Bioorganic & Medicinal Chemistry Letters最新文献

{"title":"Synthesis and biological evaluation of amino-conjugated bile acid derivatives against non-alcoholic steatohepatitis","authors":"Zhitao Wu ,&nbsp;Mingge Zhang ,&nbsp;Meng Kun Yan ,&nbsp;Chenyue Li ,&nbsp;Guoyu Pan ,&nbsp;Lijiang Xuan","doi":"10.1016/j.bmcl.2025.130210","DOIUrl":"10.1016/j.bmcl.2025.130210","url":null,"abstract":"<div><div>Non-alcoholic steatohepatitis (NASH) is emerging as a rapidly growing health concern. Bile acids (BAs) function as endocrine signaling molecules and exhibit therapeutic potential for NASH. To develop safer and more effective BA derivatives for NASH treatment, 25 amino acid-conjugated bile acid derivatives were designed and synthesized based on the pharmacological properties of the leading compound <strong>A17.</strong> The anti-lipid accumulation, anti-inflammatory and anti-fibrosis activities of these compounds were evaluated, and their structure-activity relationships were elucidated. Notably, compound <strong>C04</strong> exhibited superior in vitro activity compared to obeticholic acid and demonstrated enhanced efficacy in improving both NASH and fibrosis in preclinical murine models via oral administration. These findings suggest that <strong>C04</strong> is a promising candidate for NASH treatment and warrants further investigation.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130210"},"PeriodicalIF":2.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143727152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imide-based enones: A new scaffold that inhibits biofilm formation in Gram-negative pathogens","authors":"J. Israel Barrera-Hernández ,&nbsp;Jesús R. Pérez-Velázquez ,&nbsp;Ángel Ramírez-Trinidad ,&nbsp;Jesús Oria-Hernández ,&nbsp;Eduardo Hernández-Vázquez","doi":"10.1016/j.bmcl.2025.130206","DOIUrl":"10.1016/j.bmcl.2025.130206","url":null,"abstract":"<div><div>We prepared a series of enones containing different substituents as potential antibiofilm molecules. The design considered the structural features previously found in <em>N-</em>acylhomoserine lactones, but it replaced the labile furanone with different imides portions. After evaluation, some of the analogs inhibited 50 % or more the formation of the biofilm from <em>P. aeruginosa</em> or <em>A. baumannii</em>; moreover, substituents attached at the phenyl ring, the size of the enone as well as the type of imide seemed relevant for the selectivity against the tested pathogens<em>.</em> In the end, we performed a molecular docking study using the crystallized LasR to describe the main interactions of the ligand-receptor complex and propose a plausible mechanism of action.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130206"},"PeriodicalIF":2.5,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, and evaluation of a novel protein degrader FPFT-2216","authors":"Yasuyuki Ueda,&nbsp;Takashi Ando,&nbsp;Yoshiteru Eikyu,&nbsp;Takumi Okamoto,&nbsp;Hironori Yokoyama,&nbsp;Naoshi Kunimura,&nbsp;Daiki Kanaoka,&nbsp;Shotaro Izuno,&nbsp;Mayumi Watanabe","doi":"10.1016/j.bmcl.2025.130193","DOIUrl":"10.1016/j.bmcl.2025.130193","url":null,"abstract":"<div><div>For multiple myeloma (MM), various modalities of therapeutic drugs have been approved in recent years, and treatment outcomes for MM have greatly improved, but unmet medical needs still exist and new therapeutic drugs are needed. With the aim of developing a therapeutic drug for MM that has a scaffold different from the protein degrader immunomodulatory drugs (IMiDs), exploratory research was performed using the highly useful Huisgen cycloaddition reaction, and a novel lead compound 3-(4-(thiophen-3-yl)-<em>1H</em>-1,2,3-triazol-1-yl)piperidine-2,6-dione (FPFT-2127) was discovered. Optimization studies identified FPFT-2216, which exhibited stronger antitumor activity against MM than existing thalidomide derivatives. Furthermore, FPFT-2216 showed a synergistic combination effect with Daratumumab (Dara), a standard treatment for MM.