Russian Journal of Bioorganic Chemistry最新文献

The worldwide increasing prevalence of type 2 diabetes emphasizes the need to explore safer and more effective anti-hyperglycemic agents. Type 2 diabetes mellitus (T2DM) is characterized by excessive gluconeogenesis and the resulting endogenous glucose production. Currently used hypoglycemic agents do not act through direct inhibition of gluconeogenesis-mediated glucose production. Recently, fructose 1,6-bisphosphatase (FBPase) has emerged as a promising target to control the overproduction of glucose from gluconeogenesis, as it is a key enzyme in the middle cycle of gluconeogenesis. Several studies on FBPase inhibitors for the management of T2DM have notably shown no severe hypoglycemia, weight gain, or other serious side effects. In the present article, the authors summarize recent developments in the field of FBPase inhibitors with insights into glucose homeostasis, gluconeogenesis, mechanisms of currently available drugs, and emerging targets for the management of T2DM. Further, some strategies and structure-activity relationships (SARs) of FBPase inhibitors are discussed. This review is expected to be useful for researchers working in this area. FBPase inhibitors represent an attractive target for developing more effective and safer therapies for the treatment of T2DM and cancer. AMP mimetic inhibitors have been shown to possess an unfavorable pharmacokinetic profile; hence, efforts are required to develop covalent-allosteric, non-phosphorous-based, or natural FBPase inhibitors in the future.

Today, cancer continues to be one of the most dangerous diseases, annually causing the deaths of more than 9 million people in the world. Therefore, new and more effective methods of cancer therapy are in demand. As monoclonal antibody-based immunotherapy has already shown its effectiveness, antibody-drug conjugates (ADC), one of its successful variants, have significant and not yet fully realized potential. ADCs are monoclonal antibodies bound to cytotoxic drugs through linkers. In many clinical trials and already in standard clinical practice, ADCs have demonstrated significant advantages over the combination therapy with unmodified antibodies and chemotherapeutic drugs. Due to new achievements in the field of molecular immunology and biotechnology, the potential of ADCs is assessed as a breakthrough, which will allow ADCs to become the most sought-after anticancer drugs in the coming years. Owing to ADCs it has become possible to deliver drugs to tumor cells in a targeted manner without significant toxic effects on healthy tissues and organs. To date, 15 ADC drugs have been approved worldwide for use in clinic, and more than a hundred more drugs of this class are at various stages of clinical trials. At the same time, ADC therapy is associated with certain side effects and limited efficacy. Therefore there is a need to develop more advanced conjugates. This review describes the history of the development of ADC as a therapeutic class of molecules, their structure, targets, and mechanism of action. It also outlines the prospects and directions for further development of ADCs.

Objective: The pore-forming toxin hemolysin II (HlyII) secreted by the gram-positive bacterium Bacillus cereus is one of the main pathogenic factors of this microorganism. The action of HlyII leads to cell lysis due to pore formation on membranes. Monoclonal antibodies against the large C-terminal fragment (Met225–Ile412, HlyIILCTD) of B. cereus HlyII were obtained by the hybridoma technology using the recombinant soluble form of HlyIILCTD as an antigen. The monoclonal antibody LCTD-83 inhibited the hemolytic activity of HlyII, and the degree of protection depended on the presence or absence of proline at position 324 in the primary sequence of the toxin. The antibodies most effectively inhibited the hemolysis of erythrocytes, induced B-771 HlyII, the sequence of which contains Pro324. It was shown that the antibody interacts with the pores formed in the RBC membranes, thereby blocking the possible release of intracellular contents. Methods: HlyII and its mutant forms were obtained using recombinant E. coli BL21(DE3) producer strains. The soluble form of HlyIILCTD was obtained using the chaperone protein SlyD. Monoclonal antibodies were obtained by the hybridoma technology. The ability of antibodies to recognize antigens was characterized by the enzyme-linked immunosorbent assay and immunoblotting; immunoprecipitation was used to demonstrate interaction with the membrane pores formed by the toxin. Results and Discussion: A monoclonal antibody against the oligomeric form of the LCTD-83 antigen inhibited the hemolytic activity of B. cereus B-771 HlyII by blocking the transmembrane channels formed by the toxin. Inhibition of the cytolytic activity of the toxin by LCTD-83 depended on the presence of the Pro324 residue in the primary sequence of HlyII. Conclusions: The neutralizing monoclonal antibody LCTD-83 recognized the formed HlyII transmembrane channel and was sensitive to conformational changes during its formation. The substitution of Pro324 by Leu in the primary sequence of HlyII affected the neutralizing ability of the antibody. The LCTD-83 antibody less effectively interacts with the full-length toxin than with HlyIILCTD, which is evidenced by the fact that pore formation is accompanied by a change in the toxin conformation. In this regard, antibodies interacting with its oligomeric form are promising candidates for inhibiting the cytolytic effect of hemolysin II, and LCTD-83 has the potential to identify ways to neutralize the toxin.

