MedChemComm最新文献

{"title":"Substituted 4-methylcoumarin inhibitors of SLC26A3 (DRA) for treatment of constipation and hyperoxaluria†","authors":"Maria Ahmadi, Livia de Souza Goncalves, Alan S. Verkman, Onur Cil and Marc O. Anderson","doi":"10.1039/D3MD00644A","DOIUrl":"10.1039/D3MD00644A","url":null,"abstract":"<p >SLC26A3, also known as downregulated in adenoma (DRA), is an anion (Cl<small>⁻</small>, HCO<small>₃</small><small>⁻</small> and oxalate) exchanger in the luminal membrane of intestinal epithelial cells. Loss of DRA function in mice and humans causes congenital chloride-losing diarrhea and reduces urinary excretion of oxalate, a major constituent of kidney stones. Thus, inhibition of DRA is a potential treatment approach for constipation and calcium oxalate kidney stones. High-throughput screening previously identified 4,8-dimethylcoumarins (<strong>4a–4c</strong>) as DRA inhibitors, with lead candidate <strong>4b</strong> having an IC<small>₅₀</small> of 40–50 nM for DRA inhibition. Here, we explored the effects of varying substituents at the 8-position, and replacing 8-methyl by 5-methyl (<strong>4e–4h</strong>). A focused library of 17 substituted compounds (<strong>4d–4t</strong>) was synthesized with good yield and purity. Compounds were tested for DRA inhibition potency using Fischer rat thyroid cells stably expressing DRA and a halide-sensitive YFP. Structure–activity analysis revealed that 8-bromo- (<strong>4m–4p</strong>) and 8-fluoro-coumarins (<strong>4q–4t</strong>) were slightly less potent than the corresponding 8-chloro analogs, demonstrating that the size of methyl or chloro substituents at the coumarin 8 position affects the potency. An analog containing 8-chlorocoumarin (<strong>4k</strong>) had ∼2-fold improved potency (IC<small>₅₀</small> 25 nM) compared with the original lead candidate <strong>4b</strong>. 5,8-Dimethylcoumarins were active against DRA, but with much lower potency than 4,8-disubstituted coumarins. In mice, orally administered <strong>4k</strong> at 10 mg kg<small>⁻¹</small> reduced constipation and normalized stool water content in a loperamide-induced constipation model with comparable efficacy to <strong>4b</strong>. Pharmacokinetic analysis of orally administered <strong>4k</strong> at 10 mg kg<small>⁻¹</small> in mice indicated serum levels of &gt;10 μM for at least six hours after single dose. This study expands SAR knowledge of 4,8-disubstituted coumarin inhibitors of DRA as novel drug candidates for constipation and kidney stones.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 5","pages":" 1731-1736"},"PeriodicalIF":3.597,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140588710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","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 1,2,4-oxadiazole-based derivatives as multitarget anti-Alzheimer agents†","authors":"Mohammed Salah Ayoup, Mohamed Reda Barakat, Hamida Abdel-Hamid, Ehab Emam, Yasair S. Al-Faiyz, Aliaa A. Masoud, Doaa A. Ghareeb, Amr Sonousi and Asmaa E. Kassab","doi":"10.1039/D4MD00113C","DOIUrl":"10.1039/D4MD00113C","url":null,"abstract":"<p >A series of novel 1,2,4-oxadiazole-based derivatives were synthesized and evaluated for their potential anti-Alzheimer disease activity. The results revealed that compounds <strong>2b</strong>, <strong>2c</strong>, <strong>2d</strong>, <strong>3a</strong>, <strong>4a</strong>, <strong>6</strong>, <strong>9a</strong>, <strong>9b</strong>, and <strong>13b</strong> showed excellent inhibitory activity against acetylcholinesterase (AChE) with IC<small>₅₀</small> values in the range of 0.0158 to 0.121 μM. They were 1.01 to 7.78 times more potent than donepezil (IC<small>₅₀</small> = 0.123 μM). The newly synthesized compounds exhibited lower activity towards butyrylcholinesterase (BuChE) when compared to rivastigmine. Compounds <strong>4b</strong> and <strong>13b</strong> showed the most prominent inhibitory potential against BuChE with IC<small>₅₀</small> values of 11.50 and 15 μM, respectively. Moreover, <strong>4b</strong>, and <strong>9b</strong> were found to be more potent antioxidant agents (IC<small>₅₀</small> values of 59.25, and 56.69 μM, respectively) in comparison with ascorbic acid (IC<small>₅₀</small> = 74.55 μM). Compounds <strong>2b</strong> and <strong>2c</strong> exhibited monoamine oxidase-B (MAO-B) inhibitory activity with IC<small>₅₀</small> values of 74.68 and 225.48 μM, respectively. They were 3.55 and 1.17 times more potent than biperiden (IC<small>₅₀</small> = 265.85 μM). The prominent interactions of the compounds with the AChE active site can be used to computationally explain the high AChE inhibitory activity. The results unveiled 1,2,4-oxadiazole derivatives <strong>2c</strong> and <strong>3a</strong> as multitarget anti-AD agents. The predicted ADME properties for compounds <strong>2b</strong> and <strong>4a</strong> were satisfactory, and <strong>4a</strong> had the highest likelihood of crossing the blood–brain barrier (BBB), making it the optimum compound for future optimization.