Russian Journal of Bioorganic Chemistry最新文献

{"title":"Chemotherapeutic Boron-Containing Homocysteinamides of Human Serum Albumin","authors":"M. Wang,&nbsp;S. A. Tsyrempilov,&nbsp;I. A. Moskalev,&nbsp;O. D. Zakharova,&nbsp;A. I. Kasatova,&nbsp;V. N. Sil’nikov,&nbsp;T. S. Godovikova,&nbsp;T. V. Popova","doi":"10.1134/S1068162025010297","DOIUrl":"10.1134/S1068162025010297","url":null,"abstract":"<p><b>Objective:</b> A combination of boron neutron capture therapy and chemotherapy can ensure good efficacy in cancer treatment. The development of therapeutic constructs that combine these two functions, specifically the possibility of <i>in vitro</i> and <i>in vivo</i> visualization and a convenient platform for selective delivery to the tumor, is of great relevance today. <b>Methods:</b> In this study, we focused on human serum albumin, a well-known drug delivery platform, and developed, based on albumin functionalized with boron clusters, therapeutic constructs, which as analogs of the chemotherapeutic molecule gemcitabine and signaling molecules. To create such constructs, we developed new analogs of homocysteine thiolactone containing <i>closo</i>-dodecaborate or cobalt bis(dicarbollide) and a gemcitabine analog containing <i>closo</i>-dodecaborate attached to the C⁵ carbon atom of the nitrogenous base. <b>Results and Discussion:</b> It was demonstrated that the the conjugates modified with the gemcitabine analogs exhibit increased cytotoxicity against human glioblastoma cell lines. Among the obtained conjugates, the highest cytotoxicity is demonstrated by that containing cobalt bis(dicarbollide). The resulting structures accumulate well in the cytoplasm of cancer cells. The albumin conjugate containing cobalt <i>bis</i>(dicarbollide) and the boron-containing gemcitabine analog is capable of accumulating in the nuclei of T98G cell lines. <b>Conclusions:</b> The resulting albumin constructs showed sufficient <i>in vitro</i> activity against human glioma cells. It is expected that the obtained therapeutic conjugates will significantly enhance the anticancer efficacy of irradiation with epithermal neutrons. Combining a chemotherapeutic residue and a boron-containing group in a single construct provides potential for more effective glioma therapy.</p>","PeriodicalId":758,"journal":{"name":"Russian Journal of Bioorganic Chemistry","volume":"51 1","pages":"354 - 371"},"PeriodicalIF":1.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143396453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preparation of Boron-Containing S-Nitrosothiol Based on Homocysteinylamides of Human Serum Albumin for Combined NO-Chemical and Boron-Neutron-Capture Therapy","authors":"T. V. Popova,&nbsp;M. Van,&nbsp;T. N. Kurochkin,&nbsp;S. A. Tsyrempilov,&nbsp;O. D. Zakharova,&nbsp;V. N. Silnikov,&nbsp;T. S. Godovikova","doi":"10.1134/S1068162025010194","DOIUrl":"10.1134/S1068162025010194","url":null,"abstract":"<p><b>Objective:</b> The strategic aim of this work is to create a fluorophore-labelled, clinically relevant exogenous NO donor carrying a boron-containing compound residue based on human serum albumin (HSA) for the implementation of combined NO-chemotherapy and boron-neutron-capture therapy. <b>Methods:</b> By selective modification of the Cys34 residue of albumin with a maleimide derivative of a fluorescent dye and subsequent N-homocysteinylation with a thiolactone derivative of homocysteine containing a clozo-dodecaborate residue, a nanoconstruct for boron-neutron-capture therapy was obtained. An analogue based on the natural modifier, boron-containing homocysteine thiolactone, was synthesised by alkylation of the amino group of thiolactone with a dioxonium derivative of clozo-dodecaborate. Post-synthetic modification of the lysine residues of the protein using the boron thiolactone of homocysteine provided the introduction of SH groups into the protein and the possibility of subsequent trans-S-nitrosylation of the protein using S-nitrosoglutathione. <b>Results and Discussion:</b> It was found that 2 M of NO was conjugated to 1 M of boron-containing HSA. Boron-containing S-nitrosothiol based on albumin homocysteinylamide, without epithermal neutron irradiation, was demonstrated to be more cytotoxic against human glioblastoma cell lines than the boron-containing albumin conjugate. <b>Conclusions:</b> Thus, the approach used allows obtaining a boron-enriched structure based on a biocompatible tumor-specific protein, containing a fluorescent label and an increased number of S-nitroso groups. It is necessary for the manifestation of a chemotherapeutic effect of the construct. The practical significance of this structure lies in the possibility of a cancer treatment, combining chemo- and boron-neutron capture therapy.