Annulation Strategies Toward the Total Synthesis of Saxitoxin and Zetekitoxin AB

石房蛤毒素和 Zetekitoxin AB 全合成的成环策略

• 批准号: 7679158
• 负责人: Michael R. Krout
• 金额: $ 4.52万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2012-09-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7679158
• 关键词: Address; Alkaloids; Biological; Biological Testing; Carbodiimides; Chemicals; Chemistry; Complex; Development; Family; Goals; Guanidines; Imines; Investigation; Ion Channel; Lead; Malignant Neoplasms; Methods; Modification; Neurotoxins; Nitrogen; Phase; Preparation; Publishing; Reaction; Research; Route; Saxitoxin; Sodium Channel; Sodium Channel Blockers; Structure; Technology; Toxin; analog; cancer therapy; chemical synthesis; guanidinium; interest; novel; novel strategies; novel therapeutics; oxidation; public health relevance; voltage; zetekitoxin AB

DESCRIPTION (provided by applicant): The invention of new reaction technologies is vital to enable the development of concise and novel strategies for complex chemical synthesis. Guanidinium alkaloids saxitoxin and zetekitoxin AB are potent voltage-gated sodium channel blockers that pose significant synthetic challenges. Recent studies have identified this channel a potential target in the treatment of a variety of cancers. Isolation of a minimal quantity (<1 mg) of zetekitoxin AB, one of the most potent blockers known, has hampered further biological characterization. A modular strategy for the synthesis of saxitoxin and zetekitoxin AB via a stereoselective [4+2]-annulation is proposed. Initial studies will involve the preparation of various annulation reaction components, followed by intense investigation focused on the annulation reaction. The initial chemistry will be explored in the context of the (+)-saxitoxin. The utility of the strategy developed will then be demonstrated by a convergent stereoselective synthesis of zetekitoxin AB. PUBLIC HEALTH RELEVANCE: This proposal describes a synthetic route to the potent neurotoxin zetekitoxin AB. By developing a new chemical heteroannulation reaction, this molecule will be constructed in a convergent fashion, allowing the ready preparation of analogues for biological testing. Access to this molecule will further research on the sodium ion channel and potentially lead to new therapeutics for the treatment of cancer.

描述(由申请人提供)：新反应技术的发明对于开发用于复杂化学合成的简明而新颖的策略至关重要。胍类生物碱萨克托毒素和泽曲霉毒素AB是强有力的电压门控钠通道阻滞剂，对合成构成重大挑战。最近的研究发现，该通道是治疗多种癌症的潜在靶点。分离出极少量(1毫克)的哲特克毒素AB，这是已知的最有效的阻滞剂之一，阻碍了进一步的生物学特性。提出了一种通过立体选择性[4+2]-环合成岩藻毒素和哲氏毒素AB的模块化策略。最初的研究将涉及各种环化反应成分的制备，随后将集中于环化反应的密集研究。最初的化学作用将在(+)-岩藻毒素的背景下进行探索。所开发的策略的实用性随后将通过zetekitoxin AB的收敛立体选择性合成来证明。与公共健康相关：这项提案描述了一种合成强效神经毒素Zetekitoxin AB的路线。通过开发一种新的化学杂环反应，这种分子将以收敛的方式构建，从而可以随时准备用于生物测试的类似物。获得这种分子将进一步研究钠离子通道，并可能导致治疗癌症的新疗法。