarbonyl or succinyl protecting group and Y is not a glycine or proline residue, i.e., they are L-amino acid residues with side chains. Among them, N-benzyloxycarbonylamino-L-methionyl-2S-pyrrolidine-2-carbonitrile has pronounced antiamnesic activity. Molecular dynamics modeling showed that the large hydrophobic side chain of methionine or tryptophan residues in the inhibitor ensures its binding to the active site of DPP4, compensating for steric hindrance created by the N-protecting group. Conclusions: Using molecular dynamics modeling methods, we established a relationship between the structure of 2-S-cyanopyrrolidine amino acid derivatives and their ability to inhibit DPP4. This opens the prospect of creating new drugs, affecting the peptidergic link in the regulation of functional systems in normal conditions and in various pathological processes.

Objective: The systematic use of P–NH₂ analogs of nucleic acids as objects and/or tools in molecular biology and biomedicine is limited by the complexity of their synthesis. For almost 40 years, researchers have been looking for effective synthetic approaches to P–NH₂ oligonucleotides. These analogs, which are isostructurally identical to natural oligonucleotides, have not been further developed even though a lot of publications on their synthesis and characteristics. To develop a more straightforward and cost-effective method than those being practiced today, our group set out to modify the phosphoramidite protocol of oligonucleotide (ON) synthesis for preparing the P–NH₂ analogs of oligodeoxyribonucleotides. Methods: For the synthesis of the P–NH₂ analogs, a standard, presently widely used protocol of the phosphoramidite synthesis of oligonucleotides was taken as a basis. The P–NH₂ modification was introduced at the oxidation step via the Staudinger reaction, using (9-fluorenyl)methoxycarbonyl azide (FmocN₃). The subsequent formation of an N-unsubstituted phosphoramidate moiety in the oligonucleotide was accomplished by the removal of the Fmoc group by treatment with a strong base. The thermodynamic properties of the P–NH₂ analogs as part of complementary nucleic acid complexes formed in low-ionic-strength solutions were studied by thermal denaturation analysis with optical signal registration. Results and Discussion: It was found that to increase the efficiency of synthesis of electroneutral P–NH₂ oligonucleotides additional Fmoc cleavage step should be introduced to the protocol of automated synthesis. This step should be added after each step of oxidation of the growing oligomer chain via the Staudinger reaction. It was shown that the yield of the P–NH₂ oligonucleotide was almost entirely independent of the type of the dinucleotide fragment being modified, as well as of the localization of the P–NH₂ linkage in the chain. The attenuation of the destabilizing effect of the introduction of a single P–NH₂ linkage with decreasing ionic strength of the solution provided additional evidence for the electroneutral state of the inserted phosphoramidate linkage. Conclusions: A new approach to the automated synthesis of partially modified oligonucleotide derivatives bearing uncharged N-unsubstituted phosphoramidate linkages isostructural to native P–O linkages by an optimized solid-phase phosphoramidite protocol using the Staudinger reaction has been proposed.

Objective: To evaluate the antimicrobial effectiveness of a novel 5-(1,3-benzothiazol-2-yl)-4-[(E)-(phenylmethylidene)amino]-4H-1,2,4-triazole-3-thiol derivatives. Methods: Starting from 2-aminothiophenol, a series of novel benzothiazole tethered triazole compounds were synthesized using conventional multi-step reactions. The reaction conditions were optimized for yield. Characterization was performed using ¹H, ¹³C NMR, IR, and mass spectrometry. To determine the antimicrobial activity, both the agar well diffusion method and micro broth dilution method were employed. Molecular docking was conducted with AutoDock Vina, and ADME analysis was performed using SwissADME. The evaluation of toxicity was carried out using ADMETlab 2.0. Results and Discussion: Compound with a 2-NO₂ substitution showed potent antibacterial activity against E. coli, with an inhibition of 50 µg/mL, similar to the standard drug chloramphenicol. The derivatives containing 3-Br and thiophene substitutions exhibited excellent activity against P. aeruginosa, with an inhibition concentration of 50 µg/mL. Moreover, the compounds with substitutions of 4-Br, 2,4-F, 4-F, and thiophene showed notable antifungal activity against C. albicans at a concentration of 250 µg/mL, surpassing the effectiveness of the standard drug griseofulvin. The results of molecular docking indicated that the compounds possessing 2-NO₂, 3-Br, and 2,4-F substitutions displayed the most potent binding affinities towards their target proteins. The ADMET properties of these compounds were thoroughly evaluated and confirmed their drug-like characteristics and pharmacokinetic viability. Conclusions: The results of the antimicrobial activity assays and molecular docking studies indicate that several of the synthesized compounds demonstrated potency equal to or exceeding that of standard drugs. Furthermore, the ADMET profiles of these compounds were favourable, suggesting good pharmacokinetic properties. These findings highlight the potential of the synthesized compounds as effective antimicrobial agents, warranting further investigation and development.

Objective: Antisense oligonucleotide (ASO) and DNAzyme (Dz) agents have been suggested for suppression specific mRNA in vivo. It was reported that Dz agents are more selective in recognition their targets than ASO. However, Dz failed to produce therapeutically significant drugs due to their low efficiency. Here we compared the performance of the two types of agents in cleavage a folded RNA fragment in reconstituted system containing RNase H. Methods: Thermodynamic parameters and predicted 2D-structure of the RNA fragments were obtained using RNAFold application in UNAFold web server. To perform the experiments with RNA cleavage by enzymes we used commercial Mg₂⁺-containing reaction 10X RNAse H Buffer (200 mM Tris-HCl (pH 8.3), 150 mM DTT, 1 M KCl, 45 mM MgCl₂). Results of RNA cleavage were visualized with 20% denaturing PAGE (AA : BA (29 : 1), 7 M Urea, 1× TBE) running 150 min at 80 V. Results and Discussion: Individual ASO agents were ~3­–6 times more active in RNA cleaving than the equivalent Dz agents. Both agents demonstrated low selectivity toward RNA cleavage. Combining two Dz complementary to the abutting position of the RNA target bivalent (BDD) agent improved RNA cleavage to the level of the most active ASO agent. Conclusions: Comparing the obtained data with published earlier for RNase H—free system suggests that RNase H stabilizes the Dz:RNA complex and reduces its selectivity but significantly increase RNA cleavage efficiency. The contribution of RNase H effects on the performance of Dz agents in cell culture and in vivo should be taken in account.

Objective: The enzymatic oxidation of ferulic acid was carried out to improve their solubility and stability and provide new properties. Methods: The oxidation of ferulic acid was carried out using laccase from Trametes versicolor in sodium acetate buffer of pH 5.0 at room temperature. The two oxidized products were fractionated using column chromatography. These oxidized products, P1 and P2, demonstrated good antibiofilm and antioxidant activity compared to ferulic acid. P1 exhibited higher antibiofilm and antioxidant activity than P2. These products were characterized using FT-IR and NMR spectroscopies. Results and Discussion: A polymeric form of ferulic acid was synthesized using the enzyme laccase and fractionated using two different solvents. These fractions were purified, dried, and evaluated for antibiofilm and antioxidant potential. P1 and P2 have MIC of 125 µg against S. aureus. Sub-MIC concentrations were used for antibiofilm assays. The results suggested that P1 and P2 have good antibiofilm activity than ferulic acid. Conclusions: The predicted structure of P1 was a dimer, and P2 was synthesized as a trimer. These findings suggested that, when compared to the trimer, the dimer product of ferulic acid oxidation has good antibiofilm and antioxidant activity.