Pub Date : 2018-01-01Epub Date: 2018-02-06DOI: 10.1016/bs.alkal.2017.12.003
Aletta E van der Westhuyzen, Liliya V Frolova, Alexander Kornienko, Willem A L van Otterlo
Rigidins (2-6) are pyrrolopyrimidine alkaloids isolated from marine tunicates. Since their isolation, refinement of their total syntheses, and biochemical evaluation, interest toward this pyrrolo[2,3-d]pyrimidine scaffold as a medicinal candidate has been triggered. The derivatization of these natural products has led to the discovery of a novel range of 7-deazahypoxanthines, which exhibit extremely potent anticancer activity in human cancer cell lines. A major breakthrough toward the synthesis of rigidin and various rigidin analogues has been the application of multicomponent reactions (MCRs). The rapid assembly of molecular diversity and flexibility displayed by MCRs makes it an attractive strategy for the preparation of rigidin-inspired small molecules. Furthermore, a number of rigidin-like 7-deazaxanthine compounds have been reported in the literature and the popularity of implementing MCRs to construct these 7-deazaxanthines is highlighted here. It is our hope that the synthetic methods described in this chapter will result in the further generation of rigidin-inspired compounds that will move on from being "hits" into "leads" in the medicinal chemistry drug discovery pipeline and potentially into anticancer therapeutics.
{"title":"The Rigidins: Isolation, Bioactivity, and Total Synthesis-Novel Pyrrolo[2,3-d]Pyrimidine Analogues Using Multicomponent Reactions.","authors":"Aletta E van der Westhuyzen, Liliya V Frolova, Alexander Kornienko, Willem A L van Otterlo","doi":"10.1016/bs.alkal.2017.12.003","DOIUrl":"https://doi.org/10.1016/bs.alkal.2017.12.003","url":null,"abstract":"<p><p>Rigidins (2-6) are pyrrolopyrimidine alkaloids isolated from marine tunicates. Since their isolation, refinement of their total syntheses, and biochemical evaluation, interest toward this pyrrolo[2,3-d]pyrimidine scaffold as a medicinal candidate has been triggered. The derivatization of these natural products has led to the discovery of a novel range of 7-deazahypoxanthines, which exhibit extremely potent anticancer activity in human cancer cell lines. A major breakthrough toward the synthesis of rigidin and various rigidin analogues has been the application of multicomponent reactions (MCRs). The rapid assembly of molecular diversity and flexibility displayed by MCRs makes it an attractive strategy for the preparation of rigidin-inspired small molecules. Furthermore, a number of rigidin-like 7-deazaxanthine compounds have been reported in the literature and the popularity of implementing MCRs to construct these 7-deazaxanthines is highlighted here. It is our hope that the synthetic methods described in this chapter will result in the further generation of rigidin-inspired compounds that will move on from being \"hits\" into \"leads\" in the medicinal chemistry drug discovery pipeline and potentially into anticancer therapeutics.</p>","PeriodicalId":35785,"journal":{"name":"Alkaloids: Chemistry and Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/bs.alkal.2017.12.003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35842517","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}
Pub Date : 2017-01-01Epub Date: 2017-06-22DOI: 10.1016/bs.alkal.2017.05.001
Uwe Rinner
This chapter provides a comprehensive overview of recent achievements in the area of Galbulimima alkaloids. Following a discussion of the isolation of Galbulimima alkaloids and structural features of members of this fascinating family of secondary metabolites, biological properties of selected compounds are briefly discussed. Furthermore, the proposed biosynthetic routes toward Galbulimima alkaloids are outlined. The main section of the chapter is devoted to a detailed discussion and comparison of all total syntheses of Galbulimima alkaloids published to date.
