A Total Synthesis of Gambierol Using an Epoxide-Opening Cascade Approach

采用环氧化物开环级联法全合成甘比尔醇

• 批准号: 7799780
• 负责人: Denise Ann Colby
• 金额: $ 3.33万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2010-11-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7799780
• 关键词: Accounting; Acetals; Arrhythmia; Binding; Biological; Biological Factors; Carbon; Cells; Central Nervous System Diseases; Ciguatoxins; Complex; Consumption; Cyclic Ethers; Development; Disease; Epoxy Compounds; Event; Fishes; Gated Ion Channel; Goals; Immunosuppressive Agents; Improve Access; Ion Channel; Knowledge; Lead; Marine Toxins; Marines; Methodology; Methods; Molecular Probes; Mus; Oxygen; Potassium Channel; Reaction; Series; Shellfish; Site; Sodium Channel; Source; Structure; System; T-Cell Proliferation; Taste Perception; Testing; Therapeutic Agents; Toxin; brevetoxin; brevetoxin B; channel blockers; design; gambierol; harmful algal blooms; improved; maitotoxin; neurotoxic; novel; novel therapeutics; oxepane; polyolefin; prevent; public health relevance; red tide; success; voltage

DESCRIPTION (provided by applicant): Marine ladder polyethers, including gambierol, are the toxic constituents in many harmful algal blooms known as red tide events. These potent toxins can only be isolated in small quantities from their natural sources and the study of their biological activity could only be undertaken once their total synthesis was achieved. Unlike several other marine ladder polyethers which activate voltage-gated sodium ion channels, gambierol has been shown to inhibit voltage-gated potassium ion channels (Kv channels) in mouse taste cells. Kv channel blockers are potential therapeutic agents in the treatment of arrhythmia, diseases of the central nervous system, and as immunosuppressants. In addition, ladder polyethers and their derivatives have found use as molecular probes to elucidate the structure and function of voltage-gated ion channels, which ultimately leads to the improved design of therapeutic agents. The proposed total synthesis of the marine ladder polyether gambierol takes advantage of a directing group-free templated epoxide-opening cascade reaction that has the potential to streamline the synthesis of the toxin. The Jamison group has recently demonstrated the success of this method in simplified systems, but to date it has not been exploited in the total synthesis of a marine polyether. Improved access to the natural product and synthetic derivatives will enable further biological study and lead to a greater understanding of ion channel structure and function. The hallmark structural features of marine ladder polyethers include a series of syn/trans/syn fused cyclic ethers possessing C-C-O (carbon-carbon-oxygen) connectivity throughout the polyether framework, regardless of the intermediary ring size. One biosynthetic hypothesis that accounts for these structural features involves the epoxidation of a polyolefin, followed by an epoxide-opening cascade to form all of the ladder rings in a single step. The successful demonstration of an epoxide-opening cascade within the context of a total synthesis would additionally provide experimental support for this biosynthetic hypothesis. PUBLIC HEALTH RELEVANCE: Marine ladder polyether toxins are responsible for the neurotoxic effects resulting from the consumption of fish and shellfish during red tide events. One of these toxins, gambierol, has been shown to inhibit certain ion channels. A concise total synthesis of gambierol will provide sufficient quantities of the natural toxin and its synthetic derivatives to enable further biological study. An increased understanding of ion channel structure and function could lead to treatments for arrhythmia and disorders of the central nervous system.

描述（由申请人提供）：海洋阶梯聚醚，包括甘比醇，是许多被称为赤潮事件的有害藻华中的有毒成分。这些强效毒素只能从其天然来源中少量分离出来，只有在实现了其全合成之后才能对其生物活性进行研究。与其他几种激活电压门控钠离子通道的海洋梯形聚醚不同，甘比洛尔已被证明能抑制小鼠味觉细胞中的电压门控钾离子通道（Kv通道）。KV通道阻断剂是治疗心律失常、中枢神经系统疾病和作为免疫抑制剂的潜在治疗剂。此外，梯形聚醚及其衍生物已被发现用作分子探针来阐明电压门控离子通道的结构和功能，这最终导致治疗剂的改进设计。所提出的海洋梯形聚醚甘比醇的全合成利用了无定向基团的模板化环氧化物开环级联反应，该反应具有简化毒素合成的潜力。贾米森小组最近在简化系统中证明了这种方法的成功，但迄今为止，它还没有被用于海洋聚醚的全合成。改进天然产物和合成衍生物的获得将使进一步的生物学研究成为可能，并导致对离子通道结构和功能的更好理解。海洋梯形聚醚的标志性结构特征包括一系列顺式/反式/顺式稠合环醚，其在整个聚醚框架中具有C-C-O（碳-碳-氧）连接性，而不考虑中间环的大小。解释这些结构特征的一种生物合成假说涉及聚烯烃的环氧化，随后是环氧化物开放级联，以在单个步骤中形成所有的梯环。在全合成的背景下，环氧化物开放级联的成功演示将另外为这种生物合成假说提供实验支持。公共卫生关系：海洋梯形聚醚毒素是赤潮发生期间食用鱼类和贝类导致神经毒性效应的原因。这些毒素之一，甘比尔醇，已被证明可以抑制某些离子通道。一个简洁的全合成甘比洛尔将提供足够数量的天然毒素及其合成衍生物，使进一步的生物学研究。对离子通道结构和功能的进一步了解可能会导致心律失常和中枢神经系统疾病的治疗。