Synthesis of Bioactive Alkaloids and Peptides

描述(申请人提供)：化学合成提供了产生化疗药物的能力，化学反应是药物化学家从事药物发现过程中不可替代的工具。化学反应方法的进步缩短了将化学实体作为潜在候选药物的概念与其合成用于后续生物评价之间的间隔。因此，有机合成是一门关键学科，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意义的生物活性的复杂自然发生物质做出创造性贡献。被合成的目标包括曼唑胺A和淫羊藿苷A、纳卡多糖素A、螺环丙三胺、西芒地丁和环马豆素A。曼扎明A是从冲绳沿海发现的海绵中分离出来的第一个成员。曼扎明，包括那卡多糖素，代表了一类海洋天然产物，表现出强大的抗肿瘤、抗疟疾和抗结核病活性。此外，甘露糖胺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，缺乏详细的生物筛选材料是开发合成这一重要天然产品家族个别成员的有效途径的动力。喜满地碱是加布利玛生物碱家族中最复杂的成员之一。从历史上看，巴布亚新几内亚和澳大利亚的土著部落曾将银杏树皮的提取物用于医疗目的。喜满地丁和螺丙环丙三胺对有机化学家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，所指目标的拟议合成遵循推测的单个天然产物的生物合成。在每个合成计划中都设计了多步反应级联。与公共健康相关：化学合成使化学药物的生产成为可能，而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构思和合成之间的间隔，用于生物学评价。因此，有机合成是一门关键学科，它继续对医学和生物学领域产生关键影响。这笔赠款将集中在生物活性生物碱和多肽的合成上。

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.