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2080-2097"},"PeriodicalIF":3.597,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140838002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systematic generation and analysis of counterfactuals for compound activity predictions using multi-task models","authors":"Alec Lamens and Jürgen Bajorath","doi":"10.1039/D4MD00128A","DOIUrl":"10.1039/D4MD00128A","url":null,"abstract":"<p >Most machine learning (ML) methods produce predictions that are hard or impossible to understand. The black box nature of predictive models obscures potential learning bias and makes it difficult to recognize and trace problems. Moreover, the inability to rationalize model decisions causes reluctance to accept predictions for experimental design. For ML, limited trust in predictions presents a substantial problem and continues to limit its impact in interdisciplinary research, including early-phase drug discovery. As a desirable remedy, approaches from explainable artificial intelligence (XAI) are increasingly applied to shed light on the ML black box and help to rationalize predictions. Among these is the concept of counterfactuals (CFs), which are best understood as test cases with small modifications yielding opposing prediction outcomes (such as different class labels in object classification). For ML applications in medicinal chemistry, for example, compound activity predictions, CFs are particularly intuitive because these hypothetical molecules enable immediate comparisons with actual test compounds that do not require expert ML knowledge and are accessible to practicing chemists. Such comparisons often reveal structural moieties in compounds that determine their predictions and can be further investigated. Herein, we adapt and extend a recently introduced concept for the systematic generation of molecular CFs to multi-task predictions of different classes of protein kinase inhibitors, analyze CFs in detail, rationalize the origins of CF formation in multi-task modeling, and present exemplary explanations of predictions.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 5","pages":" 1547-1555"},"PeriodicalIF":3.597,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140615311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of chalcone analogues as anti-inflammatory agents through the regulation of NF-κB and JNK activation†","authors":"Die Zhang, Wenping Wang, Huiping Ou, Jinhua Ning, Yingxun Zhou, Jin Ke, Anguo Hou, Linyun Chen, Peng Li, Yunshu Ma and Wen Bin Jin","doi":"10.1039/D4MD00011K","DOIUrl":"10.1039/D4MD00011K","url":null,"abstract":"<p >To develop new anti-inflammatory agents with improved pharmaceutical profiles, a series of chalcone analogues were designed and synthesized. <em>In vitro</em> anti-inflammatory activity of these compounds was evaluated by screening their inhibitory effects on NO production in RAW264.7 cell lines. The most promising compounds <strong>3h</strong> and <strong>3l</strong> were selected for further investigation by assessment of their dose-dependent inhibitory activity against cytokines such as TNF-α, IL-1β, and IL-6 and PGE2 release. The further study also indicated that <strong>3h</strong> and <strong>3l</strong> could significantly suppress the expression of iNOS and COX-2 through the NF-κB/JNK signaling pathway. Furthermore, compounds <strong>3h</strong> and <strong>3l</strong> could also remarkably inhibit the mRNA expression of inflammation-related genes. Meanwhile, <strong>3h</strong> could also down-regulate ROS production. Docking simulation was conducted to position compounds <strong>3h</strong> and <strong>3l</strong> into the iNOS binding site to predict the probable binding mode. In conclusion, this series of chalcone analogues with reasonable drug-likeness obtained <em>via in silico</em> rapid prediction can be used as promising lead candidates.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2002-2017"},"PeriodicalIF":3.597,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140810525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Azole-based compounds as potential anti-Acanthamoeba agents†","authors":"Balsam Qubais Saeed, Rania Hamdy, Noor Akbar, Sreedevi Edathadan Sajeevan, Naveed Ahmed Khan and Sameh S. M. Soliman","doi":"10.1039/D4MD00029C","DOIUrl":"10.1039/D4MD00029C","url":null,"abstract":"<p > <em>Acanthamoeba castellanii</em> is an opportunistic pathogen with public health implications, largely due to its invasive nature and non-specific symptoms. Our study focuses on the potential of azole compounds, particularly those with triazole scaffolds, as anti-amoebic agents. Out of 10 compounds, compounds <strong>T1</strong> and <strong>T8</strong> exhibited effective anti-<em>Acanthamoeba</em> activity with MIC<small>₅₀</small> values of 125.37 and 143.92 μg mL<small>⁻¹</small>, respectively. Interestingly, compounds <strong>T1</strong>, <strong>T4</strong>, <strong>T5</strong> and <strong>T8</strong> revealed profound anti-excystation activity with MIC<small>₅₀</small> at 32.01, 