Bioorganic & Medicinal Chemistry最新文献

{"title":"Alkaloids from Mackinlaya species and synthetic mackinazolinone derivatives: An overview","authors":"Julie Jaouen ,&nbsp;Christian Bailly","doi":"10.1016/j.bmc.2024.118018","DOIUrl":"10.1016/j.bmc.2024.118018","url":null,"abstract":"<div><div>Mackinazolinone is the main alkaloid isolated from plants of the genus <em>Mackinlaya</em>, essentially distributed in tropical Asia and Australia. There are five <em>Mackinlaya</em> species all containing bioactive alkaloids with a tetrahydropyridoquinazolinone core such as mackinazoline (<strong>1</strong>) and mackinazolinone (<strong>2</strong>). The present review retraces the origin of mackinazolinone and compares the different chemical routes to synthesize the natural product, through different methods including classical batch synthesis, solid-phase supported synthesis, microwaved irradiation and photochemistry. A panel of about 70 mackinazolinone analogues and derivatives is presented to illustrate the diversity of chemical approaches and structures. The pharmacology of mackinazolinone has been little investigated but derivatives with antibacterial or anticancer properties have been identified. The molecular targets for these compounds are essentially unknown, but a few proteins of interest have been evoked occasionally, such as the EGFR kinase. The natural product mackinazolinone has largely inspired chemists to develop novel products and chemical processes. Hopefully, the review will now encourage pharmacologists to further explore the properties of these quinazolinones as potential anti-infectious, anticancer and/or neuroprotective agents.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118018"},"PeriodicalIF":3.3,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142700368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective photo crosslinking to methylarginine readers by sulfonium peptides.","authors":"Ting Luo, Feng Feng, Kun Zou, Yumo Zhao, Yingxiao Gao, Mingxuan Wu","doi":"10.1016/j.bmc.2024.118015","DOIUrl":"https://doi.org/10.1016/j.bmc.2024.118015","url":null,"abstract":"<p><p>Arginine methylation is an important posttranslational modification that regulates epigenetics and pre-mRNA splicing. Similar to lysine methylation, reader proteins that bind site-specific modified proteins are key mediators for arginine methylation functions. Some arginine methylation has been shown significant functions from phenotype, but the molecular mechanisms remain elusive, probably due to lack of identification of the readers. Current methods rely on methylarginine peptide tools for pull-down or binding assays, but affinities to readers are usually tens to hundreds micromolar. As a consequence, development of chemical probes that crosslink specific readers is much in demand. We recently reported a methyllysine reader-selective crosslinking strategy by sulfonium peptides. NleS⁺me2 (norleucine-ε-dimethylsulfonium) imitate dimethyllysine and crosslink tryptophan or tyrosine inside binding pocket of readers. Arginine methylation readers contain aromatic cages for methylarginine binding, that is the similar binding mechanism for methyllysine. Therefore, we developed sulfonium probes that mimic methylarginine and crosslink tryptophan or tyrosine inside reader binding pockets. Because the single electron transfer from aromatic residue to sulfonium is binding-dependent, the conjugation showed high selectivity. Therefore, such sulfonium probes could be applied broadly for methylarginine readers investigations.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"118015"},"PeriodicalIF":3.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural optimization of naturally derived Ar-turmerone, as novel neuroinflammation suppressors effective in an Alzheimer mouse model","authors":"Wei Zhou,&nbsp;Yuanyuan Chang,&nbsp;Qingwei Xiao,&nbsp;Zhujie Deng,&nbsp;Lanyue Zhang,&nbsp;Zhengqiang Yuan,&nbsp;Zhiyun Du","doi":"10.1016/j.bmc.2024.118014","DOIUrl":"10.1016/j.bmc.2024.118014","url":null,"abstract":"<div><div>Microglia-mediated neuroinflammation plays a pivotal role in neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. The modulation of chronic and sustained inflammatory processes in the brain with small molecules presents a promising therapeutic strategy for these devastating conditions. Aromatic turmerone (ar-turmerone, ART), an active constituent of turmeric essential oil derived from the edible plant <em>Curcuma longa</em>, has shown substantial potential in mitigating neuroinflammatory responses and associated cognitive deficits. Building on our previous work, we sought to discover more potent neuroinflammation suppressors by designing and synthesizing a series of ar-turmerone derivatives to