European Journal of Medicinal Chemistry最新文献

{"title":"Design and synthesis of CDK9/EZH2 dual-target inhibitors to achieve synergistic antitumor effects","authors":"Lina Tian, Jian Xiao, Yanping Zeng, Yangsha Li, Aihuan Wei, Qianqian Shen, Yixue Han, Yi Chen, Youhong Hu","doi":"10.1016/j.ejmech.2025.117773","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117773","url":null,"abstract":"Cyclin-dependent kinase 9 (CDK9) plays a pivotal role in regulating transcriptional elongation and has emerged as a promising target in cancer therapy. However, it is reported that CDK9 inhibitors cause abnormal upregulation of H3K27me3 in Diffuse Large B-cell Lymphoma (DLBCL) cell lines. Here, we designed a series of dual inhibitors targeting CDK9 and EZH2 by linking two distinct pharmacophores to achieve synergistic antitumor effects. Among these, the potent CDK9/EZH2 inhibitor <strong>D16</strong> exhibited impressive inhibitory activities, with IC₅₀ values of 83.9 nM for CDK9 and 108.6 nM for EZH2. Notably, compound <strong>D16</strong> induced more significant DNA damage and exhibited greater inhibition of DLBCL proliferation than the single-target inhibitor <strong>SNS-032</strong> or <strong>C24</strong>. In addition, <strong>D16</strong> showed potent anti-proliferative activities in various solid tumor cell lines, which may provide an innovative strategy for the treatment of cancer.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"75 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144067502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reversing an Agonist into an Inhibitor: Development of mTOR Degraders","authors":"Liquan Zhu, Siyi Fu, Longfei Ma, Zhe Chen, Qian Zeng, Ruichen Li, Yiyu Zhou, Huijuan Qian, Xuli Meng, Jingyan Ge","doi":"10.1016/j.ejmech.2025.117774","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117774","url":null,"abstract":"Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) has emerged as a powerful strategy for modulating protein function. In this study, we developed mTOR-targeting PROTACs by conjugating the mTOR agonist MHY-1485 to the Cereblon (CRBN) ligand pomalidomide, demonstrating that even activators can serve as effective warheads for targeted protein degradation. Through systematic screening, we identified PD-M6 as a potent bifunctional molecule capable of degrading mTOR (DC₅₀ = 4.8 μM), reversing the proliferative effects of MHY-1485, and inhibiting cell proliferation (IC₅₀ = 11.3 μM) while inducing autophagy, akin to the mTOR known inhibitor rapamycin. Proteomic analysis further revealed that PD-M6 downregulated key proteins in the mTOR signaling pathway, including LAMTOR1, MAPKAP1, and CASTOR1, which are involved in proteasome-mediated degradation, cell division, apoptosis, and lysosomal signaling. Notably, PD-M6 specifically induced the degradation of LAMTOR1. These findings highlight a novel approach for designing PROTACs from agonists, broadening the scope of targeted protein degradation strategies for therapeutic applications.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"132 1","pages":"117774"},"PeriodicalIF":6.7,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144083326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chromanone Derivatives: Evaluating Selective Anticancer Activity Across Human Cell Lines","authors":"Marta Sobiesiak, Nadia Fatyga, Aleksander Brzozowski, Adam Sikora, Bogumiła Kupcewicz, Małgorzata Maj","doi":"10.1016/j.ejmech.2025.117771","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117771","url":null,"abstract":"This study systematically evaluates the cytotoxic effects of chromanone derivatives on a range of human cell lines, including cancerous (MCF-7, DU-145, A549) and normal (SV-HUC-1) types. Using MTT assays, flow cytometric DNA analysis, and Annexin V staining, we assessed the impact of these derivatives on cell viability and apoptosis. Results indicate that the studied compounds exhibit diverse cytotoxic profiles across different cell lines. Notably, compounds in Group B showed enhanced selectivity for cancer cells over normal cells, with significantly lower IC50 values against MCF-7, DU-145, and A549 cells compared to the normal SV-HUC-1 cells. In contrast, the chromanone derivatives from Group A demonstrated comparable cytotoxicity between cancer and normal cells, indicating a lack of selectivity. Specifically, 3-chlorophenylchromanone derivative with 2-methylpyrazoline (B2) exhibited strong cytotoxicity against A549 cells, while demonstrating reduced efficacy in MCF-7, DU-145 and SV-HUC-1 cells. Additionally, structural variations such as halogen substitutions (Cl vs. Br) played a crucial role in modulating the activity of these compounds. These findings suggest that further optimization of substituent types and positions could enhance the selectivity and effectiveness of these compounds as potential anticancer agents. The study provides a foundation for future research aimed at developing targeted therapies with improved cancer cell selectivity and reduced toxicity to normal tissues.