Ursolic acid (UA) is a common natural compound of the pentacyclic triterpenoid class with multifaceted pharmacological activity. The diversity of sources emphasizes the potential application of UA from natural plant components for various therapeutic and prophylactic purposes. This review presents the current state of knowledge on the properties of this widespread bioactive compound, as well as information on its sources, biosynthesis and applications in pharmaceutical, cosmetic and agricultural fields. Apart from promising pharmacological effects, this review recognizes the existing obstacles in the clinical application of UA due to the low bioavailability of the triterpenoid, highlighting the need to modify delivery forms and/or improve the original UA framework through chemical modifications.

Objective: Cellular senescence has been linked to the genetics of gastrointestinal stromal tumors (GISTs). The escape of gastrointestinal stromal tumor cells from senescence leads to cellular immortality and uncontrolled proliferation. Therefore, inducing senescence is considered a crucial approach for preventing the progression of gastrointestinal stromal tumors. Sunitinib, a tyrosine kinase inhibitor, has been approved as a drug for treating gastrointestinal stromal tumors and renal cell carcinoma. However, it remains unclear whether Sunitinib exerts a protective effect by inducing cellular senescence in gastrointestinal stromal tumor cells. Methods: Cells were treated with Sunitinib. Cellular senescence was assessed using the senescence-associated β-galactosidase (SA-β-gal) staining assay and a telomerase activity kit. Gene and protein expression were measured using real-time PCR and western blot analysis. Results and Discussion: We found that Sunitinib reduced cell viability in GIST-882 cells. Additionally, Sunitinib induced oxidative stress and DNA damage by increasing mitochondrial reactive oxygen species (ROS), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and the phosphorylated form of histone H2AX (γH2AX). The SA-β-gal staining assay revealed that Sunitinib induced cellular senescence in GIST-882 cells by reducing telomerase activity and the expression of human telomerase reverse transcriptase (hTERT). Interestingly, the presence of the antioxidant N-acetyl-L-cysteine (NAC) abolished the effects of Sunitinib on cellular senescence, suggesting the involvement of ROS in this process. Further analysis showed that Sunitinib upregulated the expression of acetylated p53 and p21 while downregulating the expression of silent information regulator sirtuin 1 (SIRT1). Notably, overexpression of SIRT1 prevented Sunitinib-induced cellular senescence in GIST-882 cells, suggesting that SIRT1 plays a key role in this process. Conclusions: Taken together, our findings suggest that Sunitinib induces a “therapy-induced senescence” effect in gastrointestinal stromal tumors by inhibiting SIRT1.

Objective: Antimicrobial resistance is a major global concern in the treatment of infectious diseases. The development of multi-targeted antimicrobial agents is the key objective of this study. Herein, we report the analogue-based design, synthesis, and biological evaluation of bioisosteres of sulfonamides for broad-spectrum antimicrobial activity. Methods: A ligand-based approach utilizing bioisosteric replacement was employed to design new antimicrobial sulfonamides. Accordingly, ten novel compounds were synthesized. Their in silico binding interactions with various virulent proteins were analyzed. Results and Discussion: The antimicrobial efficacy of these compounds was assessed against both Gram-positive (Streptococcus pyogenes) and Gram-negative (Shigella flexneri) bacteria by determining their zone of inhibition (ZOI) and minimum inhibitory concentration (MIC₉₀) values. Among the synthesized compounds, 1-((4-methoxyphenyl)sulfonyl)piperazine (IVa) exhibited the highest activity, with MIC₉₀ values of 3.9 and 7.8 μg/mL against S. pyogenes and S. flexneri, respectively. The cytotoxicity of the most active compounds (IIIg and IVa) was assessed using a Live/Dead BacLight fluorescence assay. Additionally, field emission scanning electron microscopy (FE-SEM) was performed to examine bacterial cell morphological changes upon treatment. The in silico cytotoxicity profile of the synthesized compounds was evaluated using the SwissADME and TOPKAT models in Accelrys Discovery Studio 4.1. Furthermore, molecular docking studies were conducted using the CDOCKER module to investigate the binding interactions of the most active compound (IVa) with dihydropteroate synthase and microbial DNA gyrase-IV, demonstrating its multi-targeted mechanism of action. Conclusions: The results revealed that (IVa) interacts with key amino acid residues of dihydropteroate synthase with a binding energy of −193.891 kcal/mol and DNA gyrase-IV with a binding energy of −75.982 kcal/mol.

