Synthesis of Marine Neurotoxins

描述(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关于海洋神经毒素毛托毒素结构的立体化学争议，全合成缺少侧链的毛霉毒素的截短版本，毛霉毒素的全合成，以及开发用于分析和生物学研究的合适的毛霉毒素样结构的抗体。这一化学合成计划不断升级的挑战将通过一种融合战略来应对，该战略涉及在本实验室和其他实验室开发的方法。在合成计划中的特点是基于烯烃歧化的碳-碳键形成反应，新的不对称工艺和环闭合。将对合成截短的毛霉毒素类分子进行生物活性测试，开发的抗体将用于毛霉毒素的检测和测量以及进一步的生物学研究。拟议的计划还有望产生重要的新合成战略和技术，在药物发现和开发过程中得到更广泛的应用，特别是合成适合于制药研究的小的、对映体纯的构建块。总体而言，拟议工作的意义在于改善和确保环境健康、检测和测量海洋神经毒素和清洁海洋，以及防止因食用海鲜而引起的人类中毒。该项目还有望显著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