</p>","PeriodicalId":758,"journal":{"name":"Russian Journal of Bioorganic Chemistry","volume":"51 1","pages":"202 - 215"},"PeriodicalIF":1.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143396577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Live-Cell Visualization of Histone Modification Using Bimolecular Complementation","authors":"A. I. Stepanov,&nbsp;L. V. Putlyaeva,&nbsp;A. A. Shuvaeva,&nbsp;M. A. Andrushkin,&nbsp;M. S. Baranov,&nbsp;N. G. Gurskaya,&nbsp;K. A. Lukyanov","doi":"10.1134/S1068162025010261","DOIUrl":"10.1134/S1068162025010261","url":null,"abstract":"<p><b>Objective:</b> The study of histone post-translational modifications (PTMs) is a rapidly developing field, yet the tools available for detecting and interpreting these modifications are limited. Histone modifications, such as methylation, acetylation, and phosphorylation, play a crucial role in regulating chromatin dynamics and gene expression. Specific binding of histone modification “reader” domains (HMRDs) is central to this regulation, allowing for the recruitment of proteins that facilitate chromatin remodeling. This research aims to develop genetically encoded sensors based on HMRDs to study histone modifications in live cells, offering a more efficient and flexible method for studying epigenetic changes. <b>Methods:</b> We designed genetically encoded sensors that utilize HMRDs and splitFAST to bind specifically to different histone modifications. These sensors were incorporated into cells to track the dynamic changes in histone modifications. The performance of these sensors was evaluated through live-cell imaging, using fluorescent microscopy to monitor histone modifications. <b>Results and Discussion:</b> The genetically encoded sensors demonstrated high specificity and sensitivity to various histone modifications. Sensors based on SplitFAST and HMRDs MPP8 and AF9 exhibited specific distributions for H3K9me3 and H3K9ac. Moreover, the combination of these two domains with different parts of SplitFAST showed spatial proximity between H3K9me3 and H3K9ac. These findings suggest that the integration of HMRD-based sensors, MPP8 and AF9, with SplitFAST could provide valuable tools for live-cell monitoring of histone modifications and their roles in gene regulation and cellular response mechanisms. <b>Conclusions:</b> The development of genetically encoded sensors for histone modifications based on HMRDs provides a powerful new tool for studying chromatin dynamics in live cells. These sensors offer a more direct and real-time approach to understanding the complex mechanisms of histone modification and their impact on gene expression.</p>","PeriodicalId":758,"journal":{"name":"Russian Journal of Bioorganic Chemistry","volume":"51 1","pages":"320 - 329"},"PeriodicalIF":1.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143396619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DHPMs C5 Amide Bearing Benzothiazole Moiety Inhibit AChE: Design, Synthesis, In Vitro and In Silico Studies","authors":"Pardis Samiei,&nbsp;Dara Dastan,&nbsp;Ahmad Ebadi","doi":"10.1134/S1068162025010285","DOIUrl":"10.1134/S1068162025010285","url":null,"abstract":"<p><b>Objective:</b> The well-accepted hypothesis in Alzheimer’s disease (AD) emphasizes the role of the cholinergic system in the disease. Therefore, the design and development of selective AChE inhibitors have been considered a promising strategy for AD treatment. Dihydropyrimidin-2-one is a privileged heterocyclic scaffold with a wide range of biological activities. <b>Methods:</b> Our initial docking studies indicated that