{"title":"Galbulimima Alkaloids.","authors":"Uwe Rinner","doi":"10.1016/bs.alkal.2017.05.001","DOIUrl":"https://doi.org/10.1016/bs.alkal.2017.05.001","url":null,"abstract":"<p><p>This chapter provides a comprehensive overview of recent achievements in the area of Galbulimima alkaloids. Following a discussion of the isolation of Galbulimima alkaloids and structural features of members of this fascinating family of secondary metabolites, biological properties of selected compounds are briefly discussed. Furthermore, the proposed biosynthetic routes toward Galbulimima alkaloids are outlined. The main section of the chapter is devoted to a detailed discussion and comparison of all total syntheses of Galbulimima alkaloids published to date.</p>","PeriodicalId":35785,"journal":{"name":"Alkaloids: Chemistry and Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/bs.alkal.2017.05.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35297329","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}
Pub Date : 2017-01-01Epub Date: 2017-07-12DOI: 10.1016/bs.alkal.2017.06.001
Joseph P Michael
There have been substantial developments in the chemistry and biology of the acridone alkaloids in the 16years since the topic was last reviewed in this series of monographs (2000). The present survey covers the literature from mid-1999 to 2016. A brief overview of the biosynthesis of acridone alkaloids is followed by details of the occurrence and characterization of known alkaloids from new sources, and of novel alkaloids. The classes covered include simple acridone alkaloids, C-prenylacridones, furo[3,2-b]- and furo[2,3-c]acridones, pyrano[3,2-b]- and pyrano[2,3-c]acridones, and dimeric alkaloids containing acridone moieties. Syntheses of acridone alkaloids and certain analogs reported during the review period are comprehensively covered. The final section summarizes aspects of their bioactivity, including cytotoxicity and anticancer activity, antimicrobial and antiparasitic properties, and enzyme inhibition. The chapter concludes with a brief description of important bioactive synthetic analogs.
{"title":"Acridone Alkaloids.","authors":"Joseph P Michael","doi":"10.1016/bs.alkal.2017.06.001","DOIUrl":"https://doi.org/10.1016/bs.alkal.2017.06.001","url":null,"abstract":"<p><p>There have been substantial developments in the chemistry and biology of the acridone alkaloids in the 16years since the topic was last reviewed in this series of monographs (2000). The present survey covers the literature from mid-1999 to 2016. A brief overview of the biosynthesis of acridone alkaloids is followed by details of the occurrence and characterization of known alkaloids from new sources, and of novel alkaloids. The classes covered include simple acridone alkaloids, C-prenylacridones, furo[3,2-b]- and furo[2,3-c]acridones, pyrano[3,2-b]- and pyrano[2,3-c]acridones, and dimeric alkaloids containing acridone moieties. Syntheses of acridone alkaloids and certain analogs reported during the review period are comprehensively covered. The final section summarizes aspects of their bioactivity, including cytotoxicity and anticancer activity, antimicrobial and antiparasitic properties, and enzyme inhibition. The chapter concludes with a brief description of important bioactive synthetic analogs.</p>","PeriodicalId":35785,"journal":{"name":"Alkaloids: Chemistry and Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/bs.alkal.2017.06.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35343270","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}
Pub Date : 2017-01-01Epub Date: 2017-08-16DOI: 10.1016/bs.alkal.2017.07.001
Joëlle Pérard-Viret, Laith Quteishat, Rana Alsalim, Jacques Royer, Françoise Dumas
Cephalotaxus alkaloids represent a family of plant secondary metabolites known for 60 years. Significant activity against leukemia in mice was demonstrated for extracts of Cephalotaxus. Cephalotaxine (CET) (1), the major alkaloid of this series was isolated from Cephalotaxus drupacea species by Paudler in 1963. The subsequent discovery of promising antitumor activity among new Cephalotaxus derivatives reported by Chinese, Japanese, and American teams triggered extensive structure elucidation and biological studies in this family. The structural feature of this cephalotaxane family relies mainly on its tetracyclic alkaloid backbone, which comprises an azaspiranic 1-azaspiro[4.4]nonane unit (rings C and D) and a benzazepine ring system (rings A and B), which is linked by its C3 alcohol function to a chiral oxygenated side chain by a carboxylic function alpha to a tetrasubstituted carbon center. The botanical distribution of these alkaloids is limited to the Cephalotaxus genus (Cephalotaxaceae). The scope of biological activities of the Cephalotaxus alkaloids is mainly centered on the antileukemic activity of homoharringtonine (HHT) (2), which in particular demonstrated marked benefits in the treatment of orphan myeloid leukemia and was approved as soon as 2009 by European Medicine Agency and by US Food and Drug Administration in 2012. Its exact mechanism of action was partly elucidated and it was early recognized that HHT (2) inhibited protein synthesis at the level of the ribosome machinery. Interestingly, after a latency period of two decades, the topic of Cephalotaxus alkaloids reemerged as a prolific source of new natural structures. To date, more than 70 compounds have been identified and characterized. Synthetic studies also regained attention during the past two decades, and numerous methodologies were developed to access the first semisynthetic HHT (2) of high purity suitable for clinical studies, and then high grade enantiomerically pure CET (1), HHT (2), and analogs.
