European Journal of Medicinal Chemistry最新文献

{"title":"Preparation and evaluation of a novel albumin-binding heterodimer therapeutic radiopharmaceutical with remarkable tumor accumulation and retention","authors":"Biao Yang, Changyu Shan, Zhaoguo Lin, Mengyan Hu, Chunxia Qin, Dexing Zeng, Rui An, Xiaoli Lan, Yongkang Gai","doi":"10.1016/j.ejmech.2025.117589","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117589","url":null,"abstract":"The intricate heterogeneity exhibited across diverse tumor types and the inconsistent expression levels of a specific receptor within tumors make it difficult for single-targeting radiotracers to meet clinical needs. The combination of “dual-targeting” and “albumin-binding” strategies can overcome it and effectively improve tumor uptake and retention of radiopharmaceuticals, thereby enhancing the effect of tumor theranostics. In this study, an albumin binder-conjugated heterodimeric precursor L21 targeting integrin αvβ3 and CD13 was successfully developed and labeled with ⁶⁸Ga and ¹⁷⁷Lu to evaluate therapeutic potential in BxPC-3 xenograft mice. <em>In vitro</em>, [⁶⁸Ga]Ga-L21 and [¹⁷⁷Lu]Lu-L21 exhibited excellent radiochemical stability in phosphate buffered saline (PBS) or fetal bovine serum (FBS) at 37 °C for 5 h. Compared to [⁶⁸Ga]Ga-L00 without albumin binder, the introduction of albumin binder did not substantially alter the water solubility of [⁶⁸Ga]Ga-L21, but substantially increased its affinity for serum albumin in FBS. <em>In vivo</em>, [⁶⁸Ga]Ga-L21 showed significantly higher tumor uptake and longer tumor retention time than [⁶⁸Ga]Ga-L00 (0.70 ± 0.06 standardized uptake value [SUV] <em>vs</em>. 0.33 ± 0.02 SUV at 3 h, <em>P</em>=0.0004). [¹⁷⁷Lu]Lu-L21 exhibited excellent tumor uptake, tumor-to-nontumor ratios and tumor retention, with tumor uptake keeping 2.79 ± 0.30 percentage of injected radioactive dose per gram of tissue (%ID/g) even at 96 h post-injection. Biodistribution results of [¹⁷⁷Lu]Lu-L21 were consistent with SPECT imaging, demonstrating that [¹⁷⁷Lu]Lu-L21 is a promising radiopharmaceutical for tumor radionuclide therapy.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"22 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143745716","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 2,4-dianilinopyrimidine derivatives as novel p90 ribosomal S6 protein kinase (RSK) inhibitors","authors":"Chun Han, Chaohua Guo, Xumei Zheng, Lin Zhao, Miao Sun, Jian Li, Shijun Wang, Zhang Zhang, Zhijun Wang, Lintao Wu","doi":"10.1016/j.ejmech.2025.117590","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117590","url":null,"abstract":"RSK, or P90 ribosomal S6 kinase, plays a crucial role in tumor cell proliferation and survival, making it an appealing target for cancer therapies. With the aim to explore novel RSK inhibitors as anticancer agents, a series of 2,4-dianilinopyrimidine derivatives <strong>2b</strong>–<strong>2n</strong> and <strong>3a</strong>–<strong>3n</strong> have been designed and synthesized. Among them, compound <strong>3e</strong> displayed substantial kinase inhibitory activity against RSK2 (IC₅₀ = 37.89 ± 3.08 nM) and a potent antiproliferative effect against a range of cell lines, including HeLa, MIA PaCa-2, U937, SW620, HT-29, AGS, and two kinds of EGFR mutant cells (IC₅₀s = 0.189–0.572 μM). Additionally, compound <strong>3e</strong> exhibited a high affinity for RSK and effectively inhibited RSK activity in HeLa cells. It triggered significant apoptosis and caused cell cycle arrest in the G2/M phase. Moreover, <strong>3e</strong> displayed considerable <em>in vivo</em> anticancer activity while maintaining an acceptable safety profile. These findings imply that compound <strong>3e</strong>, featuring a 2,4-dianilinopyrimidine scaffold, could serve as a promising RSK inhibitor for cancer treatment.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"21 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143745235","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":"Synthesis, in vitro and in vivo evaluation, and computational modeling analysis of thioxothiazolidine derivatives as highly potent and selective α-amylase inhibitors","authors":"Anil Ravi, Sumera Zaib, Shabab Zahra, Imtiaz Khan, Hafiz Saqib Ali, Mohammed I. El-Gamal, Hanan S. Anbar","doi":"10.1016/j.ejmech.2025.117584","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117584","url":null,"abstract":"Diabetes mellitus is not only a critical health concern in this era but also a major cause of damage to other organs such as eyes, nerves, kidneys, hearts and liver. Inhibiting <em>α</em>-amylase enzyme is considered as one of the key strategies