85.53, 19.54 and 80.57 μg mL<small>⁻¹</small>, respectively, alongside limited cytotoxicity to human cells. The study underscores the potential of <strong>T1</strong>, <strong>T4</strong>, <strong>T5</strong>, and <strong>T8</strong>, thiazole-based compounds, as anti-<em>Acanthamoeba</em> agents by both eliminating amoeba viability and preventing excystation, <em>via</em> preserving the amoeba in its latent cyst form, exposing them to elimination by the immune system. Notably, compounds <strong>T1</strong>, <strong>T4</strong>, <strong>T5</strong>, and <strong>T8</strong> showed optimal molecular properties, moderate oral bioavailability, and stable complex formation with <em>Acanthamoeba</em> CYP51. They also display superior binding interactions. Further research is needed to understand their mechanisms and optimize their efficacy against <em>Acanthamoeba</em> infections.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 5","pages":" 1578-1588"},"PeriodicalIF":3.597,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140589156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, docking optimization, and evaluation of biotin-PEG4-1,8-naphthalimide as a potent and safe antitumor agent with dual targeting of ferroptosis and DNA†","authors":"Qi Wang, Si-Min Liang, Zhi-Chen Mao, Xian-Li Ma, Jian-Hua Wei, Ri-Zhen Huang and Ye Zhang","doi":"10.1039/D4MD00134F","DOIUrl":"10.1039/D4MD00134F","url":null,"abstract":"<p >A set of biotin-polyethylene glycol (PEG)-naphthalimide derivatives <strong>4a–4h</strong> with dual targeting of ferroptosis and DNA were designed and optimized using docking simulation as antitumor agents. Docking simulation optimization results indicated that biotin-PEG4-piperazine-1,8-naphthalimide <strong>4d</strong> should be the best candidate among these designed compounds <strong>4a–4h</strong>, and therefore, we synthesized and evaluated it as a novel antitumor agent. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and MGC-803 and U251 xenograft models identified <strong>4d</strong> as a good candidate antitumor agent with potent efficacy and safety profiles, compared with amonafide and temozolomide. The findings of the docking simulations, fluorescence intercalator displacement (FID), western blot, comet, 5-ethynyl-2′-deoxyuridine (EdU), flow cytometry, transmission electron microscopy, and BODIPY-581/591-C11, FerroOrange, and dihydroethidium (DHE) fluorescent probe assays revealed that <strong>4d</strong> could induce DNA damage, affect DNA synthesis, and cause cell cycle arrest in the S phase in MGC-803 cells. Also, it could induce lipid peroxidation and thus lead to ferroptosis in MGC-803 cells, indicating that it mainly exerted antitumor effects through dual targeting of ferroptosis and DNA. These results suggested that it was feasible to design, optimize using docking simulation, and evaluate the potency and safety of biotin-PEG-1,8-naphthalimide as a antitumor agent with dual targeting of ferroptosis and DNA, based on a multi-target drug strategy.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 5","pages":" 1640-1651"},"PeriodicalIF":3.597,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140588716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of ketoclomazone and its analogues as inhibitors of 1-deoxy-d-xylulose 5-phosphate synthases and other thiamine diphosphate (ThDP)-dependent enzymes†","authors":"Alex H. Y. Chan, Terence C. S. Ho, Imam Fathoni, Rawia Hamid, Anna K. H. Hirsch, Kevin J. Saliba and Finian J. Leeper","doi":"10.1039/D4MD00083H","DOIUrl":"10.1039/D4MD00083H","url":null,"abstract":"<p >Most pathogenic bacteria, apicomplexan parasites and plants rely on the methylerythritol phosphate (MEP) pathway to obtain precursors of isoprenoids. 1-Deoxy-<small>D</small>-xylulose 5-phosphate synthase (DXPS), a thiamine diphosphate (ThDP)-dependent enzyme, catalyses the first and rate-limiting step of the MEP pathway. Due to its absence in humans, DXPS is considered as an attractive target for the development of anti-infectious agents and herbicides. Ketoclomazone is one of the earliest reported inhibitors of DXPS and antibacterial and herbicidal activities have been documented. This study investigated the activity of ketoclomazone on DXPS from various species, as well as the broader ThDP-dependent enzyme family. To gain further insights into the inhibition, we have prepared analogues of ketoclomazone and evaluated their activity in biochemical and computational studies. Our findings support the potential of ketoclomazone as a selective antibacterial agent.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 5","pages":" 1773-1781"},"PeriodicalIF":3.597,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00083h?