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130193"},"PeriodicalIF":2.5,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of liver-selective glucokinase activators comprising N-(4-alkylthiazol-2-yl)benzamides and N-(3-alkyl-1,2,4-thiadiazol-5-yl)benzamides for the treatment of metabolic disorders","authors":"David S. Yoon,&nbsp;Shung Wu,&nbsp;Sean S. Chen,&nbsp;Rebecca A. Smirk,&nbsp;Robert P. Brigance,&nbsp;Wei Meng,&nbsp;Yan Shi,&nbsp;Shiwei Tao,&nbsp;Ying Wang,&nbsp;Hao Zhang,&nbsp;Arvind Mathur,&nbsp;Helen Grace Catanio,&nbsp;Stephen Kalinowski,&nbsp;Rachel Zebo,&nbsp;Jacob Zalaznick,&nbsp;Joseph Taylor,&nbsp;Bradley Zinker,&nbsp;Lisa M. Kopcho,&nbsp;Kamelia Behnia,&nbsp;Carrie Xu,&nbsp;Peter T.W. Cheng","doi":"10.1016/j.bmcl.2025.130192","DOIUrl":"10.1016/j.bmcl.2025.130192","url":null,"abstract":"<div><div>Glucokinase (“GK”) plays a critical role in regulating glucose homeostasis within the body. Proof-of-concept animal models demonstrated that small molecule GK activation enhances glucose uptake and utilization by various tissues, including liver and pancreas. Accordingly, glucokinase activators (“GKAs”) were extensively explored as a potential therapy for carbohydrate metabolism disorders. Yet in clinical trials, mechanism-based hypoglycemia was often observed when GK was activated in both liver and pancreas. One ameliorative approach was to pursue hepatocentric GKAs. Described herein is a series of liver selective GKAs based on <em>N</em>-(4-alkylthiazol-2-yl)benzamide and <em>N</em>-(3-alkyl-1,2,4-thiadiazol-5-yl)benzamide pharmacophores. Optimization efforts revealed that enhanced liver selectivity could be achieved by replacing diethylphosphonate group (compound <strong>1</strong>) with a dimethylphosphinate (compound <strong>3</strong>). Due to mutagenicity of a putative aminoheterocycle metabolite of <strong>3</strong>, subsequent amines were triaged using SOS chromotest. Efforts ultimately led to identification of thiazole-based compounds <strong>11</strong>–<strong>13</strong>, which exhibited significant glucose lowering in acute DIO (“diet-induced obese”) mouse OGTT (“oral glucose tolerance test”) studies. However, insulin secretion was observed at higher doses, and thus the desired therapeutic window between efficacy and insulin secretion was not achieved. Thiadiazole-based compounds were then explored to assess whether this modification could obviate the insulin secretion observed with the thiazole series. Several thiadiazoles were discovered with exceptionally high liver selectivity and drug liver concentrations when evaluated in mouse pharmacokinetic studies. Compounds <strong>17</strong>–<strong>19</strong> and <strong>20</strong>–<strong>22</strong> were advanced into acute DIO OGTT studies, but were inactive. Notably, a relatively higher degree of plasma protein binding was observed for the non-efficacious vs. efficacious compounds.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130192"},"PeriodicalIF":2.5,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tyrosine and proline conjugated trolox, hydroxy-cinnnamic acid and diclofenac hybrids as strong hypolipidemic and anti-inflammatory agents.","authors":"Panagiotis Theodosis-Nobelos ,&nbsp;Eleni A. Rekka","doi":"10.1016/j.bmcl.2025.130194","DOIUrl":"10.1016/j.bmcl.2025.130194","url":null,"abstract":"<div><div>Oxidative stress induces the signaling of inflammatory and apoptotic pathways leading to the progression of degenerative disorders, whilst lipid increase and oxidation is an important factor for their development and propagation. L-tyrosine and L-proline amino acids and their derivatives have shown to be implicated in several of these aspects in a positive manner. In this prospect, methyl esters of these amino acids, amidated with the antioxidants trolox and (<em>E</em>)-3-(3,5-di-<em>tert</em>-butyl-4-hydroxyphenyl)acrylic acid (hydroxylated cinnamic acid compound), as well as the classical NSAID diclofenac, were prepared and evaluated as antioxidant, anti-inflammatory and anti-hyperlipidemic agents. Almost all compounds presented high or moderate 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging and lipid peroxidation inhibitory activity, reaching up to 12 fold (in the lipid peroxidation inhibition) that of the parent antioxidant acids, such as trolox, whilst the insertion of the tyrosine moiety seemed to offer additional antioxidant potency, especially in the case of the NSAID derivative (<strong>compound 3</strong>). The majority of them displayed significant in vivo acute inflammation reduction (decrease of paw oedema, induced by carrageenan, 33–78 % at 150 μmol/kg) ability. The most active