Cyclopentannelation in Total Synthesis

全合成中的环戊烷化

• 批准号: 7596181
• 负责人: Marcus Antonius Tius
• 金额: $ 21.19万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7596181
• 关键词: Acquired Immunodeficiency Syndrome; Address; Aging; Alzheimer' s Disease; Area; Biological Assay; Biological Factors; Cachexia; Cell Proliferation; Cells; Cyclization; Cytotoxin; Evaluation; Giant Cells; Goals; HIV Infections; Illicium; Interleukin-6; Lead; Malignant Neoplasms; Metabolic syndrome; Methodology; Motivation; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pharmaceutical Preparations; Preparation; Public Health; Rattus; Reaction; Research; Research Proposals; Secure; Source; Streptomyces; Structure; Weight; Work; antimicrobial; cancer therapy; fetal; flexibility; guanacastepene A; improved; inhibitor/antagonist; interest; madindoline B; merrilactone A; nakadomarin A; neoplastic cell; novel; terpestacin

DESCRIPTION (provided by applicant): There is a renewed realization of the utility of natural products as sources for new drug leads. The practical limits on synthesis in terms of size and complexity often preclude promising natural products from consideration as drugs. The research that I propose addresses this problem in the context of three natural products. Madindoline B is derived from Streptomyces and is a selective interleukin 6 (IL-6) inhibitor. In tumor cells IL-6 stimulates cell proliferation and is also associated with cachexia. Selective inhibition of IL-6 could offer a new treatment for cancer. The original source for the madindolines no longer produces these compounds, therefore material can only be secured through synthesis. Merrilactone A, isolated from Illicium merrillianum, has potent neurotrophic activity (0.1 ¿mol/L in fetal rat cortical neurons), and is of interest as a treatment for neurodegenerative diseases such as Parkinson's and Alzheimer's, Since it constitutes only 0.004% of the dry weight of the pericarps, the supply problem can only be solved through synthesis. Terpestacin is a fungal metabolite that inhibits the formation of syncytia, large multinucleated cells that are associated with HIV infection (ID50 0.46 ug/mL) and is therefore of great interest in the treatment of AIDS. Anti angiogenic activity has been associated with terpestacin, making it interesting as an anticancer lead. All three natural products are structurally unique, therefore they may exert their respective activities through novel mechanisms. Progress in this area occurs at two levels, by discovering improved methodologies and by using them to develop new strategies for total synthesis. In parallel with the total syntheses I will continue to improve and expand the scope of the methodology. Each of the natural product total syntheses referred to above uses a cyclization reaction in the key step that my research group developed.

描述(由申请人提供)：重新认识到天然产品作为新药先导来源的效用。合成在大小和复杂性方面的实际限制往往排除了有希望的天然产物作为药物的考虑。我提出的研究在三种天然产品的背景下解决了这个问题。Madindoline B来源于链霉菌，是一种选择性的白介素6(IL-6)抑制剂。在肿瘤细胞中，IL-6刺激细胞增殖，也与恶病质有关。选择性抑制IL-6可能为癌症提供一种新的治疗方法。这种化合物的原始来源不再生产这些化合物，因此只能通过合成来确保材料的安全。延胡索内酯A是从八角中分离得到的，具有很强的神经营养活性(胎鼠皮质神经元中的0.1mol/L)，作为治疗帕金森氏症和阿尔茨海默氏症等神经退行性疾病的药物，由于它只占果皮干重的0.004%，供应问题只能通过合成来解决。Terpestain是一种真菌代谢物，可抑制与HIV感染有关的合胞体、大的多核细胞的形成(ID50为0.46微克/毫升)，因此在艾滋病的治疗中具有重要意义。抗血管生成活性一直与特拉帕斯汀有关，这使其成为一种有趣的抗癌先导。这三种天然产物在结构上都是独一无二的，因此它们可以通过新的机制发挥各自的活性。 这一领域的进展发生在两个层面上，通过发现改进的方法和利用它们制定全面综合的新战略。在全面综合的同时，我将继续改进和扩大方法学的范围。以上提到的每一种天然产物全合成都在我的研究小组开发的关键步骤中使用了环化反应。