Bioorganic & Medicinal Chemistry最新文献

{"title":"Novel agents derived from natural product β-elemene: A second round of design and synthesis to enhance antitumor properties","authors":"Zhouyan Liu ,&nbsp;Tong Li ,&nbsp;Chenglei Gu ,&nbsp;Cheng Chen ,&nbsp;Ziwei Tang ,&nbsp;Yanyan Feng ,&nbsp;Chen Zhou ,&nbsp;Jinyi Xu ,&nbsp;Jichao Chen","doi":"10.1016/j.bmc.2025.118129","DOIUrl":"10.1016/j.bmc.2025.118129","url":null,"abstract":"<div><div>Natural products play a key role in drug discovery and development. The natural sesquiterpene, <em>β</em>-elemene, has been approved as an antitumor drug in China. Despite showing few side effects, the moderate antitumor potency of <em>β</em>-elemene hampers its wide application in clinic. A second round of design and synthesis of <em>β</em>-elemene derivatives was carried out based on our previous prodrug-like ester derivatives. The resulting twenty-nine compounds (except <strong>10c</strong>) exhibited enhanced antitumor activity compared with <em>β</em>-elemene and its ester derivative <strong>3</strong>. The optimal compound <strong>10a</strong> possessed low micromolar antiproliferative activities against three human cancer cell lines (SGC-7901, HeLa, and U87), more potent than positive control cisplatin. The mechanism studies indicate that compound <strong>10a</strong> caused arrest of the cell cycle along with inhibition of microtubules, induced apoptosis via a ROS-involved mitochondrial apoptotic pathway, and dampened cell migration and invasion with changes of related protein (MMP-9 and <em>p</em>-FAK^Y397) expressions. Collectively, the promising antitumor efficacy of compound <strong>10a</strong> would make it a potential lead compound in anticancer drug development.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118129"},"PeriodicalIF":3.3,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143510686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis and biological activity of 8-hydroxy modified urolithin A derivatives as phosphodiesterase type II (PDE2) inhibitors","authors":"Feng Zhou,&nbsp;Xiaoqing Feng ,&nbsp;Zhongqiu Xu,&nbsp;Fen Yan,&nbsp;Guoqiang Song,&nbsp;Long Tang","doi":"10.1016/j.bmc.2025.118127","DOIUrl":"10.1016/j.bmc.2025.118127","url":null,"abstract":"<div><div>Urolithin A (UA) is a naturally occurring polyphenolic compound.Due to its remarkable efficacy in safeguarding the central nervous system, UA has emerged as a promising candidate for drug development targeting neurodegenerative diseases such as Alzheimer’s. However, the source of UA is limited and the activity of UA to inhibit PDE2 needs to be further improved. Therefore, this study will be optimized on the basis of UA to seek PDE2 inhibitors with better activity.</div><div>In this study, we designed a series of UA derivatives based on 4HTX as the target protein and UA as the lead compound, utilizing the binding crystal structures of 4HTX and BAY60-7550 as references. After thorough screening, we successfully identified the 8-hydroxyl group as the precise site of modification. Utilizing 2-bromo-5-hydroxybenzoic acid as our primary raw material, we synthesized a series of the 8-hydroxyl modified UA. Subsequently, we evaluated the inhibitory activity of these synthesized UA derivatives using a phosphodiesterase assay kit. Ultimately, we screened a total of 34 derivatives; among them, compounds 1f, 1q, 2d, and 2j exhibited significant inhibitory activity against PDE2 with half-maximal inhibitory concentrations of 3.05 μM, 0.67 μM, 0.57 μM, and 4.96 μM, respectively.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118127"},"PeriodicalIF":3.3,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143487102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, and biological evaluation of novel azaspirooxindolinone derivatives as potent inhibitors of ITK and BTK-dependent cancers","authors":"Gopal Mudasani ,&nbsp;Naveen Kumar Rampeesa ,&nbsp;Sreenivasa Reddy Anugu ,&nbsp;Pullareddy Muddasani ,&nbsp;Soňa Gurská ,&nbsp;Petr Džubák ,&nbsp;Marián Hajdúch ,&nbsp;Viswanath Das ,&nbsp;Rambabu Gundla","doi":"10.1016/j.bmc.2025.118116","DOIUrl":"10.1016/j.bmc.2025.118116","url":null,"abstract":"<div><div>Interleukin-2-inducible T-cell kinase (ITK) and Bruton’s tyrosine kinase (BTK) are two important members of the Tec family with crucial roles in immune system function. Deregulation in ITK and BTK activity is linked to several hematological malignancies, making them key targets for cancer immunotherapy. In this study, we synthesized a series of azaspirooxindolinone derivatives and evaluated their cytotoxic activity against ITK/BTK-negative and positive cancer cell lines, followed by enzymatic inhibition studies to assess the ITK/BTK kinase selectivity of two hit compounds. Several compounds demonstrated selective cytotoxicity against ITK- or BTK-expressing cells. Compound <strong>3<em>d</em></strong> exhibited high cytotoxicity in ITK-positive Jurkat (IC₅₀ = 3.58 µM) and BTK-positive Ramos (IC₅₀ = 3.06 µM) cells, while compound <strong>3<em>j</em></strong> showed strong cytotoxicity in Ramos (IC₅₀ = 1.38 µM) and Jurkat (IC₅₀ = 4.16 µM) cells. Compounds <strong>3<em>a</em></strong> and <strong>3<em>e</em></strong> were selectively cytotoxic in Jurkat cells (IC₅₀ = 9.36 µM and 10.85 µM, respectively), while compounds <strong>3<em>f</em></strong> and <strong>3g</strong> were highly cytotoxic in Ramos cells (IC₅₀ = 1.82 µM and 1.42 µM, respectively). None of the active compounds exhibited cytotoxicity in non-cancer cell lines (IC₅₀ &gt; 50 µM), demonstrating their selectivity for malignant cells. Enzyme inhibition assay showed that <strong>3<em>d</em></strong> is a selective ITK inhibitor (IC₅₀ = 0.91 µM) with no detectable BTK inhibition, aligning with its strong activity in ITK-positive cells. In contrast, compound <strong>3<em>j</em></strong> did not inhibit ITK or BTK enzymatically, suggesting an alternative mechanism of action. These findings highlight <strong>3<em>d</em></strong> as a promising ITK inhibitor and warrant further investigation to elucidate its mechanism of action.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118116"},"PeriodicalIF":3.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143510685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New phenylpiperazine-thiazolidine-2,4-dione hybrids targeting MAO inhibition: Synthesis, biological evaluation, kinetic study and in silico insights","authors":"Lamiaa O. El-Halaby ,&nbsp;Mohammad M. Al-Sanea ,&nbsp;Abdullah A. Elgazar ,&nbsp;Samar S. Tawfik ,&nbsp;Abdelrahman Hamdi ,&nbsp;Wafaa A. Ewes","doi":"10.1016/j.bmc.2025.118123","DOIUrl":"10.1016/j.bmc.2025.118123","url":null,"abstract":"<div><div>Monoamine oxidase inhibitors are promising drug targets for many neurological diseases such as depression, Alzheimer’s disease, and Parkinson’s disease. The current study developed new hybrid compounds by merging phenyl piperazines, and 2,4-thiazolidinedione moieties based on their reported MAO inhibitory activities. The newly synthesized derivatives were screened for their MAOs inhibitory activity using <em>in-vitro</em> fluorometric assay. Most newly synthesized compounds elicited strong inhibitory activity against both <em>h</em>MAO isozymes. Hybrids <strong>4a</strong> and <strong>4c</strong> were the most potent <em>h</em>MAO-A inhibitors with IC₅₀ values of 0.194 and 0.188 µM, respectively, compared to toloxatone as reference (IC₅₀ = 1.080 µM), meanwhile, compound <strong>4g</strong> exhibited the most potent inhibitory activity against MAO-B with an IC₅₀ value of 0.330 µM. The kinetic study of compound <strong>4c</strong> revealed that it exhibited a mixed inhibition mode with a K_i value of 3.4 nM. Compound <strong>4c</strong> was evaluated against the normal SH-SY5Y cell line and found to be non-cytotoxic at its active inhibition concentration. ADME profiles of the most active hybrids <strong>4a</strong>, <strong>4c</strong>, <strong>4j</strong>, and <strong>4k</strong> revealed that they could serve as successful drug candidates showing good CNS penetration. Molecular docking simulations were executed for the most active motifs <strong>4a</strong> and <strong>4c</strong> to demonstrate the binding pattern with the target proteins explaining their potential inhibitory activity. Lastly, this study will significantly contribute to developing novel safe, effective medications for treating various neurological disorders in the foreseeable future.