Joëlle Pérard-Viret, Laith Quteishat, Rana Alsalim, Jacques Royer, Françoise Dumas
{"title":"Cephalotaxus Alkaloids.","authors":"Joëlle Pérard-Viret, Laith Quteishat, Rana Alsalim, Jacques Royer, Françoise Dumas","doi":"10.1016/bs.alkal.2017.07.001","DOIUrl":null,"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":0.0000,"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":"26","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Alkaloids: Chemistry and Biology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/bs.alkal.2017.07.001","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2017/8/16 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"Biochemistry, Genetics and Molecular Biology","Score":null,"Total":0}
引用次数: 26
Abstract
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。