Synthesis of Marine Neurotoxins

描述（由申请人提供）：本提案描述了一项研究计划，旨在通过化学合成解决海洋神经毒素美托毒素结构的立体化学争议，缺乏侧链的美托毒素截短版本的全合成，美托毒素的全合成，以及开发用于分析和生物学研究的合适的美托毒素样结构的抗体。这个化学合成计划的不断升级的挑战将通过一个融合的战略来满足，包括在这个实验室和其他实验室开发的方法。在合成计划中的特色是基于烯烃复分解的碳-碳键形成反应，新颖的不对称方法和环闭合。合成的截短的maitotoxin样分子将被测试的生物活性和开发的抗体将成为可用于检测和测量maitotoxin和进一步的生物学研究。该计划还有望产生重要的新合成策略和技术，用于药物发现和开发过程中更广泛的应用，特别是用于合成适合药物研究的小对映体纯构建单元。总的来说，拟议工作的重要性在于改善和确保环境健康，检测和测量海洋神经毒素，清洁海洋，以及防止人类因食用海产品而中毒。该项目还有望大大提高我们在化学合成，化学生物学和医学方面的知识

DESCRIPTION (provided by applicant): This proposal describes a research program directed towards resolving a stereochemical controversy over the structure of the marine neurotoxin maitotoxin through chemical synthesis, the total synthesis of a truncated version of maitotoxin lacking the side chains, the total synthesis of maitotoxin, and the development of antibodies of suitable maitotoxin-like structures for analytical and biological studies. The escalating challenges of this chemical synthesis program will be met by a convergent strategy involving methods developed in this and other laboratories. Featured in the synthetic plans are olefin metathesis- based carbon-carbon bond forming reactions, novel asymmetric processes and ring closures. Synthetic truncated maitotoxin-like molecules will be tested for biological activity and developed antibodies will become available for the detection and measurement of maitotoxin and further biological studies. The proposed program is also expected to yield significant new synthetic strategies and technologies for broader applications in the drug discovery and development process, particularly for the synthesis of small enantiomerically pure building blocks suitable for pharmaceutical research. Overall the significance of the proposed work lies in improving and assuring environmental health, detecting and measuring marine neurotoxins and cleaning the oceans, as well as to prevent human poisoning through seafood consumption. The project is also expected to significantly advance our knowledge in chemical synthesis, chemical biology, and medicine