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118123"},"PeriodicalIF":3.3,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143464862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis and in vitro validation of bivalent binders of SARS-CoV-2 spike protein: Obeticholic, betulinic and glycyrrhetinic acids as building blocks","authors":"Martina Pedrini ,&nbsp;Luca Pozzi ,&nbsp;Francesca Sacchi ,&nbsp;Andrea Citarella ,&nbsp;Valerio Fasano ,&nbsp;Pierfausto Seneci ,&nbsp;Stefano Pieraccini ,&nbsp;Lorenzo Ruberto ,&nbsp;Helena Perez Peña ,&nbsp;Alfredo Garzino-Demo ,&nbsp;Adriana Vitiello ,&nbsp;Leonardo Sernicola ,&nbsp;Alessandra Borsetti ,&nbsp;Arianna Calistri ,&nbsp;Cristina Parolin ,&nbsp;Daniele Passarella","doi":"10.1016/j.bmc.2025.118124","DOIUrl":"10.1016/j.bmc.2025.118124","url":null,"abstract":"<div><div>SARS-CoV-2 is the virus responsible for the COVID-19 pandemic, which caused over 6.7 million deaths worldwide. The Spike protein plays a crucial role in the infection process, mediating the binding of the virus to its cellular receptor, angiotensin-converting enzyme 2 (ACE2), and its subsequent entry into target cells. Previous studies identified, through virtual screening, several natural products capable of binding to two distinct pockets of the Spike protein: triterpenoids binding to pocket 1 and bile acid derivatives binding to pocket 5. Building on these findings, our study advances the field by developing bivalent compounds <strong>1–4</strong> that through a spacer combine a triterpenoid (betulinic acid or glycyrrhetinic acid) with a semisynthetic bile acid derivative (obeticholic acid). These bivalent compounds are designed to simultaneously bind both pockets of the Spike protein, offering significant advantages over single molecules or the combination of the two natural products. <em>In vitro</em> cell assays using pseudotyped recombinant lentiviral particles with selected SARS-CoV-2 Spike proteins demonstrated that <strong>1</strong> and <strong>2</strong> exhibit enhanced activity in reducing viral entry into target cells compared to individual natural products, thus highlighting their potential as superior antiviral agents with reduced side effects.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118124"},"PeriodicalIF":3.3,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143479794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-activity relationship studies and pharmacological evaluation of 4-phenylthiazoles as dual soluble epoxide hydrolase/fatty acid amide hydrolase inhibitors","authors":"Cassandra Yuan ,&nbsp;Amanda Tsang ,&nbsp;Manuel Berumen ,&nbsp;Adriana Rodriguez ,&nbsp;Faye Yun ,&nbsp;Anesa Mesic ,&nbsp;Annie Olivares ,&nbsp;Lissette Dubon ,&nbsp;Allen Nguyen ,&nbsp;Lucy Pavana ,&nbsp;Madison Mercado ,&nbsp;Gabrielle Gorostiza ,&nbsp;Christophe Morisseau ,&nbsp;Bruce D. Hammock ,&nbsp;Ram Kandasamy ,&nbsp;Stevan Pecic","doi":"10.1016/j.bmc.2025.118112","DOIUrl":"10.1016/j.bmc.2025.118112","url":null,"abstract":"<div><div>Forty-two 4-phenylthiazole analogs, organized in two libraries <strong>4a-u</strong> and <strong>6a-u</strong>, were prepared and biologically evaluated in human fatty acid amide hydrolase (FAAH), and human, rat and mouse soluble epoxide hydrolase (sEH) inhibition assays. This structure–activity relationship (SAR) study explores the impact of electronic and steric changes on the molecule’s potency and binding affinity to better understand the structural features important for dual sEH/FAAH inhibition which will guide the development of novel treatments for pain and inflammation. Our SAR revealed that electron-donating groups on the aromatic ring of the 4-phenylthiazole moiety are particularly well tolerated by both enzymes when placed at the ortho, meta and para positions; however, the overall 3D shape of the molecule is very important for the potent FAAH inhibition, suggesting more restricted size of the FAAH binding pocket compared to sEH binding pocket. Two selected dual inhibitors, <strong>4p</strong> and <strong>4s</strong>, were tested in the rat liver microsomes stability assays and evaluated <em>in vivo</em> in the formalin test. Systemic administration