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"16 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144066675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of Potent Anti-Idiopathic Pulmonary Fibrosis (IPF) Agents Based on an o-Aminopyridinyl Alkynyl Scaffold","authors":"Yang Wang, Wenhui Fan, Yihao Guo, Li Sun, Youhong Hu, Jing Chen, Likun Gong, Zhicheng Xie","doi":"10.1016/j.ejmech.2025.117768","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117768","url":null,"abstract":"Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with high mortality and limited treatment options. Targeting multiple kinase-driven pathological processes offers a promising strategy. Using epithelial-mesenchymal transition (EMT) phenotypic screening, we optimized a series of <em>o</em>-aminopyridinyl alkynyl compounds derived from CSF-1R relatively selective inhibitor, compound <strong>1</strong>, through a structure-activity relationship (SAR) study, integrating liver and kidney cytotoxicity evaluations. Compound <strong>22</strong>, emerged as the potent antifibrotic candidate, exhibiting low cytotoxic effects against human kidney (HEK293) and hepatocyte (L02) cell lines, and minimal hERG inhibition. In addition, <strong>22</strong> showed significant inhibition against other IPF-related processes, including fibroblast-to-myofibroblast transition (FMT)-driven fibrosis in both human fetal lung fibroblasts cell line (HFL1) and primary human lung fibroblasts (HLFs), as well as pro-fibrotic M2 polarization. <em>In vivo</em>, compound <strong>22</strong> exhibited the acceptable PK properties and low toxicity profiles. In addition, oral administration of <strong>22</strong> demonstrated superior anti-fibrotic efficacy compared to Nintedanib, significantly attenuating bleomycin-induced lung fibrosis, reducing inflammation and pro-fibrotic M2-associated cytokine levels, and improving lung function. Preliminary kinase profiling indicates that compound <strong>22</strong> likely targets CSF-1R, PDGFR-α and Src family kinases to inhibit IPF progression, while sparing VEGFRs, FGFRs and Abl to minimize off-target toxicity commonly associated with multi-kinase inhibitor treatment. These findings highlight the advantages and therapeutic potential of a multi-kinase targeting strategy, enabling selective inhibition key IPF-associated kinases to develop more effective and safer anti-IPF agents.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"37 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144067332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Probing new 3-hydrazinyl indole phenacetamide derivatives as multitarget anti-Alzheimer: Synthesis, in vivo, in vitro, and in silico studies","authors":"Mona F. Said, Walaa Wadie, Enas A. Abd El-Haleim, Riham A. El Sheikh, Haidy H. El-Zoheiry","doi":"10.1016/j.ejmech.2025.117720","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117720","url":null,"abstract":"The development of multi-target directed ligands (MTDLs) amassed great attention to combat the multifactorial nature of Alzheimer’s disease (AD). The present study showcases the synthesis of a novel series of 3-hydrazinyl indole phenacetamide derivatives aimed at addressing AD and neuroinflammation by targeting acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and β-secretase (BACE1) enzymes. The primarily <em>in vivo</em> anti-inflammatory screening nominated derivatives <strong>5a-f</strong>, <strong>5h</strong>, <strong>5j</strong> and <strong>5o</strong> for the initial <em>in vitro</em> screening against AChE. Compounds <strong>5a-c, 5j,</strong> and <strong>5o,</strong> exhibited the most potent inhibitory activity against AChE and BChE, were subsequently subjected to further <em>in vivo</em> biological evaluations. Also, <strong>5a-c</strong> were inspected for their impact on hallmarks of AD and histopathological changes. <em>N</em>-phenylacetamide indole derivative bearing unsubstituted phenylhydrazinyl side chain <strong>5a</strong> depicted the most cognitive enhancement compared to the reference standard donepezil and significantly improved spatial memory capabilities, mitigated histopathological alterations, reduced AD hallmarks, AChE, BACE1, amyloid beta (Aβ), and <em>p-</em>tubulin associated unit (<em>p</em>-Tau), and modulated oxidative and inflammatory markers, GSH and IL-1β. Moreover, <em>in vitro</em> BACE1 enzyme inhibition assay revealed moderate BACE1 inhibitory activity for derivatives <strong>5a-c</strong>. Further, <em>in silico</em> docking studies for the most active derivatives <strong>5a-c</strong> in AChE and BACE1 binding pockets evidenced interacting with key amino acid residues supporting their remarkable biological activity. Furthermore, molecular dynamics simulations confirmed the stability of derivative <strong>5a</strong> within the AChE and BACE1 binding sites throughout the simulation period. <strong>Collectively,</strong> <em>N</em>-phenylacetamide indole derivative bearing unsubstituted phenylhydrazinyl side chain <strong>5a</strong> represents a promising <strong>multi-target</strong> candidate, combining AChE, BChE and BACE1 inhibition and can be considered as a lead compound for <strong>further development in AD therapy.