头豆杉生物碱是一个已知60年的植物次生代谢物家族。头杉提取物对小鼠白血病有显著的抗白血病活性。Cephalotaxine (CET)(1)是该系列生物碱的主要成分,由Paudler于1963年从drupacea Cephalotaxus中分离得到。随后,中国、日本和美国的研究小组发现了有希望的抗肿瘤活性的新cephalalotaxus衍生物,引发了该家族广泛的结构阐明和生物学研究。这个头孢烷家族的结构特征主要依赖于它的四环生物碱主链,它包括一个氮杂环- 1-氮杂环[4.4]壬烷单元(环C和D)和一个苯氮平环系统(环a和B),它通过它的C3醇功能连接到一个手性氧化侧链,通过一个羧基功能连接到一个四取代的碳中心。这些生物碱的植物分布仅限于头杉属(头杉科)。Cephalotaxus生物碱的生物活性范围主要集中在homharringtonine (HHT)的抗白血病活性(2),尤其在治疗孤儿髓系白血病方面表现出明显的益处,早在2009年就获得了欧洲医药管理局(European Medicine Agency)的批准,2012年获得了美国食品和药物管理局(US Food and Drug Administration)的批准。其确切的作用机制部分被阐明,并且早期认识到HHT(2)在核糖体机制水平上抑制蛋白质合成。有趣的是,经过二十年的潜伏期,头杉生物碱的话题再次出现,成为新的自然结构的多产来源。到目前为止,已经鉴定和表征了70多种化合物。在过去的二十年里,合成研究也重新受到关注,许多方法被开发出来,以获得第一个适合临床研究的高纯度半合成HHT(2),然后是高纯度的对映体纯CET (1), HHT(2)和类似物。
{"title":"Cephalotaxus Alkaloids.","authors":"Joëlle Pérard-Viret, Laith Quteishat, Rana Alsalim, Jacques Royer, Françoise Dumas","doi":"10.1016/bs.alkal.2017.07.001","DOIUrl":"10.1016/bs.alkal.2017.07.001","url":null,"abstract":"<p><p>Cephalotaxus alkaloids represent a family of plant secondary metabolites known for 60 years. Significant activity against leukemia in mice was demonstrated for extracts of Cephalotaxus. Cephalotaxine (CET) (1), the major alkaloid of this series was isolated from Cephalotaxus drupacea species by Paudler in 1963. The subsequent discovery of promising antitumor activity among new Cephalotaxus derivatives reported by Chinese, Japanese, and American teams triggered extensive structure elucidation and biological studies in this family. The structural feature of this cephalotaxane family relies mainly on its tetracyclic alkaloid backbone, which comprises an azaspiranic 1-azaspiro[4.4]nonane unit (rings C and D) and a benzazepine ring system (rings A and B), which is linked by its C3 alcohol function to a chiral oxygenated side chain by a carboxylic function alpha to a tetrasubstituted carbon center. The botanical distribution of these alkaloids is limited to the Cephalotaxus genus (Cephalotaxaceae). The scope of biological activities of the Cephalotaxus alkaloids is mainly centered on the antileukemic activity of homoharringtonine (HHT) (2), which in particular demonstrated marked benefits in the treatment of orphan myeloid leukemia and was approved as soon as 2009 by European Medicine Agency and by US Food and Drug Administration in 2012. Its exact mechanism of action was partly elucidated and it was early recognized that HHT (2) inhibited protein synthesis at the level of the ribosome machinery. Interestingly, after a latency period of two decades, the topic of Cephalotaxus alkaloids reemerged as a prolific source of new natural structures. To date, more than 70 compounds have been identified and characterized. Synthetic studies also regained attention during the past two decades, and numerous methodologies were developed to access the first semisynthetic HHT (2) of high purity suitable for clinical studies, and then high grade enantiomerically pure CET (1), HHT (2), and analogs.</p>","PeriodicalId":35785,"journal":{"name":"Alkaloids: Chemistry and Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/bs.alkal.2017.07.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10270704","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}
Pub Date : 2017-01-01Epub Date: 2017-02-28DOI: 10.1016/bs.alkal.2017.01.001
Shigeru Arai, Masaya Nakajima, Atsushi Nishida