investigate their structure–activity relationships. Microglia-based cellular evaluations revealed that naphthyl-substituted (<strong>7c</strong>) and <em>N</em>-substituted amides (<strong>7a</strong>) demonstrated the most pronounced inhibitory effects against NO, TNF-α, and IL-1β release <em>in vitro</em>. Furthermore, in a lipopolysaccharide (LPS)-induced neuroinflammation model of Alzheimer’s disease in mice, these two compounds significantly reduced proinflammatory cytokine release, protected neurons from damage, and ameliorated memory impairments and cognitive deficits in Morris water maze tests. This structural optimization of ar-turmerone yielded highly potent anti-neuroinflammatory compounds, which may serve as promising agents for the treatment of neuroinflammation-related neurodegenerative disorders.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118014"},"PeriodicalIF":3.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142719919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The journey of antibody-drug conjugates for revolutionizing cancer therapy: A review","authors":"Fatima Akram ,&nbsp;Amna Murrawat Ali ,&nbsp;Muhammad Tayyab Akhtar ,&nbsp;Taseer Fatima ,&nbsp;Ifrah Shabbir ,&nbsp;Ikram ul Haq","doi":"10.1016/j.bmc.2024.118010","DOIUrl":"10.1016/j.bmc.2024.118010","url":null,"abstract":"<div><div>Antibody-drug conjugates (ADCs) represent a powerful class of targeted cancer therapies that harness the specificity of monoclonal antibodies to deliver cytotoxic payloads directly to tumor cells, minimizing off-target effects. This review explores the advancements in ADC technologies, focusing on advancing next-generation ADCs with novel payloads, conjugation strategies, and enhanced pharmacokinetic profiles. In particular, we highlight innovative payloads, including microtubule inhibitors, spliceosome modulators, and RNA polymerase inhibitors, that offer new mechanisms of cytotoxicity beyond traditional apoptosis induction. Additionally, the introduction of sophisticated conjugation techniques, such as site-specific conjugation using engineered cysteines, enzymatic methods, and integration of non-natural amino acids, has greatly improved the homogeneity, efficacy, and safety of ADCs. Furthermore, the review delves into the mechanistic insights into ADC action, detailing the intracellular pathways that facilitate drug release and cell death, and discussing the significance of bioconjugation methods in optimizing drug-antibody ratios (DARs). The establishment of comprehensive databases like ADCdb, which catalog vital pharmacological and biological data for ADCs, is also explored as a critical resource for advancing ADC research and clinical application. Finally, the clinical landscape of ADCs is examined, with a focus on the evolution of FDA-approved ADCs, such as Gemtuzumab Ozogamicin and Trastuzumab Emtansine, as well as emerging candidates in ongoing trials. As ADCs continue to evolve, their potential to revolutionize cancer therapy remains immense, offering new hope for more effective and personalized treatment options. ADCs also offer a significant advancement in targeted cancer therapy by merging the specificity of monoclonal antibodies with cytotoxic potency of chemotherapeutic agents. Hence, this dual mechanism intensifies tumor selectivity while minimizing systemic toxicity, paving the way for more effective and safer cancer treatments.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118010"},"PeriodicalIF":3.3,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142700367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of protein post-translational modifications with site-specifically incorporated non-canonical amino acids","authors":"Jiayu Gu ,&nbsp;Lihui Lao ,&nbsp;Yulin Chen ,&nbsp;Shixian Lin","doi":"10.1016/j.bmc.2024.118013","DOIUrl":"10.1016/j.bmc.2024.118013","url":null,"abstract":"<div><div>Despite the important functions of protein post-translational modifications (PTMs) in numerous cellular processes, understanding the biological roles of PTMs remains quite challenging. Here, we summarize our efforts in recent years to incorporate a variety of non-canonical amino acids (ncAAs) to study the biological functions of protein PTMs in mammalian cells, with a focus on the use of ncAA tools to probe the biological functions of various protein PTMs. We design length-tunable lipidation mimics for studying lipidation function and designing protein drugs. We highlight the use of genetically encoded lysine aminoacylations as chemical baits to identify aminoacylated lysine ubiquitination. Finally, we discuss the use of genetically encoded electron-rich Trp derivatives to design binding affinity-enhancing histone methylations readers.