RSC medicinal chemistry最新文献

{"title":"Discovery of selective, metabolically stable pyrazole-based FLT3 inhibitors for the treatment of acute myeloid leukemia†","authors":"Lorenza Destro, Valentina Crippa, Daniela Gabbia, Marco Roverso, Sara Bogialli, Paolo Zardi, Giovanni Marzaro, Luca Mologni and Alfonso Zambon","doi":"10.1039/D4MD00956H","DOIUrl":"10.1039/D4MD00956H","url":null,"abstract":"<p >Acute myeloid leukemia (AML) is the most prevalent form of acute leukemia in adults, representing a substantial medical need, as the standard of care has not changed for the past two decades, and the long-term outcome remains dismal for a large fraction of patients. Approximately 30% of AMLs carry activating mutations of the FLT3 kinase. Unfortunately, single-agent FLT3 inhibitor therapy has met limited clinical efficacy, underscoring a strong rationale for the development of more selective and more potent inhibitors. Here we present the design, synthesis and biological evaluation of a series of biphenyl substituted pyrazoyl-ureas, an underexplored scaffold in medicinal chemistry, as novel FLT3 inhibitors with a putative type II binding mode. Optimized compounds show nanomolar activity against isolated FLT3 (230 nM for compound <strong>10q</strong>) and on FLT3-driven cell lines (280 nM and 18 nM for compound <strong>10q</strong> against MV4.11 and MOLM-14 cells respectively), with no toxicity against control cell lines, limited metabolism in human microsomes and a reliable SAR; furthermore, profiling of compound <strong>10q</strong> against a panel of kinases highlights c-Kit as the only other hit. Overall, we show that the series has a narrow selectivity profile and metabolic stability, and the mode of action of the inhibitors through FLT3 is confirmed by strong suppression of FLT3 and STAT5 phosphorylation.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 4","pages":" 1766-1780"},"PeriodicalIF":4.1,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483512","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":"Identification of 5-amino-1,3,4-thiadiazole appended isatins as bioactive small molecules with polypharmacological activities.","authors":"Uzma Azam, Waqar Ahmed Humayun, Amrutha K Avathan Veettil, Yang Liu, Oguz Hastürk, Mao Jiang, Sonja Sievers, Peng Wu, Muhammad Moazzam Naseer","doi":"10.1039/d4md00770k","DOIUrl":"10.1039/d4md00770k","url":null,"abstract":"<p><p>The identification of heterocyclic small molecules that cover unexplored chemical space is of great importance for the development of new small-molecule therapeutics. In this study, we synthesized a series of 5-amino-1,3,4-thiadiazoles appended isatins (UZ-1-20) that exhibited polypharmacological properties, as evaluated in a cell-painting assay assessing induced cellular morphological changes. A high hit rate ranging from 55% to 80% was observed for the tested compounds at varied concentrations. The most active compounds showed significant activity in inducing cellular morphological changes with a measured induction value of more than 30% and shared a high biological profiling similarity with an antifungal agent itraconazole and a chemokine receptor inhibitor. The synthesized compounds exhibited moderate to good antiproliferative activity against tested cancer cell lines in the MTT assay. Molecular docking studies were performed to theoretically probe and compare the binding modes between the most active UZ compounds and ITZ or BI-6901, respectively. Additionally, ADMET analysis indicated favorable pharmacokinetic parameters including good oral bioavailability, balanced hydrophilicity, and minimal toxicity. Overall, the findings in this study highlight the potential of developing the aminothiadiazole appended isatins as bioactive agents.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483517","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":"Aspirin <i>vs.</i> ibuprofen: unveiling the distinct cyclooxygenase-1/2 behaviour and dual efficacy of their synthesized analogues <i>via</i> molecular modeling and <i>in vitro</i> biological assessment.","authors":"Amandeep Kaur, Hafiz Muzzammel Rehman, Vipin Kumar Mishra, Gurmeet Kaur, Mandeep Kaur, Mohammad K Okla, Masaud Shah, Manisha Bansal","doi":"10.1039/d4md00751d","DOIUrl":"https://doi.org/10.1039/d4md00751d","url":null,"abstract":"<p><p>Dual inhibition of cyclooxygenase isozymes along with the platelet aggregation activities <i>via</i> the arachidonic acid pathway may offer a better anti-inflammatory agent with enhanced cardiac safety. Although the literature is more focused on COX-2 selectivity, sufficient or improved COX-1/COX-2 selectivity has garnered significant attention recently since it can ensure cardiovascular safety. Herein, in this regard, novel derivatives of non-steroidal anti-inflammatory drugs containing amide, thiourea, thiosemicarbazide, and triazole functionalities were synthesized and characterized. Calculations on the <i>in silico</i> drug-likeness and toxicological properties demonstrated the suitability of the compounds for oral administration. Meanwhile, the molecular docking results suggested two different mechanistic pathways