This review focuses on the total synthesis of lundurines A-C. Their main structural feature is a unique cyclopropa[b]indole core that has been found only in these alkaloids. In addition to this characteristic structure, the biological activity makes them as attractive synthetic targets. However, almost two decades passed from their isolation and structural determination in 1995 to their first total synthesis. The first part of this review summarizes the synthetic approaches to the tri- and tetracyclic ring systems of lundurine as well as an inter- and intramolecular cyclopropanation strategy that gives the cyclopropa[b]indole core. The second part presents a detailed description of four total syntheses that were reported from 2014 to 2016. In addition, the asymmetric total synthesis of the related alkaloids grandilodine C and lapidilectine B is described.
{"title":"Total Synthesis of Lundurine and Related Alkaloids: Synthetic Approaches and Strategies.","authors":"Shigeru Arai, Masaya Nakajima, Atsushi Nishida","doi":"10.1016/bs.alkal.2017.01.001","DOIUrl":"https://doi.org/10.1016/bs.alkal.2017.01.001","url":null,"abstract":"<p><p>This review focuses on the total synthesis of lundurines A-C. Their main structural feature is a unique cyclopropa[b]indole core that has been found only in these alkaloids. In addition to this characteristic structure, the biological activity makes them as attractive synthetic targets. However, almost two decades passed from their isolation and structural determination in 1995 to their first total synthesis. The first part of this review summarizes the synthetic approaches to the tri- and tetracyclic ring systems of lundurine as well as an inter- and intramolecular cyclopropanation strategy that gives the cyclopropa[b]indole core. The second part presents a detailed description of four total syntheses that were reported from 2014 to 2016. In addition, the asymmetric total synthesis of the related alkaloids grandilodine C and lapidilectine B is described.</p>","PeriodicalId":35785,"journal":{"name":"Alkaloids: Chemistry and Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/bs.alkal.2017.01.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35297331","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}
Pub Date : 2016-01-01DOI: 10.1016/s1099-4831(16)30008-6
Hans-Joachim Knölker
{"title":"In thematic volumes of The Alkaloids seminal developments in areas of exceptional interest are summarized.","authors":"Hans-Joachim Knölker","doi":"10.1016/s1099-4831(16)30008-6","DOIUrl":"https://doi.org/10.1016/s1099-4831(16)30008-6","url":null,"abstract":"","PeriodicalId":35785,"journal":{"name":"Alkaloids: Chemistry and Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/s1099-4831(16)30008-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34557871","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}
Pub Date : 2015-01-01DOI: 10.1016/bs.alkal.2014.09.001
Stephen G Davies, James E Thomson
The structurally related natural products (-)-homaline, (-)-hopromine, (-)-hoprominol, and (-)-hopromalinol have been collectively termed the homalium alkaloids. All four alkaloids possess bis-ζ-azalactam structures, but differ only by the identities of the side chain on each lactam ring. Since their isolation (from the leaves of Homalium pronyense Guillaum found in the forests of New Caledonia), there have been several syntheses of homaline, hopromine, hoprominol, and hopromalinol in both racemic and enantiopure forms. The most highly yielding and versatile strategy for their synthesis employs the conjugate addition of an enantiopure lithium amide reagent to an α,β-unsaturated ester as the key stereodefining step. This methodology has been used in the syntheses of all four members of the homalium alkaloid family and their stereoisomers.