substitution at the para position of the C4 aryl in the DHPM ring could interact with the gorge of the active site. Accordingly, we designed and synthesized eight DHPM derivatives to test the hypothesis. <b>Results and Discussion:</b> The results indicated that the DHPM with a benzothiazolyl carbamyl moiety at C5 and an OCF₃ group at the para position of the C4 aryl ring was the most potent inhibitor. The propargyloxy group was less potent than the OCF₃ group but had the same ligand efficiency. <b>Conclusions:</b> Introducing electron-rich substitutions of proper size increased activity, but the ligand efficiency remained constant. <i>In silico</i> studies revealed that the para substitution of the aryl ring interacted with the gorge residues in the R-enantiomer.</p>","PeriodicalId":758,"journal":{"name":"Russian Journal of Bioorganic Chemistry","volume":"51 1","pages":"340 - 353"},"PeriodicalIF":1.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143396646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent Advances in Liposomes Efficacy as a Drug Delivery Platform for Melanoma Treatment","authors":"Elham Zarenezhad,&nbsp;Zahra Kazeminejad,&nbsp;Mahsa Rostami Chijan,&nbsp;Mahmoud Osanloo,&nbsp;Ensieh Nournia,&nbsp;Abdolmajid Ghasemian,&nbsp;Mahrokh Marzi","doi":"10.1134/S1068162025010030","DOIUrl":"10.1134/S1068162025010030","url":null,"abstract":"<p>Melanoma is the predominant skin cancer with the potential for metastasis. The disease has inferred an enhancing trend worldwide during recent years, needing proper therapeutic approaches. Liposomes place among the leading vesicular drug delivery platforms, permitting controlled release, targeted therapy, and hence exerting minimal off-target toxicity. They can be prepared in various sizes, entrap various hydrophilic and hydrophobic medicines, and load various lipid- and water -soluble drugs and compounds in relatively high amounts. Liposomes protect the cargo and endure within the biological structures against degradation and clearance. They are biologically inert and biodegradable and decrease the toxicity, antigenicity, or pyrogenicity of medicinal compounds. The combination therapy of liposomal delivery with chemotherapeutics and immunotherapy approaches has been promising. In this study, we provide the results of a biological activity evaluation of liposomes in melanoma cancer. This review will be useful in different disciplines, such as organic chemistry, pharmacology, medicinal chemistry, biochemistry, and oncology.</p>","PeriodicalId":758,"journal":{"name":"Russian Journal of Bioorganic Chemistry","volume":"51 1","pages":"93 - 116"},"PeriodicalIF":1.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143396674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nano-frFAST: Design of a New Genetically-Encoded Far-Red Fluorescent Label","authors":"E. L. Sokolinskaya,&nbsp;Yu. A. Bogdanova,&nbsp;I. N. Myasnyanko,&nbsp;A. I. Sokolov,&nbsp;S. A. Krasnova,&nbsp;M. S. Baranov","doi":"10.1134/S1068162025010145","DOIUrl":"10.1134/S1068162025010145","url":null,"abstract":"<p><b>Objective:</b> The design of a new fluorogen-activating protein nano-frFAST and a series of fluorogens with an extended π-system are presented. <b>Methods:</b> The formation of imines of the corresponding cinnamaldehydes followed by [2 + 3]-cycloaddition was used for the synthesis of arylallylidene-imidazolones. The arylallylidene-rhodanine synthesis was performed by Knoevenagel condensation of the corresponding cinnamaldehydes with rhodanine. The other compounds were synthesized by condensation of arylidene-imidazolone analogues with isonicotinaldehyde. The new protein was screened <i>in vitro</i> and its optical properties were studied. Spectrofluorimetric titration was performed to evaluate the binding constant. Imaging of the [nano-frFAST–HPAR-DOM]-labeled cellular structures was performed by the wide-field fluorescence microscopy. <b>Results and Discussion:</b> We have shown that (<i>Z</i>)-5-((<i>E</i>)-3-(4-hydroxy-2,5-dimethoxyphenyl)allylidene)-2-thioxothiazolidin-4-one (hereafter, HPAR-DOM) can act as an excellent fluorogen for the nano-frFAST protein. We have demonstrated that the nano-frFAST–HPAR-DOM complex can be used in fluorescent labeling of individual compartments of the living HeLa Kyoto cells in the far-red region of the spectrum. <b>Conclusions:</b> We have developed the novel fluorogen-activating protein nano-frFAST and the fluorogen HPAR-DOM for this protein and demonstrated that this pair can be used as a genetically encoded far-red fluorescent label in living cells.