The application of fluorescent markers in the study of nanoparticle interaction with living matter has proven to be a highly effective method. Numerous studies have demonstrated the rapid and efficient uptake of nanoparticles by the cells, with the use of fluorescent markers in microscopic observations playing a pivotal role. These methods facilitate not only the observation of qualitative changes in fluorescence intensity but also the quantitative assessment of changes occurring during delivery system components influx into the body. Synthetic dyes can be integrated into the structure of a polymer (polylactide or modified hyaluronic acid) during the production of nanoparticles with a fluorescent marker, without the formation of new chemical bonds between the fluorophore and the nanoparticle. However, the tracking of such systems is often inefficient due to poor solubility and diffusion of the components in the biological environment. Conversely, the incorporation of fluorescent tags via chemical modification of the functional groups of polymers with dyes appears to be a far more promising alternative, as it allows the production of strong conjugates that serve as markers of the system itself. Furthermore, the covalent binding of fluorophores to the polymer addresses problems such as the inaccuracy of localization associated with the release of the tag from the nanoparticle and its further penetration into non-target cells and organelles. This review presents a detailed critical evaluation of the methods of introduction and the classes of fluorescent markers used to modify polymers, based on lactic, glycolic and hyaluronic acids, for drug delivery.

Objective: In order to discover new antitumor small molecules, research has been conducted on quinazoline derivatives to explore potential new compounds. Methods: A series of 2,4,7-trisubstituted quinazoline derivatives containing an aminomethyl piperidine moiety were designed and synthesized. The MTT assay was used to evaluate the inhibitory effect of the compounds on the proliferation of various tumor cell lines (Eca-109, A549, PC-3, MGC-803), and the IC₅₀ values were calculated. Cell cycle analysis, cell migration assays, colony formation assays, and apoptosis assays were performed to investigate the antitumor mechanism of compound (XVIe). Results and Discussion: Compound (XVIe) exhibited the most potent antiproliferative activity against MGC-803 cells, with an IC₅₀ value of 0.74 μM, significantly lower than that of 5-fluorouracil. Additionally, compound (XVIe) effectively inhibited the migration and colony formation of MGC-803 cells, induced G0/G1 phase arrest, and increased ROS accumulation, ultimately leading to apoptosis of MGC-803 cells. Meta-substituents in the benzene ring demonstrated superior antiproliferative activity compared to para- and ortho-substituents. The sequence of antiproliferative activity for the meta-substituted compounds against the four cancer cell lines was: methyl > ethoxy > fluorine ≈ methoxy > chlorine. Conclusions: Compound (XVIe) demonstrated significant antitumor activity and holds potential for further development as an antitumor drug.

ctive: Novel 2,3-diarylsubstituted-1,3-thiazolidin-4-one derivatives (IVa–IVm) were synthesized by reacting thioglycolic acid and Schiff bases (IIIa–IIIm) in the presence of 1,4-dioxane and ZnCl₂ using the conventional method. Methods: The structures of these compounds were confirmed by FT-IR, ¹H NMR, and mass spectrometry. The disc diffusion method was used to screen the antimicrobial activity of the newly synthesized compounds. Gram-negative (P. aeruginosa and E. coli) and Gram-positive (B. subtilis and S. aureus) bacterial strains were selected for antibacterial activity, using ciprofloxacin as a standard drug. Simultaneously, fungal strains (C. albicans and A. niger) were tested for antifungal activity using the standard drug fluconazole. Results and Discussion: The results of the study suggested that the synthesized derivatives showed good antibacterial and antifungal activity against all tested organisms. Conclusions: Compounds substituted with –OH, –Cl, –NO₂, and –OCH₃ groups on the aryl ring showed the maximum antibacterial and antifungal activity.

Objective: Pyrimidine derivatives exhibit diverse biological activities, including antifungal, analgesic, antimicrobial, anti-inflammatory, and anticancer properties. This study focuses on the synthesis and evaluation of novel 5-carboxamide-2-oxo-tetrahydropyrimidine derivatives for their antibacterial and antifungal potential. Methods: Various 2-oxo-tetrahydropyrimidine-5-carboxamide derivatives (VIa–VIn) were synthesized via the reaction of N-arylacetoacetamides, urea, and substituted benzaldehydes in ethanol as a solvent, using a catalytic amount of ferric chloride with a trace of HCl. The progress of the reaction was monitored by TLC, and the products were purified by recrystallization. The structures of the synthesized compounds were characterized by IR, ¹H NMR spectroscopy, and mass spectrometry, with further confirmation by elemental analysis. Results and Discussion: The antibacterial and antifungal activities of all synthesized compounds were evaluated against standard microbial strains, including Gram-negative bacteria (Pseudomonas aeruginosa, Escherichia coli), Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis), and fungi (Aspergillus niger, Candida albicans). Compounds (VIc), (VIe), (VIg), (VII), (VIj), (VIk), and (VIn) exhibited significant antibacterial activity against both Gram-negative and Gram-positive bacteria. Similarly, compounds (VIc), (VId), (VIe), (VII), (VIj), (VIk), and (VIn) demonstrated potent antifungal activity against A. niger and C. albicans. Several of these compounds showed greater potency than standard antibiotics and antifungal drugs. Conclusions: In this study, novel pyrimidine derivatives were synthesized and evaluated for their antibacterial and antifungal properties. The results suggest that these compounds hold promise as potential leads for the development of new antimicrobial agents. Further research is necessary to elucidate their mechanism of action and assess their in vivo efficacy.