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118013"},"PeriodicalIF":3.3,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142719917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RAD18-catalysed formation of ubiquitination intermediate mimic of proliferating cell nuclear antigen PCNA","authors":"Liying Zhang ,&nbsp;Zhiheng Deng ,&nbsp;Yunxiang Du ,&nbsp;Ziyu Xu ,&nbsp;Tianyi Zhang ,&nbsp;Zebin Tong ,&nbsp;Huasong Ai ,&nbsp;Lu-Jun Liang ,&nbsp;Lei Liu","doi":"10.1016/j.bmc.2024.118016","DOIUrl":"10.1016/j.bmc.2024.118016","url":null,"abstract":"<div><div>The 2-((2-chloroethyl)amino)ethane-1-thiol (CAET)-based chemical trapping strategy is a practical tool for mechanistic studies of E3-catalysed ubiquitination. However, the construction of ubiquitination intermediate mimics (E2-Ub-substrate conjugates) via CAET has been limited to peptides, while its application to folded protein substrates remains unexplored. Here, we report that disulfide bond formation between E2-Ub (RAD6A-Ub) and the folded protein substrate PCNA (proliferating cell nuclear antigen) occurs upon the addition of the PCNA-associated E3 ligase RAD18. Leveraging this finding, we employed intein splicing technology to generate a stable, covalently linked RAD18-RAD6A-Ub-PCNA complex, enabling chemical crosslinking mass spectrometry (CX–MS) analysis to study the structure of this complex. This work showcases use of a substrate-associated E3 ligase to promote disulfide bond formation between an E2-Ub conjugate and a folded substrate for CAET-based trapping, thereby expanding the scope of this technique.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118016"},"PeriodicalIF":3.3,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142700369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and biological evaluation of lappaconitine analogues as potential anti-neuroinflammatory agents by side chain modification and scaffold hopping strategy","authors":"Feng Xing ,&nbsp;Hong-Yi Su ,&nbsp;He-Yang Zhong ,&nbsp;Yu-Zhu Li ,&nbsp;Yin-Yong Zhang ,&nbsp;Lin Chen ,&nbsp;Xian-Li Zhou","doi":"10.1016/j.bmc.2024.118012","DOIUrl":"10.1016/j.bmc.2024.118012","url":null,"abstract":"<div><div>Neuroinflammation mediated by microglia is widely recognized as a key pathophysiological mechanism in neurodegenerative diseases. Lappaconitine (LA) is a natural C₁₈-diterpenoid alkaloid isolated from <em>Aconitum sinomontanum</em> Nakai, and previous study showed that LA and its derivatives inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 cells. However, the anti-neuroinflammatory effects of LA and its derivatives on microglia are still not clear. Here, LA analogues were designed and synthesized, and the anti-neuroinflammatory activity of the synthesized compounds was screened using LPS-induced overexpression of NO in BV-2 microglia. The screening results showed that compound <strong>10</strong> displayed the highest ability to inhibit NO production (IC₅₀ = 9.98 ± 1.6 µM). Mechanistic investigations revealed that compound <strong>10</strong> attenuated LPS-activated neuroinflammation through suppression of TLR4/MyD88/NF-κB pathway in BV-2 microglia. Acute toxicity assays showed that compound <strong>10</strong> (LD₅₀ = 508.1 mg/kg) was safer relative to LA (LD₅₀ = 30.6 mg/kg). Collectively, our findings show that compound <strong>10</strong> could have potential as anti-neuroinflammatory agents.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118012"},"PeriodicalIF":3.3,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142719920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of 3-(2-aminobenzo[d]thiazol-5-yl) benzamide derivatives as potent anticancer agents via ROR1 inhibition","authors":"Fang Luo ,&nbsp;Jie Liu ,&nbsp;Rongtao Wang,&nbsp;Huiyin Yang,&nbsp;Ting Zhong,&nbsp;Mingzhi Su,&nbsp;Yanhua Fan","doi":"10.1016/j.bmc.2024.118011","DOIUrl":"10.1016/j.bmc.2024.118011","url":null,"abstract":"<div><div>Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a member of the receptor tyrosine kinase family, which was overexpressed in non-small cell lung cancer (NSCLC) and essential for cell proliferation, migration and invasion. Recently, accumulating evidences indicated that ROR1 played a critical role in maintaining the balance between the Src survival pathway and the p38 apoptotic pathway. Hence, ROR1 was considered as an attractive therapeutic target for the development of anticancer drugs. However, only a few small molecule ROR1 inhibitors were reported until now. Herein, a series of 3-(2-aminobenzo[<em>d</em>]thiazol-5-yl) benzamide derivatives were designed and synthesized via bioisosterism and simplification strategy guided by the lead compound <strong>9a</strong>. MTT assay showed that compound <strong>7h</strong> exhibited the best anti-cancer