for the anti-inflammatory and anti-platelet effects <i>via</i> COX-2 and COX-1 inhibition. Compounds 3 and 12 were shown to be the most efficient based on their excellent docking scores and favorable interactions, particularly with the selective side-pocket residues of COX-2 and main catalytic residues of COX-1. Furthermore, molecular dynamics simulation confirmed that compounds 3 and 12 exhibited good interactions at the active sites, having stable binding throughout 100 ns. Overall, two major findings were made in the current study. (i) Compound 12 bearing the triazole moiety proved to be the most effective cyclooxygenase inhibitor with IC₅₀ values of 95.11 and 98.73 μM against COX-1 and COX-2 isozymes, respectively. It also maintained its anti-platelet activity (IC₅₀ = 277.67 μM), confirming the dual functioning of compound 12. (ii) Compound 3 purely behaved as an anti-platelet agent (IC₅₀ = 261.0 μM) in contrast to aspirin with fare inhibitory effects against COX-2.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11865951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143543005","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":"X-ray crystallographic and kinetic studies of biguanide containing aryl sulfonamides as carbonic anhydrase inhibitors†","authors":"Chiara Baroni, Murat Bozdag, Gioele Renzi, Viviana De Luca, Clemente Capasso, Carla Bazzicalupi, Silvia Selleri, Marta Ferraroni, Fabrizio Carta and Claudiu T. Supuran","doi":"10.1039/D4MD01018C","DOIUrl":"10.1039/D4MD01018C","url":null,"abstract":"<p >Here, we report a small series of dual-targeting compounds that combine the prototypical carbonic anhydrase (CA) zinc-binding sulfonamide moiety with the biguanide group of metformin, an emerging anticancer drug. The compounds reported similar <em>in vitro</em> inhibition profiles on a panel of physiologically relevant human (h)CAs, with marked selectivity for the cancer related IX and XII isoforms. The binding modes of representative inhibitors <strong>5b</strong> and <strong>5c</strong> within the active site of the hCA isoforms II and XII-mimic were assessed by X-ray crystallography, thus allowing us to clarify molecular features that may be useful for the design of more specific and potent inhibitors. For instance, we identified a mutation in the hCA XII-mimic which was found responsible for the selectivity of the ligands toward the tumor associated isoform. Interestingly, in the hCA II/<strong>5c</strong> complex, a second inhibitor molecule was bound to the catalytic cleft, probably affecting the inhibition properties of the canonical zinc-bound inhibitor.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 4","pages":" 1633-1640"},"PeriodicalIF":4.1,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11809658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399920","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":"Relocating NSAIDs into the endoplasmic reticulum induces ER stress-mediated apoptosis in cancer cells†","authors":"Tripti Mishra, Preeti, Jaypalsing Ingle, Aditi Saha and Sudipta Basu","doi":"10.1039/D4MD00936C","DOIUrl":"10.1039/D4MD00936C","url":null,"abstract":"<p >The endoplasmic reticulum (ER) is a vital subcellular organelle that orchestrates numerous essential biological processes, including protein synthesis and processing. Disruption of ER function can lead to ER stress, a condition closely associated with the progression and development of cancer. Consequently, inducing ER stress in cancer cells has emerged as an unconventional yet promising therapeutic approach. However, selectively targeting the ER within cancer cells remains a significant challenge. To address this, we have designed and synthesized a novel small-molecule library composed of non-steroidal anti-inflammatory drugs (NSAIDs), fluorescent probes, and ER-targeting moieties. Through screening the library in cancer cells, we identified a promising compound: an ibuprofen derivative conjugated with a dansyl group as a dual fluorescence tag and ER-targeting moiety. This ibuprofen derivative successfully localized into the ER of HCT-116 colon cancer cells within 3 h, induced ER stress by upregulating key stress markers such as CHOP, GRP94, IRE-1α, PERK, and Cas-12, while simultaneously inhibiting Cox-2. The resulting ER stress triggered autophagy by upregulating Beclin and LC3-II/LC3-I as autophagy markers, followed by apoptosis, culminating in significant cancer cell death, particularly when combined with bafilomycin A, 10-hydroxycamptothecin and obatoclax. This NSAID-based ER stress inducer provides a powerful tool for exploring the chemical biology of NSAIDs in the ER and holds great potential for advancing ER-targeted cancer therapies in combination with other anti-cancer drugs.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 4","pages":" 1600-1605"},"PeriodicalIF":4.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256624","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":"Isozyme-specific inhibition of GSTP1-1: a crucial element in cancer-targeting drugs","authors":"Belal O. Al-Najjar, M. Helal, Fadi G. Saqallah and B. Bandy","doi":"10.1039/D4MD00872C","DOIUrl":"10.1039/D4MD00872C","url":null,"abstract":"<p >Selectively targeting cancer cells has been a main challenge in cancer therapy. The purpose is to spare normal cells and minimize side effects. Targeting the antioxidant enzymes (<em>i.e.