of <strong>4p</strong> and <strong>4s</strong> via intraperitoneal injection decreased nociceptive behavior (i.e., licking of the injected paw) in male rats, and this effect was dose-dependent for both compounds. Two doses, 1 and 3 mg/kg of <strong>4p</strong>, decreased nociceptive behavior to a similar extent to that of 30 mg/kg ketoprofen, a traditional nonsteroidal anti-inflammatory drug. However, only 3 mg/kg of <strong>4s</strong> decreased nociceptive behavior compared to vehicle-treated animals, and this effect was comparable to ketoprofen-treated animals. Taken together, these findings reveal the antinociceptive potential of 4-phenylthiazole-based dual FAAH and sEH inhibitors and suggest pharmacodynamic differences within this class of inhibitors despite similar potencies <em>in vitro</em>.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118112"},"PeriodicalIF":3.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143445264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of niclosamide as a p300/transcription factor protein–protein interaction inhibitor","authors":"Dhina Fitriastuti ,&nbsp;Kazuki Miura ,&nbsp;Satoshi Okada ,&nbsp;Hiroyuki Hirano ,&nbsp;Hiroyuki Osada ,&nbsp;Hiroyuki Nakamura","doi":"10.1016/j.bmc.2025.118114","DOIUrl":"10.1016/j.bmc.2025.118114","url":null,"abstract":"<div><div>Protein-protein interactions (PPIs) are crucial in various biological processes and are attractive targets for drug discovery. In this study, we identified niclosamide (<strong>9</strong>) as a novel inhibitor of the hypoxia-inducible factor 1α (HIF-1α)/p300 PPI from the RIKEN NPDepo compound library using a fluorescence anisotropy-based screening method. We synthesized niclosamide azide (<strong>10</strong>) as a photoaffinity labelling probe to identify the p300 binding site of compound <strong>9</strong> and elucidated the binding mode using photoaffinity labelling experiments and molecular docking simulations. Furthermore, we demonstrated that compound <strong>9</strong> inhibited not only HIF-1α/p300 PPI but also p300-transcription factor PPIs, including interaction with p53 and STAT3, thereby suppressing the expression of BAX and c-MYC, respectively.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118114"},"PeriodicalIF":3.3,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143438086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimizing biofilm inhibitors: Balancing activity and toxicity in 2N-aminated 5-aryl-2-aminoimidazoles","authors":"Lynn Maetens ,&nbsp;Banibrata Maiti ,&nbsp;Freya Cools ,&nbsp;Stefan Verheye ,&nbsp;Dirk Daelemans ,&nbsp;Leentje Persoons ,&nbsp;Liesbet Temmerman ,&nbsp;Amanda Kieswetter ,&nbsp;Erik V. Van der Eycken ,&nbsp;Guglielmo A. Coppola ,&nbsp;Thijs Vackier ,&nbsp;Hans P. Steenackers","doi":"10.1016/j.bmc.2025.118115","DOIUrl":"10.1016/j.bmc.2025.118115","url":null,"abstract":"<div><div>To evaluate the effect of amination on biofilm inhibition against <em>Escherichia coli</em>, <em>Pseudomonas aeruginosa</em> and <em>Staphylococcus aureus,</em> representative compounds of two previously described 5-aryl-2-aminoimidazole (5-Ar-2-AI) classes were aminated by installing an amino group at the end of the substituted <em>n</em>-alkyl chain. Amination led to an improvement in activity for one of the two classes, the 2<em>N</em>-substituted 5-Ar-2-AI class. Based on these findings, a more extensive library of 2<em>N</em>-substituted-aminated 5-Ar-2-AIs was synthesized having different <em>n</em>-alkyl and halogen substitutions on the 2<em>N</em>-position and the 4(5)-phenyl ring, respectively. Compounds were evaluated for their biofilm inhibitory activity against <em>E. coli</em>, <em>P. aeruginosa</em>, <em>S. aureus</em>, <em>Staphylococcus epidermidis</em> and MRSA. Additionally, their toxicity was tested on eight continuous cell lines, peripheral blood mononuclear cells and <em>Caenorhabditis elegans,</em> along with their genotoxicity on Capan-1. Halogenation and elongation of the <em>n</em>-alkyl substituent showed a positive effect on biofilm inhibitory activity, but also increased toxicity. Compromising between activity and toxicity, a non-halogenated 2<em>N</em>-substituted-aminated 5-Ar-2-AI compound with an intermediate <em>n</em>-heptyl substitution demonstrated promising broad-spectrum biofilm inhibition, making it a suitable candidate for further research in anti-infectious medical applications.