trolox-proline hybrid (compound <strong>4)</strong> exhibited more than two fold increased inhibition in comparison to the well-established NSAIDs ibuprofen and diclofenac. They were also moderate inhibitors of soybean lipoxygenase, however active, in several cases, compared to their parent acid molecules. The most profound activity of the compounds was the reduction of the plasma lipidemic indices (Triton-induced hyperlipidemia in rats). Compound <strong>5</strong> was the most potent, with decrease in triglycerides, total cholesterol and low density lipoprotein, by 56 %, 87 %, and 72 %, respectively at 150 μmol/kg (<em>i.p</em>.), slightly better than that of simvastatin. Thus, the insertion of proline and tyrosine moieties seem to improve the anti-inflammatory activity of parent acids and NSAIDs, resulting in compounds with two or more pharmacological features (including hypolipidemic activity), which might be beneficial in cases characterized by inflammatory, oxidative, hyperlipidemic and degenerative conditions.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130194"},"PeriodicalIF":2.5,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of DS-1150b, a novel xanthene compound for activating GLUT4 translocation","authors":"Masaki Meguro ,&nbsp;Fuminao Doi ,&nbsp;Tsuyoshi Soneda ,&nbsp;Shinji Furuzono ,&nbsp;Masahiro Konishi ,&nbsp;Jun Harada ,&nbsp;Jun Tanaka ,&nbsp;Shinichi Inoue ,&nbsp;Makoto Ono ,&nbsp;Katsuji Kagechika","doi":"10.1016/j.bmcl.2025.130191","DOIUrl":"10.1016/j.bmcl.2025.130191","url":null,"abstract":"<div><div>The glucose transporter 4 (GLUT4) is a high-affinity glucose transporter that is predominantly expressed in the skeletal muscle, myocardium, and adipose tissue, and is the rate-limiting transporter of insulin-stimulated glucose uptake. Compounds that enhance the process of GLUT4 translocation in skeletal muscle would provide a novel treatment for type 2 diabetes mellitus. After a high-throughput screening (HTS) campaign and medicinal chemistry efforts, we identified the xanthene compound DS-1150b (16·<em>t</em>BuNH₂) as a novel potent GLUT4 translocation enhancer. DS-1150b was found to promote GLUT4 translocation in L6-myotubes in rats and showed a glucose-lowering effect in an oral glucose tolerance test (oGTT) in a Zucker fatty rat model. Identification of naphthalene analog DS20060511 is also briefly described.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130191"},"PeriodicalIF":2.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143684849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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 hypoxic-activation prodrug TH-302 derivatives","authors":"Zhengyi Li ,&nbsp;Xingchen Yang ,&nbsp;Shun Wang ,&nbsp;Hongzhao Ma ,&nbsp;Ke Yang ,&nbsp;Jing Shi ,&nbsp;Xin Wang","doi":"10.1016/j.bmcl.2025.130189","DOIUrl":"10.1016/j.bmcl.2025.130189","url":null,"abstract":"<div><div>This study aims to design and develop novel and efficient anti-hypoxic cell tumor drugs. Using the TH-302 as lead compound, structural modifications are conducted to synthesize a series of novel derivatives to investigate the structural activity relationship (SAR) against ovarian cancer cell line (SKOV3) and glioblastoma cell line (U87MG) in vitro. The structural modifications mainly include four aspects: changes in substituents on N; changes in isomers; changes in nitro group position; changes in substituting halogens in phosphoramide mustard. The results of CCK-8 assay indicate that the steric hindrance and electronic effects of substituents on N have significant impacts on the activity, while changes in nitro group positions have minimal effects on the activity, and Bromo-phosphoramide mustard exhibits better activity than Chloro-phosphoramide mustard. Compounds <strong>15c</strong> and <strong>16d</strong> exhibit significantly superior antitumor activity compared to TH-302, with IC₅₀ values of 42 μM and 32 μM for SKOV3 cells, and IC₅₀ values of 47 μM and 41 μM for U87MG cells, respectively.