</em> GST) for the purpose of selectively killing cancer cells has attracted much attention in the past few decades. The intention of lowering the antioxidant enzymes is “tipping” the ROS concentrations to levels above the cytotoxic threshold. This would result in extensive damage to the cellular macromolecules and organelles leading to cell death. Here we focused on the glutathione <em>S</em>-transferase pi 1 (GSTP1), because it is one of the overexpressed antioxidant enzymes in cancer and has been targeted for the purpose of killing cancer cells. However, most available GSTP1 inhibitors do not show selectivity towards the isozyme. This can potentially lead to many side effects. Therefore, the search for optimal selective GSTP1 inhibitors is still underway. The novelty of this review stems from highlighting the significance of selectively targeting GSTP1. We also addressed the structural feature of the enzyme which challenges the design of novel selective GSTP1 inhibitors. We then provide guidelines to help resolve these challenges to help design future compounds. The first objective of this review is to present a brief literature review to highlight the importance of selectively targeting GSTP1. Briefly, the lack of selectivity towards GSTP1 has resulted in extensive side effects which limited reaching advanced clinical trials. We screened publications on many potential inhibitors, including some that reached phase I and II clinical trials, for their ability to bind with GSTP1, GSTM, and GSTA. All compounds appear to bind different GST isozymes (at least to some extent). The second objective is to present differences in the structures of GST isotypes (GSTP1, GSTM, GSTA) which could allow selectively targeting a certain isotype. Our modelling results highlight the importance of certain structural moieties for better selective binding to GSTP1.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 4","pages":" 1516-1531"},"PeriodicalIF":4.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365818","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":"The physics-AI dialogue in drug design†","authors":"Pablo Andrés Vargas-Rosales and Amedeo Caflisch","doi":"10.1039/D4MD00869C","DOIUrl":"10.1039/D4MD00869C","url":null,"abstract":"<p >A long path has led from the determination of the first protein structure in 1960 to the recent breakthroughs in protein science. Protein structure prediction and design methodologies based on machine learning (ML) have been recognized with the 2024 Nobel prize in Chemistry, but they would not have been possible without previous work and the input of many domain scientists. Challenges remain in the application of ML tools for the prediction of structural ensembles and their usage within the software pipelines for structure determination by crystallography or cryogenic electron microscopy. In the drug discovery workflow, ML techniques are being used in diverse areas such as scoring of docked poses, or the generation of molecular descriptors. As the ML techniques become more widespread, novel applications emerge which can profit from the large amounts of data available. Nevertheless, it is essential to balance the potential advantages against the environmental costs of ML deployment to decide if and when it is best to apply it. For hit to lead optimization ML tools can efficiently interpolate between compounds in large chemical series but free energy calculations by molecular dynamics simulations seem to be superior for designing novel derivatives. Importantly, the potential complementarity and/or synergism of physics-based methods (<em>e.g.</em>, force field-based simulation models) and data-hungry ML techniques is growing strongly. Current ML methods have evolved from decades of research. It is now necessary for biologists, physicists, and computer scientists to fully understand advantages and limitations of ML techniques to ensure that the complementarity of physics-based methods and ML tools can be fully exploited for drug design.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 4","pages":" 1499-1515"},"PeriodicalIF":4.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11788922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190324","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":"Probing structural requirements for thiazole-based mimetics of sunitinib as potent VEGFR-2 inhibitors†","authors":"Alaa A. Abd Elhameed, Ahmed R. Ali, Hazem A. Ghabbour, Said M. Bayomi and Nadia S. El-Gohary","doi":"10.1039/D4MD00754A","DOIUrl":"10.1039/D4MD00754A","url":null,"abstract":"<p >Novel thiazole analogs <strong>3a</strong>, <strong>3b</strong>, <strong>4</strong>, <strong>5</strong>, <strong>6a–g</strong>, <strong>8a</strong>, <strong>8b</strong>, <strong>9a–c</strong>, <strong>10a–d</strong> and <strong>11</strong> were designed and synthesized as molecular mimetics of sunitinib. <em>In