</p>","PeriodicalId":758,"journal":{"name":"Russian Journal of Bioorganic Chemistry","volume":"51 1","pages":"128 - 136"},"PeriodicalIF":1.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143396676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Construct Design, Isolation, and Purification of the Human GPR17 Receptor Monomeric Form for Structural and Functional Studies","authors":"N. A. Safronova,&nbsp;A. P. Luginina,&nbsp;A. A. Sadova,&nbsp;M. B. Shevtsov,&nbsp;O. V. Moiseeva,&nbsp;V. I. Borshchevskiy,&nbsp;A. V. Mishin","doi":"10.1134/S106816202501025X","DOIUrl":"10.1134/S106816202501025X","url":null,"abstract":"<p><b>Objective:</b> G protein-coupled receptors (GPCRs) are a family of seven transmembrane domain proteins with more than 800 members in the human genome. They play a key role in the regulation of most of the processes in the human body and are the targets of one third of all modern drugs. Despite their importance in pharmacology, many GPCRs remain orphan receptors, i.e., their endogenous ligands are unknown. An orphan receptor GPR17, a class A GPCR representative, is predominantly expressed in the central nervous system and plays an important role in regulating the formation of the myelin sheath of neurons. It is a potential target for the development of new drugs against various disorders, such as multiple sclerosis, Alzheimer’s disease, and ischemia. The aim of this work was to prepare GPR17 for structural and functional studies starting from protein modification and ending with the receptor production. <b>Methods:</b> A screening of different genetically engineered constructs was performed, a series of point mutations were analyzed, and a significant number of potential ligands for this receptor were tested. The constructs were expressed in the Sf9 insect cell line using the Bac-to-Bac approach. The membrane fraction was extracted, the protein was solubilized into DDM/CHS detergent micelles, followed by purification by a metal affinity chromatography. Functional analysis of the purified protein included analytical gel filtration, polyacrylamide gel electrophoresis, and thermal stability analysis. <b>Results and Discussion:</b> Stabilizing point mutations were identified and the optimal position of the partner protein was found. The conditions for the expression, isolation, and purification of GPR17 were optimized to produce a sufficiently stable and monomeric protein sample suitable for further structural and functional studies. <b>Conclusions:</b> GPR17 is an orphan GPCR and the actively studied pharmacological target. The structural and functional investigation of this protein is a relevant problem for modern science and biomedicine. As a result of an in-depth study of GPR17, several stabilizing receptor modifications were developed, and optimal conditions for recombinant protein production were found. Our results can be used for further structural and functional studies of GPR17 and can serve as an example of a strategy that can be applied to perform investigation of other GPCRs.</p>","PeriodicalId":758,"journal":{"name":"Russian Journal of Bioorganic Chemistry","volume":"51 1","pages":"308 - 319"},"PeriodicalIF":1.