for controlling chronic hyperglycemia. Therefore, the current work focuses on design and discovery of a series of thioxothiazolidine derivatives (<strong>5a-u</strong> and <strong>6a-g</strong>) as selective <em>α</em>-amylase inhibitors. The target compounds were synthesized using the Knoevenagel condensation approach and evaluated for their <em>α</em>-amylase and <em>α</em>-glucosidase inhibitory activities. The <em>in vitro</em> assay results demonstrated that the tested thioxothiazolidine derivatives possess significantly high potency than the standard drug acarbose against <em>α</em>-amylase but were inactive against <em>α</em>-glucosidase. Among them, compound <strong>5r</strong> exhibited remarkable inhibitory potential depicting an IC₅₀ value of 0.71 ± 0.01 μM, significantly outperforming acarbose against <em>α</em>-amylase. <em>In vivo</em> results further demonstrated that the treatment of diabetic rats with compound <strong>5r</strong> led to a significant reduction in blood glucose level, indicating its effectiveness in managing hyperglycemia. Biochemical profiling of the treated rats revealed favorable outcomes, including improved urea, creatinine, ALT, AST, ALP, and HbA1C values. Furthermore, <em>in vivo</em> testing in diabetic rats also demonstrated that treatment with compound <strong>5r</strong> caused significant histopathological improvements in the kidney, liver and pancreas compared to acarbose. The Lineweaver-Burk plot analysis indicated that compound <strong>5r</strong> inhibits <em>α</em>-amylase through a mixed type of inhibition mechanism. Furthermore, molecular docking and dynamics simulations confirmed the <em>in vitro</em> findings while pharmacokinetic properties suggested compound <strong>5r</strong> as a favorable drug candidate for the treatment of diabetic complications.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"183 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143745717","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 And Challenges in Immunosuppressive Antibody Drug Conjugates","authors":"Aiman A. Yaseen, L. Nathan Tumey","doi":"10.1016/j.ejmech.2025.117576","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117576","url":null,"abstract":"Since the approval of Mylotarg™ in 2000 for acute myeloid leukemia, antibody-drug conjugates (ADCs) have significantly advanced precision medicine, particularly for oncology applications. ADCs combine an antibody, a linker, and a payload to result in a targeted therapeutic that minimizes toxicity resulting from systemic drug exposure. This review explores the innovative application of ADC technology towards immunosuppressive therapeutics, primarily focusing on antibody-mediated delivery of glucocorticoids (GCs). Despite their potent anti-inflammatory effects, the clinical use of GCs is limited by adverse systemic effects including osteoporosis, high blood sugar, adrenal insufficiency, weight gain, and glaucoma. Therefore, targeted delivery via ADCs presents a promising strategy to enhance therapeutic efficacy while reducing toxicity. Herein, we review the current status of immune-suppressing ADC technology, starting with early investigations of CD163-targeted dexamethasone and moving to the design of ADCs employing next-generation ultra-potent GCs. Additionally, we will discuss the current status of anti-inflammatory ADCs that employ non-glucocorticoid immune-suppressive medications. Throughout, we will highlight preclinical and clinical data that serves to derisk and drive investment in this new therapeutic class. In parallel, we will focus on ADC design principles that illustrate the importance of careful selection of payload, linker, and conjugation technology in this emerging field.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"31 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143737123","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 environment-sensitive fluorescent ligands for SHP2 imaging in living cells and tumor sections","authors":"Dong Liang ,&nbsp;Chen Yu ,&nbsp;Chuanhao Guo ,&nbsp;Yan Lan ,&nbsp;Shiyi Chen ,&nbsp;Yu Zhang ,&nbsp;Lupei Du ,&nbsp;Deqing Sun ,&nbsp;Minyong Li ,&nbsp;Wei Zhao","doi":"10.1016/j.ejmech.2025.117573","DOIUrl":"10.1016/j.ejmech.2025.117573","url":null,"abstract":"<div><div>SHP2, a non-receptor protein tyrosine phosphatase, is a key regulator of the cellular signal transduction pathways. Its dysregulation has been associated with the pathogenesis of various diseases, notably cancers. In this study, we developed a series of small-molecule fluorescent probes targeting the allosteric site of SHP2 for the first time, which resulted in high affinity and specific SHP2 binding. These probes exhibited a significant Stokes shift, which was crucial for minimizing the phototoxicity and ensuring superior imaging quality. <strong>SHP-PS2</strong>, the top-performing probe, exhibited an IC₅₀ of 2.88 μmol/L against SHP2 and a <em>K</em>_<em>d</em> of 1.85 μmol/L in binding studies, with accurate SHP2 localization in living cells and tumor sections. These probes were straightforward to use and were effective tools for conveniently detecting SHP2, which had the potential to advance research in SHP2-related molecular pharmacology and drug discovery.