</strong>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"10 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143980203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"D-Alanine Functionalized Iridium(III) Complexes as Two-Photon Photo-Antibiotics for Bacteria-Specific Ablation in Infected Macrophages","authors":"Jun Shu, Hui Jiang, Minwei Lin, Jinzhe Liang, Yukun Zhao, Diqing Luo, Jinquan Wang, Hui Chao","doi":"10.1016/j.ejmech.2025.117758","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117758","url":null,"abstract":"The prevalence of bacterial resistance, driven by extensive antibiotic overuse, significantly threatens patient safety. Consequently, it is urgent and helpful for the clinician to develop new antibacterial therapy techniques. In this study, we designed a novel photodynamic antibacterial therapeutic strategy by functionalizing D-alanine on Iridium(III) complexes. The synergistic D-alanine metabolic labeling function and two-photon photodynamic eradication capacity of Ir(III) complexes enable bacterial imaging and elimination of bacterial pathogens within host cells. These two-photon photoantibiotics effectively inhibit bacterial biofilm formation and efficiently eliminate intracellular bacterial infections in macrophages, enabling real-time dynamic monitoring of antimicrobial efficacy. Furthermore, both in vitro and in vivo experiments demonstrated superior antibacterial performance compared to conventional antibiotics alone.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"6 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144066676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of a Potent and Selective Peptide Inhibitor with D-amino Acids Targeting the BRD4 ET Domain for Renal Cancer Therapy","authors":"Nan Jiang, Mengting Lou, Nan Wu, Yifei Geng, Miao-Miao Niu, Yang Zhou, Shizhu Zhang","doi":"10.1016/j.ejmech.2025.117767","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117767","url":null,"abstract":"Renal cancer is a highly aggressive tumor that poses a serious threat to human health. BRD4, as an important epigenetic regulator, is tightly associated with the development of renal cancer. Given the unique biological stability of D-amino acids, they have shown great potential for application in the field of cancer therapy. Currently, there are no reports on D-amino acid inhibitors targeting the ET domain of BRD4. Herein, we discovered a peptide inhibitor containing D-amino acids (BEP-2) targeting the BRD4 ET domain through virtual screening. BEP-2 showed an excellent binding affinity for BRD4 (<em>K</em>_d = 0.45 ± 0.03 nM). MD simulations demonstrate that BEP-2 can stably bind to the BRD4 ET domain. Moreover, BEP-2 displayed good inhibitory activity against 786-O and ACHN renal cancer cells and maintained high stability in serum. Additionally, BEP-2 inhibited the growth of 786-O cell xenograft tumors in nude mice. In summary, these data imply that BEP-2 is a promising antitumor drug that offers new perspectives for the treatment of renal cancer.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"130 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144066677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ellipticine Derivatives as Toll-like Receptor 3 Inhibitor for Treating Acute Hepatitis","authors":"Zhuoxian Cao, Meixin Liu, Mingze Yang, Xiao Li, Xiaoxiao Xia, Kui Cheng","doi":"10.1016/j.ejmech.2025.117762","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117762","url":null,"abstract":"Toll-like receptor 3 (TLR3) has been shown to influence various liver diseases. By screening a natural product molecular library, we discovered that Ellipticine exhibits moderate TLR3 inhibitory effects, with an IC₅₀ value of 5.66 ± 1.03 μM. Subsequent optimization of Ellipticine led to the development of the most potent compound, <strong>SMU-14a,</strong> which achieved an IC₅₀ of 0.18 ± 0.02 μM among all 31 derivatives. <strong>SMU-14a</strong> effectively inhibits IL-6 secretion in mouse peritoneal macrophages triggered by polyinosinic-polycytidylic acid (Poly I:C, a TLR3 