The Total Synthesis of Zetekitoxin AB

Zetektoxin AB 的全合成

• 批准号: 9038174
• 负责人: Ryan Deluca
• 金额: $ 0.69万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9038174
• 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; 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（由适用提供）：该研究项目涵盖了显着潜在的鸟苷毒药，Zetekitoxin AB（ZTX）的总合成。 ZTX具有具有皮摩尔活性的挥发性钠通道（NAV）的特殊能力。然而，与相关的鸟肾毒物相比，导致其活性增加的结构特征仍然未知。对ZTX的合成努力将基于先前合成的中间体，在赞助实验室合成相关的鸟嘌呤毒素，Gonyautoxin（GTX）中。该途径由铑催化的氧化环化来突出显示，以访问ZTX的BIS-瓜尼迪岛核心。合成方法将被探索和开发，以访问ZTX的大环乳酰胺和N-羟基氨基甲酸盐功能。 ZTX的柔性合成将允许对ZTX类似物进行重点检查，这些ZTX类似物可以洞悉与钠通道的特定相互作用。电生理测定将使用全细胞电压钳技术针对所有钠通道同工型（NAV1.1-9和NAX）进行，因为迄今仅针对三种同工型进行了ZTX。这将提供丰富的信息方法，以揭示对任何单个渠道同工型的特异性。具有皮摩尔活性的特定同工型抑制剂将是研究受伤神经元中特定通道同工型分布的极为有价值的工具。蛋白质诱变会 还用于探测与特定氨基酸相互作用的相互作用，该相互作用保留了假设对小分子结合至关重要的相互作用。该项目的总体目标是完成ZTX的总合成，并提高对ZTX的结合效率的NAV通道的理解。从这项研究中积累的知识可能会导致新的简化小分子，这些分子有望治疗感染和神经性疼痛。