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118115"},"PeriodicalIF":3.3,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143479915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemical modification for improving drug-like molecular properties of climacostol, a natural resorcinolic lipid","authors":"Gabriele Lupidi ,&nbsp;Elisabetta Catalani ,&nbsp;Federico Buonanno ,&nbsp;Dario Gentili ,&nbsp;Simone Giorgi ,&nbsp;Vishnuprasad Ponnarassery Aravindakshan ,&nbsp;Serena Gabrielli ,&nbsp;Kashi Brunetti ,&nbsp;Anna Maria Fausto ,&nbsp;Simona Picchietti ,&nbsp;Claudio Ortenzi ,&nbsp;Enrico Marcantoni ,&nbsp;Davide Cervia","doi":"10.1016/j.bmc.2025.118113","DOIUrl":"10.1016/j.bmc.2025.118113","url":null,"abstract":"<div><div>Small organic molecules are compounds that are manufactured through chemical synthesis. One of the key advantages of small molecules is that they have a low molecular weight and simple chemical structures. This allows more predictability to their pharmacokinetics and pharmacodynamics, which means that dosing is simpler. To use small molecules as a useful tool to address human health issues, the collaboration between disciplines, especially chemistry and biology, is essential. In recent years in our laboratories, we have demonstrated that climacostol, a 5-alkenyl resorcinolic produced by eukaryotic microorganisms as secondary metabolite and obtained by our synthetic strategy too, it shows important biological and pharmacological activities. These ones are highly dependent on the 5-alkenyl chain, and chemical modifications to the resorcinolic moiety can be exploited to achieve higher toxicity against pathogen microbes and protists than climacostol. In this study, we have designed and made a synthetic strategy for a new analogue of climacostol (<strong>AN3</strong>), and evaluated how the new hydroxyl group at position four in the aromatic ring influences its biological effects on prokaryotic and free-living protists and on non-target cells/organisms, especially with regard to cytotoxic properties.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118113"},"PeriodicalIF":3.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, biological evaluation, and mechanism of action of new pyrazines as anticancer agents in vitro and in vivo","authors":"Jin-Xia Lan ,&nbsp;Le-Jun Huang ,&nbsp;Si-Shuang Kang ,&nbsp;Hao-Huang ,&nbsp;Sheng-Lan Liu ,&nbsp;Wei Dai ,&nbsp;Xin-Liang Xu ,&nbsp;Jin-Yang Wang ,&nbsp;Guang-Zhao Shu ,&nbsp;Wen Hou","doi":"10.1016/j.bmc.2025.118108","DOIUrl":"10.1016/j.bmc.2025.118108","url":null,"abstract":"<div><div>Cancer is the second leading cause of mortality worldwide. The development of innovative antitumor pharmaceuticals is urgently needed to alter this circumstance. <em>N</em>-heterocycles, pyrazines for example are prevalent pharmacophores in the architecture of anticancer medicines. This research involved the design and synthesis of seventy-seven new pyrazine derivatives, followed by an evaluation of their anticancer activity <em>in vitro</em> and <em>in vivo</em>. Several new pyrazines exhibiting remarkable antiproliferative activity and selectivity were identified. The links between structure and function were analyzed, and the mechanisms of action were examined. Our mechanistic investigations indicated that these chemicals triggered mitochondria-associated apoptosis in cancer cells. Moreover, they suppressed the phosphorylation of STAT3, concomitant with the down-regulation of BcL-2, BcL-XL, c-Myc, XIAP, GLI1, TAZ, MCL1, JAK1, JAK2 and up-regulation of Bax, p21. Furthermore, the lead compounds <strong>B-11</strong> and <strong>C-27</strong> demonstrated significant anticancer activity <em>in vivo</em> in the SKOV3 xenograft nude mouse model. Our research establishes a basis for the identification of pyrazines as JAK/STAT3 inhibition based anticancer lead compounds.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118108"},"PeriodicalIF":3.3,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}