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"290 ","pages":"Article 117573"},"PeriodicalIF":6.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143737124","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":"Synthesis and identification of azocoumarin derivatives toward imaging of α-synuclein aggregates in the brain","authors":"Meiting Mao ,&nbsp;Yu Zhou ,&nbsp;Huihui Zhang ,&nbsp;Pengxin Deng ,&nbsp;Jie Yang ,&nbsp;Jing Zhong ,&nbsp;Na Li ,&nbsp;Qiangqiang Liu ,&nbsp;Xianghui Li ,&nbsp;Xiaoai Wu ,&nbsp;Yan Cheng","doi":"10.1016/j.ejmech.2025.117587","DOIUrl":"10.1016/j.ejmech.2025.117587","url":null,"abstract":"<div><div>To identify α-synuclein aggregation in synucleinopathies is still challenging, due to the lack of specific probes for α-synuclein aggregates with efficient brain uptake. In this work, compact molecules based on coumarin scaffold were synthesized and evaluated for detection and bioimaging of α-synuclein aggregates in the brain. Among the developed compounds, azocoumarin <strong>5</strong> containing push-pull electronic architecture featured selective fluorescence enhancement towards α-synuclein aggregates in comparison to other β-sheet protein species (β-amyloid, tau). In addition, azocoumarin [¹⁸F]<strong>Cou-NNF</strong> was succesfully developed, and demonstrated its potential as radiotracer for imaging brain α-synuclein aggregates, owing to its favorable affinity for α-synuclein aggregates accompanied with efficient brain uptake and little defluorination in vivo. Overall, compact azocoumarin provides an effective lead structure for developing α-synuclein probes, and N=N bond shows promise in enhancing selective affinity for α-synuclein aggregates.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"290 ","pages":"Article 117587"},"PeriodicalIF":6.0,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736334","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":"TCM theory-inspired discovery of DNJ-flavonoid conjugates as broad-spectrum anti-SARS-CoV-2 agents by primarily targeting ER-associated glycoprotein folding process","authors":"Yan-Yun Liu ,&nbsp;Zheng-Ao Li ,&nbsp;Yu-Zheng Zhou ,&nbsp;Sen-Lin Wang ,&nbsp;Zong-Peng Chen ,&nbsp;Si-Xu Liu ,&nbsp;Peng Zhan ,&nbsp;Ying-Jun Zhou ,&nbsp;Zan-Xian Xia ,&nbsp;Xu Deng","doi":"10.1016/j.ejmech.2025.117582","DOIUrl":"10.1016/j.ejmech.2025.117582","url":null,"abstract":"<div><div>The global COVID-19 pandemic caused by SARS-CoV-2 has underscored the urgent need for the development of new broad-spectrum antivirals to combat its high mutation rate and the emerging variants. Host ER α-glucosidases I/II are promising host-targeted therapeutic targets for the development of broad-spectrum antivirals against viral strains that depend on ERQC for infectivity. Herein, we designed and synthesized a series of TCM theory-inspired DNJ-flavonoid conjugates as novel α-glucosidase inhibitors, which were screened against their <em>in vitro</em> antiviral activities in non-replicative SARS-CoV-2 pseudovirus (PsV) assay. Remarkably, <strong>DNJ-20</strong> not only demonstrated remarkable inhibition activity against α-glucosidase and viral entry process, but also exerted potent and broad-spectrum anti-coronaviral activity against SARS-CoV-2 pseudovirus (PsV), several SARS-CoV-2 variants, as well as HCoV-229E and HCoV-OC43, with EC₅₀ values up to 1.49 μM, which is more potent than the benchmark α-glucosidase inhibitor UV-4 (<strong>DNJ-3</strong>). Besides, it had no observable cytotoxicity in HeLa-ACE2, HEK-293T and Beas-2B cells. Therefore, TCM theory-inspired DNJ-flavonoid conjugates can be served as promising drug leads for pan-coronavirus therapeutic development to combat current and future coronavirus pandemics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"290 ","pages":"Article 117582"},"PeriodicalIF":6.0,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143734353","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":"Exploiting structural variability in the kinase back-pocket to modulate polypharmacology of TAM