Total Synthesis of the Anticancer Agent Haterumalide NA

抗癌剂Haterumalide NA的全合成

• 批准号: 6891833
• 负责人: MATTHEW O DUFFEY
• 金额: $ 4.83万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-23 至 2006-04-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6891833
• 关键词: Porifera; alkenes; antineoplastics; chemical synthesis; drug design /synthesis /production; method development; neoplasm /cancer pharmacology; postdoctoral investigator; silicon compounds; stereochemistry

DESCRIPTION (provided by applicant): Haterumalide NA is a recently isolated macrolide from an Okinawan sponge Ircinia sp. It was found to exhibit strong cytotoxicity against P388 leukemia cells. The goal of this research project is to develop a concise, modular, and efficient enantioselective synthesis of haterumalide NA. To achieve this synthesis, new methodology will be developed for the stereosetective formation of tri- and tetrasubstituted olefins. This novel process will be a two-step sequence consisting of the synthesis of substituted cycloalkenylsiloxanes from propargyl alcohols followed by metal-mediated coupling with an organohalide. The development of this synthesis will create sufficient quantities of haterumalide NA for further exploration of its biological activity. Furthermore, the novel methodology proposed and the flexible synthetic scheme will permit straightforward access to analogs of haterumalide NA that may lead to a structure activity profile and the discovery of new anticancer drugs.

描述（由申请人提供）：Haterumalide NA 是最近从冲绳海绵 Ircinia sp. 中分离出来的大环内酯。发现它对 P388 白血病细胞表现出强烈的细胞毒性。该研究项目的目标是开发一种简洁、模块化、高效的 hatrumalide NA 对映选择性合成方法。为了实现这种合成，将开发用于三取代和四取代烯烃的立体定向形成的新方法。这种新颖的方法将是一个两步序列，包括从炔丙醇合成取代的环烯基硅氧烷，然后与有机卤化物进行金属介导的偶联。这种合成的发展将产生足够数量的哈特马内酯 NA，用于进一步探索其生物活性。此外，所提出的新方法和灵活的合成方案将允许直接获得哈特马利特 NA 的类似物，这可能导致结构活性概况和新抗癌药物的发现。