TOTAL SYNTHESIS OF AZASPIRACIDS

描述(由申请人提供)：本提案描述了一项旨在全合成阿司匹酸-L、-2、-3和-6及其片段的研究计划，用于生物和分析目的。这些海洋神经毒素是从贻贝中分离出来的，是人类海鲜中毒和大鼠肿瘤形成的病原体。这些极其稀缺的生物毒素只有极少量地被分离出来，还有待化学合成，以便在释放供人类食用之前，用于迫切需要的分析工作，在海鲜中检测和量化它们。这个小组已经取得了相当大的进展，我们独特地定位于完成所有四种氮阿司匹酸的高效全合成，开发针对它们的抗体，并研究它们的作用机制和全部生物学性质。后一项调查将与生物学专家合作进行，预计将特别导致开发(通过抗体生产)用于确定毒素的生物测定。拟议工作的意义主要在于改善和确保环境健康，检测和测量海洋生物毒素，清洁海洋，以及防止海鲜中毒对人类的健康造成短期(例如恶心、呕吐、严重腹泻和胃痉挛)和长期(例如肺、肝、脾和淋巴细胞损害以及癌症)的健康危害。该项目还有望促进我们在化学合成方面的知识，并对药物发现和开发过程产生有利影响。

DESCRIPTION (provided by applicant): This proposal describes a research program directed towards the total synthesis of azaspiracids-l, -2, -3, and -6, and fragments thereof, for biological and analytical purposes. Isolated from the mussel Mytilus edulis, these marine neurotoxins are the causative agents of seafood poisoning in humans and tumorogenesis in rats. These extremely scarce biotoxins have been isolated only in minute quantities and it remains for chemical synthesis to render them available for the acutely needed analytical work to detect and quantify them in seafood before releasing it for human consumption. Considerable progress has been made already by this group, uniquely positioning us to accomplish the efficient total synthesis of all four azaspiracids, develop antibodies against them, and investigate their mechanism of action and full spectrum of biological properties. The latter investigations will be carried out in collaboration with biology experts and are expected to result, in particular, in the development (through antibody production) of a bioassay for the determination of the toxins. The significance of the proposed work lies primarily in improving and assuring environmental health, detecting and measuring marine biotoxins, and cleaning the oceans, as well as to prevent seafood poisoning in humans that may include both short (e.g. nausea, vomiting, severe diarrhea and stomach cramps) and long term (e.g. lung, liver, spleen and lymphocyte damage as well as cancer) health hazards. The project is also expected to advance our knowledge in chemical synthesis and impact favorably the drug discovery and development process.