BIORELEVANT TOTAL SYNTHESIS OF THE ELEUTHEROBIN CORE

刺五加酶核心的生物相关全合成

• 批准号: 6514335
• 负责人: THOMAS G LACOUR
• 金额: $ 3.83万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-29 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6514335
• 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.

这种完全合成的Eleutherobin核心提出，作为其主要目标，通过一种有效的和生物相关的路线来构建这种极其有效的抗肿瘤海洋产品。刺五加红素和紫杉醇与盘状除草剂和伊波硫酮具有共同的作用机制和微管蛋白结合域，这一事实表明，尽管结构上截然不同，但这些抗癌药物在结合部位都具有相似的形式。结构性(债券)重组可以提供积极的形式。这种重排是否在体内发生，或者是否可以被证明是合成有用的，这是需要提出的重要问题，也是拟议合成的一个关键特征。在这个想法中设想的重组包括一种新的碎片化。用于测试碎裂的基材的现成施工也将从该计划开始。被问到的其他有趣的化学问题探索了相关的环内功能ROMP相互作用，包括氧化还原途径和烯酮的立体选择性异构化，以及在分子间相互作用中施加这种立体控制(例如，使用与上述仿生重排中活性中心的拟议作用相关的“贝利斯-希尔曼”反应)。整个方法预计将在15-20个步骤中完成，还应通过中间体和容易衍生的类似物(特别是硫代和氮醚)提供重要的SAR信息，提供快速获得灯盏花素和石棉素(相关的生物活性二萜)的途径，并提供一种新的裂解方法来获得中环。