vitro</em> antitumor activity of the obtained compounds was investigated against HepG2, HCT-116, MCF-7, HeP-2 and HeLa cancer cell lines. The obtained data showed that compounds <strong>3b</strong> and <strong>10c</strong> are the most potent members toward HepG2, HCT-116, MCF-7 and HeLa cells. Moreover, compounds <strong>3a</strong>, <strong>3b</strong>, <strong>6g</strong>, <strong>8a</strong> and <strong>10c</strong> were assessed for their <em>in vitro</em> VEGFR-2 inhibitory activity. Results proved that compound <strong>10c</strong> exhibited outstanding VEGFR-2 inhibition (IC<small>₅₀</small> = 0.104 μM) compared to sunitinib. Compound <strong>10c</strong> paused the G0–G1 phase of the cell cycle in HCT-116 and MCF-7 cells and the S phase in HeLa cells. Additionally, compound <strong>10c</strong> elevated caspase-3/9 levels in HCT-116 and HeLa cells, leading to cancer cell death <em>via</em> apoptosis. Furthermore, compound <strong>10c</strong> showed a significant reduction in tumor volume in Swiss albino female mice as an <em>in vivo</em> breast cancer model. Docking results confirmed the tight binding interactions of compound <strong>10c</strong> with the VEGFR-2 binding site, with its binding energy surpassing that of sunitinib. <em>In silico</em> PK studies predicted compound <strong>10c</strong> to have good oral bioavailability and a good drug score with low human toxicity risks.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 3","pages":" 1329-1349"},"PeriodicalIF":4.1,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028891","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, antimicrobial activity, stability, and mechanism of action of bioresorbable ceragenins†","authors":"Shawn Gubler, Aaron Zaugg, Rebekah Yi, Elliot Sherren, Elizabeth Milner, Wesley Conyer, Tate May, Tim Jack, Tanner Heaton, Joel Christopherson, Preston Higbee, Emma Powers, Meg Takara, Anna Linder, Boston Boyack, Fetutasi Pauga, Morgann Salmon, Miriam Thomas, Mariko Shiraki, Shenglou Deng and Paul B. Savage","doi":"10.1039/D4MD00990H","DOIUrl":"10.1039/D4MD00990H","url":null,"abstract":"<p >Device-related infections (DRIs) from bacterial/fungal biofilms that form on surfaces are a major cause of death in first-world countries. DRIs and the increasing prevalence of antibiotic resistant strains require development of new antimicrobials for improved antimicrobial prophylaxis. New antimicrobial prophylaxis practices necessitate novel agents to combat a broad spectrum of both fungi and bacteria, to be less toxic to patients, and to be locally administrable to prevent perturbations to a patient's microbiome. A class of antimicrobials that we have previously developed to fit these criteria is ceragenins. Here we describe the design, synthesis, and characterization of a new series of ceragenins that is composed of and degrades into endogenous compounds: cholic acid, B alanine, and glycerides. From this series we identify an optimized bioresorbable ceragenin that has comparable antimicrobial activities to other ceragenins, degrades rapidly through the action of lipase and at pH 7.2, and has a similar mechanism of action to previously developed ceragenins.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 3","pages":" 1425-1440"},"PeriodicalIF":4.1,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080965","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":"Nitroaromatic-based triazene prodrugs to target the hypoxic microenvironment in glioblastoma†","authors":"Cláudia Braga, Margarida Ferreira-Silva, M. Luísa Corvo, Rui Moreira, Alexandra R. Fernandes, João Vaz and Maria J. Perry","doi":"10.1039/D4MD00876F","DOIUrl":"10.1039/D4MD00876F","url":null,"abstract":"<p >Hypoxia is a hallmark of the glioblastoma multiforme microenvironment and represents a promising therapeutic target for cancer treatment. Herein, we report nitroaromatic-based triazene prodrugs designed for selective activation by tumoral endogenous reductases and release of the cytotoxic methyldiazonium ion <em>via</em> a self-immolative mechanism. While compounds bearing a 2-nitrofuran bioreductive group were more efficiently activated by nitroreductases, 4-nitrobenzyl prodrugs <strong>1b</strong>, <strong>1d</strong> and <strong>1e</strong> elicited a more pronounced cytotoxic effect against LN-229 and U-87 MG glioblastoma cell lines under hypoxic conditions when compared to temozolomide (TMZ), the golden standard for glioblastoma treatment. This cytotoxic response aligns with the increased apoptosis levels in LN-229 cells and senescence induction in U-87 MG cells, promoted by prodrugs <strong>1d</strong> and <strong>1e</strong>, under hypoxic conditions. These results highlight the potential of these hypoxia-activated nitroaromatic-based triazene prodrugs for selective delivery of the cytotoxic methyldiazonium ion and support further optimization to provide a safer alternative for glioblastoma treatment.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 3","pages":" 1350-1362"},"PeriodicalIF":4.1,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028875","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}