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143396616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative Analysis of Biomolecular Condensates on a Modified Support","authors":"A. S. Shtork,&nbsp;Iu. I. Pavlova,&nbsp;J. I. Svetlova,&nbsp;M. S. Iudin,&nbsp;E. N. Grafskaia,&nbsp;V. A. Manuvera,&nbsp;S. E. Alieva,&nbsp;A. M. Varizhuk,&nbsp;V. N. Lazarev,&nbsp;T. S. Vedekhina","doi":"10.1134/S1068162025010182","DOIUrl":"10.1134/S1068162025010182","url":null,"abstract":"&lt;p&gt;&lt;b&gt;Objective:&lt;/b&gt; Biomolecular condensates are associates of biopolymers formed in aqueous solutions &lt;i&gt;via&lt;/i&gt; “liquid-liquid” phase separation. Aberrant phase transitions of proteins or nucleic acids underlie several pathologies, and the need for their &lt;i&gt;in vitro&lt;/i&gt; models stimulates the development of methods for biocondensate investigation. This work addresses the key problem of visualizing labeled protein-RNA condensates using fluorescence microscopy. &lt;b&gt;Methods:&lt;/b&gt; The SARS-CoV-2 N-protein with a C-terminal hexahistidine tag was expressed in &lt;i&gt;Escherichia coli&lt;/i&gt; BL21-Gold(DE3) and isolated by metal chelate chromatography. The N-protein was labeled with the RED dye, which emits fluorescence in the far-red range of the spectrum, using the RED-NHS dye. Commercially available RNA isolated from Torula yeast was used as random RNA to obtain condensates with the N-protein and SR-rich peptide. In experiments to test the colocalization of the condensate components, a labeled modified oligonucleotide forming an SL4 hairpin with an elongated stem was added to the random RNA. To obtain the APTES support, chemically polished glass was treated with 3-aminopropyltriethoxysilane in ethyl alcohol at pH 4.5–5.5. To obtain the DSC-APTES support, the APTES support was additionally functionalized by treating with &lt;i&gt;N&lt;/i&gt;,&lt;i&gt;N&lt;/i&gt;′-disuccinimidyl carbonate in the presence of diisopropylethylamine in anhydrous acetone. A quantitative assessment of condensate formation was performed using fluorescence microscopy data. The FastTrack program was used to assess droplet mobility. The Droplet_Calc program was used to assess the droplet area and curvature coefficient. &lt;b&gt;Results and Discussion:&lt;/b&gt; The mobility of the condensates in a sample layer on glass complicates data processing. In previous studies, condensate immobilization on 3-aminopropyltriethoxysilane-treated glass (APTES), was proposed to overcome this problem. The APTES support allows non-covalent RNA/DNA binding but is suboptimal for proteins. By treating APTES with &lt;i&gt;N&lt;/i&gt;,&lt;i&gt;N&lt;/i&gt;′-disuccinimidyl carbonate, we obtained an alternative support, DSC-APTES, which allows covalent binding of protein fragments via lysine residues. A comparative analysis of known condensates on the abovementioned supports revealed their decreased mobility on APTES/DSC-APTES, and the optimal type of support modification depended on the condensate composition. Condensate immobilization improved image quality and increased the colocalization of the oligonucleotide and protein components. It also facilitated the quantitative analysis of the phase separation based on the condensate fractions. New software, Droplet_Calc, was developed to automate condensate identification and fraction calculation. The results confirmed the advantages of APTES and DSC-APTES over glass when analyzing the concentration dependence of the condensate fraction and creating phase diagrams. &lt;b&gt;Conclusions:&lt;/b&gt; Thus, the optimization of the support a","PeriodicalId":758,"journal":{"name":"Russian Journal of Bioorganic Chemistry","volume":"51 1","pages":"273 - 284"},"PeriodicalIF":1.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143396450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemical Synthesis of Novel DDR1 Inhibitors and Their Activity Against Gefitinib-Resistant Non-Small Cell Lung Cancer","authors":"Xuemei Xu,&nbsp;Siyu Chen,&nbsp;Doudou Sun,&nbsp;Xuebao Wang,&nbsp;Zhouyang Xu","doi":"10.1134/S1068162025010108","DOIUrl":"10.1134/S1068162025010108","url":null,"abstract":"<p><b>Objective:</b> The discoidin domain receptor-1 (DDR1) has been demonstrated as a potential target in gefitinib-resistant non-small cell lung cancer (NSCLC). However, drug development in this area remains limited. Therefore, this study aims to chemically synthesize novel DDR1 inhibitors and explore their activity against gefitinib-resistant NSCLC. <b>Methods:</b> The structures of the synthesized compounds were confirmed by electrospray ionization mass spectrometry (ESI-MS), ¹H, ¹³C NMR, and elemental analysis, followed by kinase screening experiments. The inhibitory impact of these compounds on the