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130189"},"PeriodicalIF":2.5,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of ATP competitive PDHK1/2 dual inhibitors","authors":"Hongtao Xu ,&nbsp;Dong Ding ,&nbsp;Xingchun Han ,&nbsp;Kun Miao ,&nbsp;Chungen Liang ,&nbsp;Hongying Yun ,&nbsp;Wei Zhu ,&nbsp;Fabian Dey ,&nbsp;Dan Zhao ,&nbsp;Yao Wu ,&nbsp;Michael Reutlinger ,&nbsp;June Yang ,&nbsp;Guanglei Zhai ,&nbsp;Zhaohu Lin ,&nbsp;Chiho Li ,&nbsp;Waikong Wu ,&nbsp;Bruce Xu ,&nbsp;Li Han ,&nbsp;Shuai Chen ,&nbsp;Xinyi Huang ,&nbsp;Ge Zou","doi":"10.1016/j.bmcl.2025.130190","DOIUrl":"10.1016/j.bmcl.2025.130190","url":null,"abstract":"<div><div>Multiple screening approaches were carried out to identify novel chemistry starting for Pyruvate Dehydrogenase Kinases (PDHKs) inhibitors. Through hit triaging efforts and structure-based optimization, two series of ATP competitive inhibitors with single digit nanomolar enzymatic potency for PDHK1/2 and around 10–100-fold selectivity over PDHK4/3 were discovered. Approach of covalent inhibitor was explored to successfully improve the cellular target engagement to single digit micromolar range.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130190"},"PeriodicalIF":2.5,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In-vitro evaluation of cationic Lipopeptides as adjuvant candidate for DNA plasmid vaccine","authors":"Syahrul Febrian Hasbullah ,&nbsp;Ace Tatang Hidayat ,&nbsp;Tarwadi ,&nbsp;Adinda Nurhidayatul Fajri ,&nbsp;Nurlelasari ,&nbsp;Desi Harneti ,&nbsp;Kindi Farabi ,&nbsp;Unang Supratman ,&nbsp;Rani Maharani","doi":"10.1016/j.bmcl.2025.130183","DOIUrl":"10.1016/j.bmcl.2025.130183","url":null,"abstract":"<div><div>Lipopeptides with different fatty acids (palmitic, palmitoleic, stearic, oleic, and linoleic acids) conjugated to CHSPKKKRKV were synthesised by a solid-phase peptide method using the Fmoc strategy (Fmoc-SPPS) on 2-CTC (2-chlorotritylchloride) resin. The lipopeptides were purified by RP-HPLC and characterised by ToF-ESI-MS and 1D-NMR. The capability of the lipopeptide to interact with the plasmid was evaluated by DNA agarose gel electrophoresis. The particle size of the lipopeptide/DNA complexes was determined by dynamic light scattering assay and TEM analysis. The biological activities including cytotoxicity, nitrite oxide (NO) release, and IL-6 and TNF-α production were evaluated in RAW 264.7 cells. ToF-ESI-MS revealed [M + 2H]²⁺ and [M + 3H]³⁺ ion peaks which were validated by ¹H NMR and ¹³C NMR, confirming the lipopeptide molecular structure. All lipopeptides condensed and protected the DNA plasmid from enzymatic degradation at the lipopeptide/DNA mass ratio of 2:1. In addition, the size of the cationic lipopeptide/DNA complexes ranged from ∼250 to 700 nm. The lipopeptides showed moderate cytotoxicity with IC₅₀ values ranging from 120 to 190 ppm, induced NO release (275–1060 ppm) and IL-6 (40–497 pg) and TNF-α (150–270 pg) production with the highest level achieved by C_(18,0)-CHSPKKKRKV. In conclusion, CHSPKKKRKV-based lipopeptides with different fatty acids are potential adjuvant candidates but further evaluation in animal models is required.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130183"},"PeriodicalIF":2.5,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143636525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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 aminopyrimidine derivatives as EGFR inhibitors","authors":"Huabing Wang ,&nbsp;Yule Gui ,&nbsp;Shengkai Cui,&nbsp;Xinyi Long,&nbsp;Weizheng Fan,&nbsp;Chunlei Tang","doi":"10.1016/j.bmcl.2025.130188","DOIUrl":"10.1016/j.bmcl.2025.130188","url":null,"abstract":"<div><div>The treatment of non-small cell lung cancer (NSCLC) is significantly challenged by the development of acquired resistance to third-generation epidermal growth factor receptor (EGFR) inhibitors, such as Osimertinib, which limits their therapeutic efficacy. Using the EGFR ^{L858R/T790M/C797S} inhibitor Brigatinib as a reference compound, we designed and synthesized 24 target compounds with aminopyrimidine as the core structure. Among these, the representative compound <strong>IIB-5</strong> demonstrated potent inhibition of EGFR^{L858R/T790M/C797S}, achieving an IC₅₀ value of 18.81 nM. It also exhibited strong inhibition against Ba/F3-EGFR^{L858R/T790M/C797S} cells with an IC₅₀ of 97.12 nM, showing a five-fold potency increase over Brigatinib. Compound <strong>IIB-5</strong> provides a valuable reference for further research on EGFR inhibitors.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130188"},"PeriodicalIF":2.5,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}