The Total Synthesis of Zetekitoxin AB

Zetektoxin AB 的全合成

• 批准号: 8907202
• 负责人: Ryan Deluca
• 金额: $ 5.07万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-12 至 2017-03-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8907202
• 关键词: Acute Pain; Address; Affinity; Alkylation; Amino Acids; Beryllium; Binding; Biological Assay; Carbodiimides; Cells; Coupling; Cyclization; Electrophysiology (science); Esters; Evaluation; Goals; Guanidines; Homology Modeling; Individual; Inflammation; Inhibitory Concentration 50; Inorganic Sulfates; Ion Channel Protein; Ketones; Knowledge; Lead; Libraries; Ligands; Mediating; Methodology; Methods; Mutagenesis; Nerve Pain; Neurons; Panamanian; Paralysed; Poison; Positioning Attribute; Protein Isoforms; Proteins; Rana; Research Project Grants; Rhodium; Route; SCN1A protein; Skin; Sodium Channel; Specificity; Structure; Testing; Time; Toxin; Unspecified or Sulfate Ion Sulfates; Voltage-Clamp Technics; analog; base; design; extracellular; flexibility; functional group; gonyautoxins; guanidinium; improved; inhibitor/antagonist; injured; insight; mutant; painful neuropathy; protein function; public health relevance; receptor; small molecule; tool; voltage; zetekitoxin AB

 DESCRIPTION (provided by applicant): This research project encompasses the total synthesis of the remarkably potent guanidinium poison, zetekitoxin AB (ZTX). ZTX has an exceptional ability to block volatage-gated sodium channels (NaV) with picomolar activity. However, the structural features responsible for its increased activity compared to related guanidinium poisons remains unknown. Synthetic efforts toward ZTX will be based on previously synthesized intermediates accessed in the sponsoring lab's synthesis of the related guanidinium toxin, gonyautoxin (GTX). The route is highlighted by a rhodium-catalyzed oxidative cyclization to access ZTX's bis-guanidinium core. Synthetic methodology will be explored and developed accordingly to access ZTX's macroclactam and N-hydroxycarbamate functionalities. A flexible synthesis of ZTX would allow a focused examination of ZTX analogues that could provide insight into specific interactions with sodium channels. Electrophysiology assays will be performed using whole-cell voltage-clamp techniques against all sodium channel isoforms (NaV1.1-9 and NaX), as ZTX has only been tested against three isoforms to date. This will provide an information rich approach to reveal specificity towards any individual channel isoform. A specific isoform inhibitor with picomolar activity would be an extremely valuable tool to study the distribution of specific channel isoforms in injured neurons. Protein mutagenesis will also be used to probe proposed interactions with specific amino acid residues hypothesized to be crucial for small molecule binding. This project's overall goal is to complete the total synthesis of ZTX and increase understanding of NaV channels with respect to ZTX's binding efficacy. The knowledge accrued from this study could lead to new simplified small molecules that hold promise for treating inflammation and neuropathic pain.

 描述（由申请人提供）：该研究项目包括强效胍毒物泽特毒素 AB (ZTX) 的全合成。 ZTX 具有以皮摩尔活性阻断电压门控钠通道 (NaV) 的卓越能力。然而，与相关胍盐毒物相比，其活性增加的结构特征仍不清楚。 ZTX 的合成工作将基于先前合成的中间体，该中间体是在赞助实验室合成相关胍毒素、膝沟藻毒素 (GTX) 时获得的。该路线的亮点是通过铑催化的氧化环化来进入 ZTX 的双胍核心。将相应地探索和开发合成方法，以获取 ZTX 的大环内酰胺和 N-羟基氨基甲酸酯功能。 ZTX 的灵活合成将允许对 ZTX 类似物进行集中检查，从而深入了解与钠通道的特定相互作用。将使用全细胞电压钳技术针对所有钠通道亚型（NaV1.1-9 和 NaX）进行电生理学测定，因为迄今为止 ZTX 仅针对三种亚型进行了测试。这将提供一种信息丰富的方法来揭示任何单个通道亚型的特异性。具有皮摩尔活性的特定亚型抑制剂将是研究受损神经元中特定通道亚型分布的极其有价值的工具。蛋白质突变会 也可用于探测与假设对小分子结合至关重要的特定氨基酸残基的相互作用。该项目的总体目标是完成ZTX的全合成，并增加对NaV通道与ZTX结合功效的了解。这项研究积累的知识可能会产生新的简化小分子，有望治疗炎症和神经性疼痛。