BIORELEVANT TOTAL SYNTHESIS OF THE ELEUTHEROBIN CORE

刺五加酶核心的生物相关全合成

• 批准号: 6055778
• 负责人: THOMAS G LACOUR
• 金额: $ 3.09万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-29 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6055778
• 关键词: alkylation; analog; antineoplastics; binding sites; chemical structure function; chemical synthesis; diterpenes; drug design /synthesis /production; marine toxins; tubulin

This total synthesis of the eleutherobin core proposes, as its main objective, to construct this extremely potent antitumor marine product by an efficient and biologically relevant route. The fact that eleutherobin and taxol share a common mechanism of action and tubulin binding domain with discodermolide and the epothilones suggests the possibility that, although structurally quite different, these anticancer agents each achieve similar forms at the binding site. Structural (bond) reorganization may furnish the active form. Whether such rearrangement occurs in vivo or can be shown to be synthetically useful are important questions to ask and comprise a key feature of the proposed synthesis. Reorganizations envisioned in this idea include a novel fragmentation. Ready construction of substrates appropriate to test the fragmentation will also flow from this plan. Other interesting chemical questions asked explore pertinent intraannular functional romp interactions, including redox pathways and stereoselective isomerization of enones, as well as exerting such stereocontrol in an intermolecular interaction (for example, using a "Bayliss-Hillman" reaction) related to a proposed role of the active site in the aforementioned biomimetic rearrangement. The overall approach, which projects completion in a competitive 15-20 steps, should also supply important SAR information by way of its intermediates and easily derived analogues (especially thio- and aza-ethers), afford rapid access to the briarellins and asbestinins (related, bioactive diterpenes), and provide a novel fragmentation methodology to afford medium rings.

作为其主要目标，该五加素核心的全合成提出通过有效和生物相关的途径构建这种极其有效的抗肿瘤海洋产品。五加素和紫杉醇与discodermolide和埃博霉素具有共同的作用机制和微管蛋白结合结构域，这一事实表明，尽管在结构上完全不同，但这些抗癌剂在结合位点处各自实现相似的形式。 结构（债券）重组可以提供活性形式。 这种重排是否发生在体内或可以显示为合成有用的是要问的重要问题，并包括所提出的合成的关键特征。 在这个想法中设想的重组包括一个新的分裂。 适合于测试碎裂的基底的现成构造也将从该计划中流出。 其他有趣的化学问题问探索相关的环内功能romp相互作用，包括氧化还原途径和立体选择性异构化的烯酮，以及发挥这样的立体控制在分子间的相互作用（例如，使用“贝利斯-希尔曼”反应）有关的活性位点在上述仿生重排的拟议作用。 整体的方法，项目完成在一个有竞争力的15-20个步骤，还应提供重要的SAR信息的方式，其中间体和容易衍生的类似物（特别是硫醚和氮杂醚），提供快速获得briarelins和石棉（相关的，生物活性二萜），并提供一种新的碎片化方法，以提供中环。