Total Synthesis of Cytotoxic Garcinia Natural Products

细胞毒性藤黄果天然产物的全合成

• 批准号: 6740373
• 负责人: Tristan H Lambert
• 金额: $ 4.11万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-24 至 2006-04-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6740373
• 关键词: Diels Alder reaction; biological products; chemical addition; chemical reaction; chemical synthesis; combinatorial chemistry; cytotoxicity; drug design /synthesis /production; evaporation; neoplasm /cancer pharmacology; neoplastic cell; plant extracts; predoctoral investigator

DESCRIPTION (provided by applicant): Many members of the Garcinia family of natural products have been shown to display significant cytotoxicity against a range of cancer cell lines. The goal of the proposed research is to develop a short and efficient synthesis of a member of this family, gaudichaudiic acid G. A key step in the proposed synthesis is a novel one-pot, three component coupling reaction. This sequence, which involves a Diels-Alder reaction, aldol condensation, and hetero-Michael addition, will allow for the exceedingly facile preparation of the tricyclic core common to the Garcinia xanthonoids. Coupling of this core fragment to a complex but readily prepared phenolic fragment will complete the total synthesis of guadichaudiic acid G. In addition, coupling of this core to alternative phenolic fragments will allow rapid access to additional members of this family including naturally occurring morellic acid and scortechinone B as well as a potentially limitless number of unnatural analogues. In this way, a library of garcinia-type products will be generated and assayed for cytotoxicity against cancer cell lines with the ultimate goal being to identify a compound with superior biological activity.

描述(由申请人提供)：藤黄系列天然产品的许多成员已被证明对一系列癌细胞具有显著的细胞毒性。这项研究的目标是开发一种短而有效的合成该家族的成员Gaudichaudiic酸G。建议合成的关键步骤是一锅三组分的新型偶联反应。这一序列包括Diels-Alder反应、Aldol缩合和杂迈克尔加成，将允许非常容易地制备藤黄酮类化合物所共有的三环核心。将这一核心片段与复杂但容易制备的酚类片段偶联将完成愈创木二酸G的全合成。此外，将该核心与替代酚类片段偶联将允许快速获得该家族的更多成员，包括自然产生的莫瑞酸和蝎子素B以及潜在的无限数量的非天然类似物。通过这种方式，将产生一个石蒜类产物的文库，并对其进行对癌细胞株的细胞毒性测试，最终目标是鉴定出具有优异生物活性的化合物。