agonist) and also downregulates TNF-α in human peripheral blood mononuclear cells. Mechanistically, <strong>SMU-14a</strong> reduces the phosphorylation of p65, ERK, and TBK1 through the NF-κB, MAPK, and IRF3 signaling pathways, thereby inhibiting the production of inflammatory cytokines. In vivo, <strong>SMU-14a</strong> was found to effectively decrease the release of the inflammatory factor IL-6 and reduce serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), demonstrating a potent anti-inflammatory effect and protecting the liver from internal damage. In summary, we have developed a potent Ellipticine derivative, <strong>SMU-14a</strong>, which demonstrates significant anti-inflammatory effects by blocking the NF-κB, MAPK, and IRF3 signaling pathways, thereby providing substantial hepatoprotective effects against acute hepatitis.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"32 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143980171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in Fluorescent Natural Products for Imaging Localization and Biological Applications","authors":"Guiqian Fang, Daili Liu, Yuanzhuo Wang, Qingqiang Yao","doi":"10.1016/j.ejmech.2025.117759","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117759","url":null,"abstract":"Natural products play a crucial role in biological activities, yet the quest for novel natural products faces increasing challenges due to the complexities of structural exploration and efficacy evaluation. Besides, traditional methods for evaluating natural products primarily focus on non-fluorescent efficacy studies at animal level or multicellular accumulation level, lacking of intuitive fluorescence presentation at the single cell or organelle level. This limitation disrupts our understanding of the effectiveness of natural products and constrains their biological activities. The most striking example is that fluorescent natural products offer a unique but often overlooked dual function: they not only exhibit biological activities but also may provide real-time fluorescent signals for tracking within biological systems. This review highlights the exciting advances in imaging localization of fluorescent natural products combined with advanced imaging techniques, summarizes the structural characteristics and application criteria of fluorescent natural products, and explores their feasibility in visual localization and biological activities. This synthesis underscores the need for a systematic exploration of fluorescent natural products, towards a transformative impact on drug development and disease understanding.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"58 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143946003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 C-12 modified ocotillol-type derivatives as novel P-glycoprotein modulators for overcoming multidrug resistance","authors":"Cheng Chen ,&nbsp;Ziqian Hao ,&nbsp;Jiaxuan Chen ,&nbsp;Shuang Li,&nbsp;Yongyuan Su,&nbsp;Suwei Jiang,&nbsp;Lin Ma,&nbsp;Hanqi Lv,&nbsp;Xinjie Pei,&nbsp;Peng Zhang,&nbsp;Hongbo Wang,&nbsp;Gangqiang Yang","doi":"10.1016/j.ejmech.2025.117757","DOIUrl":"10.1016/j.ejmech.2025.117757","url":null,"abstract":"<div><div>Ocotillol-type ginsenoside derivatives exhibit significant potential as modulators of P-glycoprotein (Pgp). To date, structural investigations of Ocotillol-type saponins have predominantly focused on modifications at the C-3 position of the A-ring, with limited exploration of the C-12 position on the C-ring. In this study, we designed and synthesized a series of C-12 modified ocotillol-type derivatives and assessed their efficacy in reversing multidrug resistance (MDR) in KBV cells. Most of the newly synthesized derivatives exhibited minimal cytotoxicity and potent MDR reversal capabilities. Notably, compound <strong>9e</strong> emerged as the most effective agent in reversing tumor MDR in vitro, showing more than twice the potency of verapamil. Furthermore, <strong>9e</strong> displayed high selectivity for Pgp, being 40- and 20-fold more effective than verapamil in inhibiting Rh123 efflux and enhancing doxorubicin sensitivity, respectively. Molecular docking analysis revealed that <strong>9e</strong> possesses a unique T-shaped configuration that occupies the access channel of Pgp, obstructing the peristaltic extrusion mechanism of TM12 and TM9, thereby inhibiting the efflux function of Pgp. Overall, <strong>9e</strong> represents a promising lead compound for the development of novel Pgp modulators to overcome MDR in cancer therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"294 ","pages":"Article 117757"},"PeriodicalIF":6.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143980204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}