properties with IC₅₀ values of 18.16, 8.11 and 3.5 μM against A549, PC9 and H1975 cells, respectively. Meanwhile, the selectivity index (SI) of compound <strong>7h</strong> for H1975 cells was 22.86 compared to that of the lead compound <strong>9a</strong> of 1.83, which is at least 12 fold higher than that of lead compound <strong>9a</strong>, suggesting that <strong>7h</strong> had a favorable safety profile. In addition, the molecular docking, CETSA and DARTS assays suggested that compound <strong>7h</strong> might be a novel small molecule ROR1 inhibitor. More importantly, compound <strong>7h</strong> significantly suppressed the migration and invasion of H1975 cells <em>in vitro</em> by blocking Src survival pathway and reactivating the p38 apoptotic pathway, and induced H1975 cell cycle arrest in G1 phase. Collectively, our work suggested that the ROR1 inhibitor <strong>7h</strong> might be a novel drug candidate for NSCLC treatment.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118011"},"PeriodicalIF":3.3,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142700370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thiazolidinedione-based structure modification of ergosterol peroxide provides thiazolidinedione-conjugated derivatives as potent agents against breast cancer cells through a PI3K/AKT/mTOR pathway","authors":"Siqi Deng ,&nbsp;Lu Wang ,&nbsp;Shuang Tian ,&nbsp;Jiale Wu ,&nbsp;Yu Lin ,&nbsp;Haijun Wang ,&nbsp;Xiaoshan Guo ,&nbsp;Cuicui Han ,&nbsp;Wenkang Ren ,&nbsp;Ying Long Han ,&nbsp;Jianwen Zhou ,&nbsp;Ming Bu","doi":"10.1016/j.bmc.2024.118007","DOIUrl":"10.1016/j.bmc.2024.118007","url":null,"abstract":"<div><div>Ergosterol peroxide (EP) is a steroidal compound isolated from the traditional Chinese medicine <em>Ganoderma lucidum</em>. However, EP is limited by its solubility and moderate potency in antitumor studies. In the present study, a series of novel ergosterol peroxide-3-thiazolidinedione derivatives were designed and synthesized, by changing the linker between ergosterol peroxide and thiazolidinedione, it is expected to obtain compounds with better antitumor activity. The cytotoxicity screening showed that compound <strong>13o</strong> is the most active derivative against the MCF-7 cell line with an IC₅₀ of 3.06 μM, and exhibited stronger antitumor activity compared to the parent EP. Further <em>in vitro</em> and <em>vivo</em> studies showed that compound <strong>13o</strong> may reduced the mitochondrial membrane potential, increased the reactive oxygen species level and blocked the cell cycle in G0/G1 phase, and induced apoptosis of tumor cells by inhibiting the PI3K/Akt/mTOR pathway. <em>In vivo</em> 4T1 mouse model of breast cancer showed that <strong>13o</strong> not only continued to inhibit tumor proliferation but also had a stronger effect than the marketed drug 5-fluorouracil, compound <strong>13o</strong> had a good safety profile <em>in vivo</em>. The results suggest that compound <strong>13o</strong> may represent a novel, highly potent and low-toxicity structural lead for the development of new breast cancer chemotherapies.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118007"},"PeriodicalIF":3.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell-penetrating anti-sense peptide nucleic acids targeting sulfatase 2 inhibit adipogenesis in human mesenchymal stem cells","authors":"Daram Jung ,&nbsp;Sungjin Ahn ,&nbsp;Yeasel Jeon ,&nbsp;Minhee Kim ,&nbsp;In Guk Park ,&nbsp;Areum Kim ,&nbsp;Minsoo Noh","doi":"10.1016/j.bmc.2024.118009","DOIUrl":"10.1016/j.bmc.2024.118009","url":null,"abstract":"<div><div>Targeting the genes regulate the lineage commitment of human mesenchymal stem cells (hMSCs) to adipocytes provides a promising strategy for addressing obesity. In this study, we investigated the therapeutic potential of cell-penetrating anti-sense peptide nucleic acids (PNAs) designed to enhance solubility and hybridization properties, specifically targeting sulfatase 2 (SULF2), a potential reciprocal regulator of adipocyte and osteoblast differentiation in hMSCs. Cell-penetrating modified PNA oligomers effectively inhibit SULF2 gene transcription, leading to significant reductions in adiponectin protein synthesis and intracellular lipid droplet accumulation during adipogenesis in human bone marrow-derived MSCs (hBM-MSCs). Notably, PNA oligomer compound <strong>5</strong> exhibited the most potent anti-adipogenic activity, with an IC₅₀ value of 0.28 μM. These findings show the potential of SULF2-targeting cell-penetrating PNA oligomers as novel therapeutic agents for obesity-related metabolic diseases.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 118009"},"PeriodicalIF":3.3,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}