{"title":"The homalium alkaloids: isolation, synthesis, and absolute configuration assignment.","authors":"Stephen G Davies, James E Thomson","doi":"10.1016/bs.alkal.2014.09.001","DOIUrl":"https://doi.org/10.1016/bs.alkal.2014.09.001","url":null,"abstract":"<p><p>The structurally related natural products (-)-homaline, (-)-hopromine, (-)-hoprominol, and (-)-hopromalinol have been collectively termed the homalium alkaloids. All four alkaloids possess bis-ζ-azalactam structures, but differ only by the identities of the side chain on each lactam ring. Since their isolation (from the leaves of Homalium pronyense Guillaum found in the forests of New Caledonia), there have been several syntheses of homaline, hopromine, hoprominol, and hopromalinol in both racemic and enantiopure forms. The most highly yielding and versatile strategy for their synthesis employs the conjugate addition of an enantiopure lithium amide reagent to an α,β-unsaturated ester as the key stereodefining step. This methodology has been used in the syntheses of all four members of the homalium alkaloid family and their stereoisomers.</p>","PeriodicalId":35785,"journal":{"name":"Alkaloids: Chemistry and Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/bs.alkal.2014.09.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33072642","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}
Pub Date : 2015-01-01DOI: 10.1016/bs.alkal.2014.09.002
Ana Silvia Suassuna Carneiro Lúcio, Jackson Roberto Guedes da Silva Almeida, Emídio Vasconcelos Leitão Da-Cunha, Josean Fechine Tavares, Jos Maria Barbosa Filho
This chapter presents an overview of the chemistry and pharmacology of the alkaloids found in species of the Annonaceae family. The occurrence of alkaloids from Annonaceae species, as well as their chemical structures and pharmacological activities are summarized in informative and easy-to-understand tables. Within the Annonaceae family, the genera Annona, Duguetia, and Guatteria have led to many important publications. Valuable and comprehensive information about the structure of these alkaloids is provided. The alkaloids of the aporphine type represent the predominant group in this family. Many of the isolated alkaloids exhibit unique structures. In addition to the chemical structures, the pharmacological activities of some alkaloids are also presented in this chapter. Thus, the leishmanicidal, antimicrobial, antitumor, cytotoxic, and antimalarial activities observed for these alkaloids are highlighted. The chapter is presented as a contribution for the scientific community, mainly to enable the search for alkaloids in species belonging to the Annonaceae family.
{"title":"Alkaloids of the Annonaceae: occurrence and a compilation of their biological activities.","authors":"Ana Silvia Suassuna Carneiro Lúcio, Jackson Roberto Guedes da Silva Almeida, Emídio Vasconcelos Leitão Da-Cunha, Josean Fechine Tavares, Jos Maria Barbosa Filho","doi":"10.1016/bs.alkal.2014.09.002","DOIUrl":"https://doi.org/10.1016/bs.alkal.2014.09.002","url":null,"abstract":"<p><p>This chapter presents an overview of the chemistry and pharmacology of the alkaloids found in species of the Annonaceae family. The occurrence of alkaloids from Annonaceae species, as well as their chemical structures and pharmacological activities are summarized in informative and easy-to-understand tables. Within the Annonaceae family, the genera Annona, Duguetia, and Guatteria have led to many important publications. Valuable and comprehensive information about the structure of these alkaloids is provided. The alkaloids of the aporphine type represent the predominant group in this family. Many of the isolated alkaloids exhibit unique structures. In addition to the chemical structures, the pharmacological activities of some alkaloids are also presented in this chapter. Thus, the leishmanicidal, antimicrobial, antitumor, cytotoxic, and antimalarial activities observed for these alkaloids are highlighted. The chapter is presented as a contribution for the scientific community, mainly to enable the search for alkaloids in species belonging to the Annonaceae family.</p>","PeriodicalId":35785,"journal":{"name":"Alkaloids: Chemistry and Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/bs.alkal.2014.09.002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33072645","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}