Synthesis of Bioactive Alkaloids and Peptides

描述（由申请人提供）：化学合成提供了生产化疗药物的能力，化学反应是从事药物发现过程的药物化学家不可替代的工具。化学反应方法的进步缩短了作为潜在候选药物的化学实体的概念与其合成用于随后的生物学评价之间的间隔。因此，有机合成是一门重要的学科，继续对医学和生物学领域产生重要影响。这项正在进行的拟议研究的目标是为合成具有临床重要生物活性的复杂天然物质做出创造性贡献。用于合成的靶标包括manzamine A和ircinal A、nakadomarin A、螺原罗辛三明、himmandine和cyclomarin A。Manzamine A是其家族中第一个从冲绳海岸发现的海绵中分离出来的成员。曼扎胺，包括Nakadomarin，代表了一个家庭的海洋天然产物，表现出强大的抗肿瘤，抗疟疾，抗结核病活性。此外，manzamine A选择性地抑制与阿尔茨海默病进展有关的两种主要激酶。与许多海洋天然产品一样，缺乏用于详细生物筛选的材料是开发合成这一重要天然产品家族各个成员的有效途径的动机。Himalodine是Galblulimima生物碱家族中最复杂的成员之一。历史上，巴布亚新几内亚和澳大利亚的土著部落曾将Galblimima belgraveana的树皮提取物用于药用目的。对有机化学家来说，希姆莱定和螺原罗辛三明的吸引力在于它们特殊的结构复杂性。这些目标是通过全合成解决的最复杂的生物碱之一。在大多数情况下，所示靶标的拟议合成遵循单个天然产物的推测生物合成。多步反应级联已被设计到每个合成计划。公共卫生相关性：化学合成使生产化学药剂成为可能，化学反应是药物化学家从事药物发现的关键工具。反应方法学的进步缩短了候选药物概念和其生物学评价合成之间的间隔。因此，有机合成是一门重要的学科，继续对医学和生物学领域产生关键影响。这项资助将集中在生物活性生物碱和肽的合成。

DESCRIPTION (provided by applicant): Chemical synthesis provides the capacity to produce chemotherapeutic agents, and chemical reactions are the irreplaceable tools of the medicinal chemist engaged in the drug discovery process. Advances in chemical reaction methods reduce the interval between the conception of the chemical entity as a potential drug candidate and its synthesis for subsequent biological evaluation. As a consequence, organic synthesis is a critical discipline that continues to have an important impact on the fields of both medicine and biology. The objectives of this ongoing proposed research are to make creative contributions to the synthesis of complex naturally occuring substances possessing clinically significant biological activity. The targets for synthesis include manzamine A & ircinal A, nakadomarin A, spiro-prorocentrimine, himandridine, and cyclomarin A. Manzamine A was the first member in its family to be isolated from marine sponges found off the coast of Okinawa. The manzamines, including nakadomarin, represent a family of marine natural products that exhibit potent antitumor, antimalarial, and antituberculosis activity. Additionally, manzamine A selectively inhibits two main kinases implicated in the progression of Alzheimer's disease. As with many marine natural products, a lack of material for detailed biological screening is the motivation for the development of efficient routes to the synthesis of the individual members of this important family of natural products. Himandridine is one of the most complex members of the Galbulimima family of alkaloids. Historically, the native tribes of Papua New Guinea and Australia have used extracts of the bark of Galbulimima belgraveana for medicinal purposes. The attraction of both Himandridine and spiro-prorocentrimine to the organic chemist is their exceptional structural complexity. These targets are among the most complex alkaloids being addressed by total synthesis. The proposed syntheses of the indicated targets, in most instances, follow the speculated biosyntheses of the individual natural products. Multi-step reaction cascades have been designed into each of the synthesis plans. PUBLIC HEALTH RELEVANCE: Chemical synthesis enables the production chemotsherapeutic agents, and chemical reactions are the critical tools of the medicinal chemist engaged in drug discovery. Advances in reaction methodology reduce the interval between drug candidate conception and its synthesis for biological evaluation. Consequently, organic synthesis is a critical discipline that continues to have a pivotal impact on the fields of both medicine and biology. This grant will focus on the synthesis of bioactive alkaloids and peptides.