proliferation of PC-9 cells and gefitinib-resistant cell lines (PC-9GR and HCC827GR) was evaluated using the cell counting kit-8 (CCK-8) assay. Furthermore, the invasion capability of the cells was assessed using the Transwell assay. Additionally, Western blot analysis was employed to explore the targeting effects of these compounds on DDR1. <b>Results and Discussion:</b> Twenty-four 4,6-disubstituted pyrimidine derivatives were synthesized in series A, B, and C. Some compounds in series A and C exhibited promising inhibitory effects against DDR1 and DDR2, with compounds (<b>A04</b>), (<b>A05</b>), and (<b>C04</b>) demonstrating more pronounced activities. Moreover, compounds (<b>A02</b>), (<b>A03</b>), (<b>A07</b>), and (<b>C04</b>) significantly impeded the viability of PC-9 and PC-9GR cells, with (<b>A07</b>) exhibiting the strongest inhibition, with half-maximal inhibitory concentration (IC₅₀) values of 1.12 ± 0.07, 1.03 ± 0.18, and 1.56 ± 0.19 µM against PC-9, PC-9GR, and HCC827GR cells, respectively. Furthermore, 1 µM of (<b>A03</b>) and (<b>A07</b>) significantly inhibited the protein expression of <i>p</i>-DDR1 and DDR1, with compound (<b>A07</b>) being the most significant inhibitor (<i>p</i> &lt; 0.001). Additionally, the Transwell assay demonstrated that 1 µM of (<b>A07</b>) substantially inhibited the invasion of PC-9 (<i>p</i> = 0.0003) and PC-9GR cells (<i>p</i> = 0.0019). <b>Conclusions:</b> The newly synthesized DDR1 inhibitor (<b>A07</b>) effectively inhibits the proliferation and invasion of gefitinib-resistant NSCLC cells, offering a potential new therapeutic option for treating NSCLC.</p>","PeriodicalId":758,"journal":{"name":"Russian Journal of Bioorganic Chemistry","volume":"51 1","pages":"285 - 297"},"PeriodicalIF":1.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143396574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thiazolidine Based Quinazoline Hybrids: Synthesis, Docking, DFT, Molecular Dynamic Study, and In Vitro Antidiabetic Evaluation","authors":"S. Gharge,&nbsp;S. G. Alegaon,&nbsp;S. D. Ranade,&nbsp;R. S. Kavalapure","doi":"10.1134/S106816202501011X","DOIUrl":"10.1134/S106816202501011X","url":null,"abstract":"<p><b>Objective:</b> This study aimed to design, synthesize, and evaluate thiazolidinedione and rhodanine-based quinazoline derivatives (<b>Va–Vc</b>) as dual inhibitors of α-amylase and α-glucosidase, with an investigation into their pharmacokinetic properties and mechanism of action using a computational approach. <b>Methods:</b> The compounds were designed computationally and synthesized using appropriate synthons. <i>In silico</i> molecular docking and molecular dynamics simulations were employed to explore their interactions with α-amylase, GLUT-4, and homology-modeled α-glucosidase. Pharmacokinetic properties, including drug-likeness, ADME, and toxicity, were predicted. Network pharmacology and experimental validation were used to assess the modulation of PI3K-AKT, MAPK, and EGFR signaling pathways, as well as inhibitory activities against α-amylase, α-glucosidase, and glucose uptake by yeast cells. <b>Results and Discussion:</b> The derivatives exhibited promising inhibitory activities. Substituted benzylidine thiazolidine-2,4-dione showed IC₅₀ values of 22.59 ± 0.30 µM for α-amylase and 43.50 ± 1.23 µM for α-glucosidase, with 58.23 ± 0.14% glucose uptake. Substituted benzylidene-4-oxo-2-thioxothiazolidin-3-yl acetic acid displayed IC₅₀ values of 13.48 ± 1.38 µM for α-amylase and 65.94 ± 0.14 µM for α-glucosidase, with 57.23 ± 0.13% glucose uptake. These compounds modulated key signaling pathways, contributing to their inhibitory effects and favorable pharmacokinetic profiles. <b>Conclusions:</b> The study highlights the potential of thiazolidinedione and rhodanine-based quinazoline derivatives as novel α-amylase and α-glucosidase inhibitors, offering promising therapeutic potential for managing diabetes mellitus. </p>","PeriodicalId":758,"journal":{"name":"Russian Journal of Bioorganic Chemistry","volume":"51 1","pages":"177 - 201"},"PeriodicalIF":1.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143396576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}