Synthesis, Structure and Detection of Azaspiracid

氮杂螺酸的合成、结构及检测

• 批准号: 7153536
• 负责人: Craig J. Forsyth
• 金额: $ 29.67万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7153536
• 关键词: Achievement; Acute; Amino Acids; Applications Grants; Architecture; Arts; Back; Biological; Biological Assay; Biological Factors; Carbon; Chemicals; Chronic; Complement component C1s; Complex; Consumption; Depth; Detection; Development; Dinophyceae; Environmental Monitoring; Enzyme-Linked Immunosorbent Assay; Europe; Haptens; Human; Immunochemistry; Individual; Laboratories; Link; Marine Toxins; Marines; Medical Surveillance; Methodology; Methods; Molecular; Mus; Necrosis; Organic Synthesis; Poisoning; Relative (related person); Research; Risk; Shellfish; Standards of Weights and Measures; Structure; Surveillance Program; System; Thermodynamics; Toxicology; Toxin; Uncertainty; Vertebral column; Work; azaspiracid; base; enantiomer; exposed human population; hemiketal; improved; in vivo; neurotoxic; novel; novel strategies; stereochemistry; tumor

DESCRIPTION (provided by applicant): The objectives of this grant application are to continue and expand research directed towards the full characterization, total synthesis, and environmental detection of the azaspiracid natural products. The azaspiracids are marine toxins that accumulate in shellfish cultivated and collected for human consumption. Azaspiracids are likely to be produced by the dinoflagellate Protoperidinium crassipes, that has widespread geographical distribution. The toxins have a unique mode of action, are neurotoxic, necrotic, and tumor promoting in mice. They have caused numerous human poisonings via the consumption of contaminated shellfish, and their surveillance and quantitative detection is critical to minimize further human exposures. The structures of the azaspiracids are complex and only partially defined. They are amino acids of enormous proportion, having 40 contiguous carbons in their backbone and containing an unprecedented array of structural features. These include THF-fused trioxadispiroketal moiety and a polycyclic spiroaminal terminus. The specific aims of this proposal are to develop efficient syntheses of both enantiomers of the C26-C40 spiroaminal-containing domain, develop enantioselective syntheses of the the trioxadispiroketal-containing C1-C20 domain, develop standards and haptens for the sensitive and quantitative environmental monitoring of the azaspiracids, completely define the stereochemistry of azaspiracid-1, and develop an enantioselective total laboratory synthesis of azaspiracid-1. This work will continue to contribute to understanding of the structure, occurrence, toxicology, and chemical and biological reactivity of the azaspiracids. It will provide continued impetus for fundamental developments in organic synthesis, including novel strategies and tactics for the total synthesis of complex molecular architecture. A novel immunostereochemical study is proposed to aid in the complete structural definition of the azaspiracids. This approach fuses synthetic organic, natural products, and immunochemistry to support structural elucidation and the development of an ELISA system for the universal detection of all of the azaspiracids that are currently known.

描述（由申请人提供）：本拨款申请的目的是继续并扩大针对氮杂螺酸天然产物的全面表征、全合成和环境检测的研究。氮杂螺旋酸是一种海洋毒素，在供人类食用的养殖和收集的贝类中积累。氮杂螺酸可能是由具有广泛地理分布的甲藻 Protoperidinium crassipes 产生的。这些毒素具有独特的作用方式，对小鼠具有神经毒性、坏死性和促肿瘤作用。它们通过食用受污染的贝类而导致大量人类中毒，对其进行监测和定量检测对于最大限度地减少人类进一步接触至关重要。氮杂螺酸的结构很复杂并且仅部分确定。它们是比例巨大的氨基酸，主链中有 40 个连续的碳，并且包含前所未有的一系列结构特征。这些包括 THF 稠合的三氧二螺缩酮部分和多环螺胺末端。该提案的具体目标是开发含 C26-C40 螺胺醛结构域的两种对映体的有效合成，开发含三氧二螺缩酮的 C1-C20 结构域的对映选择性合成，开发用于敏感和定量环境监测的标准和半抗原azaspiracids，完全定义了azaspiracid-1的立体化学，并开发了azaspiracid-1的对映选择性全实验室合成。这项工作将继续有助于理解氮杂螺酸的结构、发生、毒理学以及化学和生物反应性。它将持续推动有机合成的基础发展，包括复杂分子结构全合成的新策略和策略。提出了一项新的免疫立体化学研究，以帮助完成氮杂螺酸的结构定义。这种方法融合了合成有机、天然产物和免疫化学，以支持结构阐明和 ELISA 系统的开发，以普遍检测目前已知的所有氮杂螺酸。