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140589234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of bacterial RNA polymerase function and protein–protein interactions: a promising approach for next-generation antibacterial therapeutics","authors":"Jiqing Ye, Cheuk Hei Kan, Xiao Yang and Cong Ma","doi":"10.1039/D3MD00690E","DOIUrl":"10.1039/D3MD00690E","url":null,"abstract":"<p >The increasing prevalence of multidrug-resistant pathogens necessitates the urgent development of new antimicrobial agents with innovative modes of action for the next generation of antimicrobial therapy. Bacterial transcription has been identified and widely studied as a viable target for antimicrobial development. The main focus of these studies has been the discovery of inhibitors that bind directly to the core enzyme of RNA polymerase (RNAP). Over the past two decades, substantial advancements have been made in understanding the properties of protein–protein interactions (PPIs) and gaining structural insights into bacterial RNAP and its associated factors. This has led to the crucial role of computational methods in aiding the identification of new PPI inhibitors to affect the RNAP function. In this context, bacterial transcriptional PPIs present promising, albeit challenging, targets for the creation of new antimicrobials. This review will succinctly outline the structural foundation of bacterial transcription networks and provide a summary of the known small molecules that target transcription PPIs.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 5","pages":" 1471-1487"},"PeriodicalIF":3.597,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140588681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Benzenesulfonamide decorated dihydropyrimidin(thi)ones: carbonic anhydrase profiling and antiproliferative activity†","authors":"Hakan Aslan, Gioele Renzi, Andrea Angeli, Ilaria D'Agostino, Roberto Ronca, Maria Luisa Massardi, Camilla Tavani, Simone Carradori, Marta Ferraroni, Paolo Governa, Fabrizio Manetti, Fabrizio Carta and Claudiu T. Supuran","doi":"10.1039/D4MD00101J","DOIUrl":"10.1039/D4MD00101J","url":null,"abstract":"<p >In the last decades, carbonic anhydrases (CAs) have become the top investigated innovative pharmacological targets and, in particular, isoforms IX and XII have been widely studied due to the evidence of their overexpression in hypoxic tumors. The frantic race to find new anticancer agents places the quick preparation of large libraries of putative bioactive compounds as the basis of a successful drug discovery and development programme. In this context, multi-component and, in general, one-step reactions are becoming very popular and, among them, Biginelli's reaction gave clean and easy-to-isolate products. Thus, we synthesized a series of Biginelli's products (<strong>10–17a–b</strong>) and similar derivatives (<strong>20–21</strong>) bearing the benzenesulfonamide moiety, which is known to inhibit CA enzymes. Through the stopped-flow technique, we were able to assess their ability to inhibit the targeted CAs IX and XII in the nanomolar range with promising selectivity over the physiologically relevant isoforms I and II. Crystallography studies and docking simulations helped us to gain insight into the interaction patterns established in the enzyme–inhibitor complex. From a chemical similarity-based screening of in-house libraries of compounds, a diphenylpyrimidine (<strong>23</strong>) emerged. The surprisingly potent inhibitory activity of <strong>23</strong> for CAs IX and XII along with its strong antiproliferative effect on two (triple-negative breast cancer MDA-MB-231 and glioblastoma U87MG) cell lines laid the foundation for further investigation, again confirming the key role of CAs in cancer.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 1929-1941"},"PeriodicalIF":3.597,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00101j?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140625091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pyrazolopyridine-based kinase inhibitors for anti-cancer targeted therapy†","authors":"Pallabi Halder, Anubhav Rai, Vishal Talukdar, Parthasarathi Das and Naga Rajiv Lakkaniga","doi":"10.1039/D4MD00003J","DOIUrl":"10.1039/D4MD00003J","url":null,"abstract":"<p >The need for effective cancer treatments continues to be a challenge for the biomedical research community. In this case, the advent of targeted therapy has significantly improved therapeutic outcomes. Drug discovery and development efforts targeting kinases have resulted in the approval of several small-molecule anti-cancer drugs based on ATP-mimicking heterocyclic cores. Pyrazolopyridines are a group of privileged heterocyclic cores in kinase drug discovery, which are present in several inhibitors that have been developed against various cancers. Notably, selpercatinib, glumetinib, camonsertib and olverembatinib have either received approval or are in late-phase clinical studies. This review presents the success stories employing pyrazolopyridine scaffolds as hinge-binding cores to address various challenges in kinase-targeted drug discovery research.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 5","pages":" 1452-1470"},"PeriodicalIF":3.597,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140588982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}