inhibitors","authors":"Megan D. Hopkins, Dehui Zhang, Zhilong Chen, Andrew L. McIver, Justus M. Huelse, Jyoti P. Mahajan, Kaikai Lyu, Xiangbo Yang, Michael A. Stashko, Brittany Smith, Tsz Y. Yeung, H. Shelton Earp, Stephen V. Frye, Deborah DeRyckere, Dmitri Kireev, Douglas K. Graham, Xiaodong Wang","doi":"10.1016/j.ejmech.2025.117561","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117561","url":null,"abstract":"TAM kinases play dual roles in tumor cells and the innate immune system. While they have redundant functions, the TAM kinases are differentially required in specific contexts. Therefore, inhibition of specific TAM kinases or pairs of TAM kinases will be desirable in different tumor types. We exploited the relatively more diversified back pocket of TAM kinases to modulate the polypharmacology of small molecule inhibitors and discovered several inhibitors with distinct selectivity profiles. The lead compound <strong>45</strong> (UNC8212) displayed potent inhibitory activities toward the TAM family. Its target engagement was confirmed by NanoBRET and cell-based assays. It also had favorable pharmacokinetic properties via intravenous and intraperitoneal routes.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"31 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143734354","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 and Optimization of a Novel Carboxamide Scaffold with Selective Antimalarial Activity","authors":"Alicia Wagner, Roger Trombley, Maris Podgurski, Anthony A. Ruberto, Meng Cui, Caitlin A. Cooper, William E. Long, Gia-Bao Nguyen, Adriana A. Marin, Sarah Lee Mai, Franco Lombardo, Steven P. Maher, Dennis E. Kyle, Roman Manetsch","doi":"10.1016/j.ejmech.2025.117572","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117572","url":null,"abstract":"Artemisinin combination therapies (ACTs) are critical components of malaria control worldwide. Alarmingly, ACTs have begun to fail, owing to the rise in artemisinin resistance. Thus, there is an urgent need for an expanded set of novel antimalarials to generate new combination therapies. Herein, we have identified a 1,2,4-triazole-containing carboxamide scaffold that, through scaffold hopping efforts, resulted in a nanomolar potent deuterated picolinamide (<strong>110</strong>). The lead compound of this class (<strong>110</strong>) displays moderate aqueous solubility (13.4 μM) and metabolic stability (CLint_app HLM 17.3 μL/min/mg) <em>in vitro</em>, as well as moderate oral bioavailability (% F 16.2) in <em>in vivo</em> pharmacokinetic studies. Compound <strong>110</strong> also displayed activity against various <em>P. falciparum</em> isolates with different genetic backgrounds and a slow-to-moderate rate of killing (average parasite reduction ratio 2.4), making the series appealing for further development.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"15 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143734356","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 Novel Tetrahydroquinoline Derivatives as Potent, Selective, and Orally Available AR Antagonists","authors":"Leer Yuan, Jianing Liao, Yiyang Qin, Lvtao Cai, Minkui Zhang, Jinbiao Liao, Dan Li, Tingjun Hou, Rong Sheng","doi":"10.1016/j.ejmech.2025.117566","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117566","url":null,"abstract":"Androgen receptor (AR) antagonists are the first-line medicine for the treatment of prostate cancer (PCa) in clinic. In our previous work, the tetrahydroquinoline derivative <strong>AT2</strong> was identified as a novel scaffold AR antagonist via virtual screening and structural modifications, while its poor pharmacokinetic properties hindered further development. Herein, we report the systematic structural optimizations of <strong>AT2</strong> and discover a novel tetrahydroquinoline derivative <strong>C2</strong> as potent AR antagonist with an IC₅₀ value of 0.019 μM, accompanied with excellent selectivity over other nuclear receptors (PR, GR, MR). Further biological assays revealed that <strong>C2</strong> significantly inhibited LNCaP cell proliferation, and efficiently reduced PSA protein expression. Especially, <strong>C2</strong> showed superior efficacy against AR^F877L/T878A mutants compared to darolutamide and enzalutamide. Furthermore, <strong>C2</strong> demonstrated excellent oral bioavailability, indicating the potential to enhance <em>in vivo</em> efficacy and to serve as a promising therapeutic option for PCa treatment.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"23 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723634","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}