Cyclopentannelation in Total Synthesis

全合成中的环戊烷化

• 批准号: 7391779
• 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/7391779
• 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; guanacastepene A; improved; inhibitor/antagonist; interest; madindoline B; merrilactone A; nakadomarin A; neoplastic cell; novel; size; 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）：人们重新认识到天然产物作为新药物先导物来源的实用性，在尺寸和复杂性方面的实际限制常常使有前景的天然产物无法作为药物进行考虑。 Madindoline B 是一种源自链霉菌的天然产物，它是一种选择性白细胞介素 6 (IL-6) 抑制剂，可在肿瘤细胞中刺激细胞增殖，并与细胞增殖相关。选择性抑制 IL-6 可以为癌症提供一种新的治疗方法，而 Madindolines 的原始来源不再产生这些化合物，因此只能通过合成来获得具有有效神经营养活性的 Merrilactone A。 0.1 mol/L（在胎儿大鼠皮质神经元中），并且作为神经退行性疾病（如帕金森病和阿尔茨海默病）的治疗方法很有意义，因为它仅占神经退行性疾病的 0.004% Terpestacin 是一种真菌代谢物，可抑制与 HIV 感染相关的合胞体（ID50 0.46 ug/mL）的形成，因此供应问题非常重要。 Terpestacin 的抗血管生成活性与治疗艾滋病有关，这使得它作为抗癌先导药物受到关注，因此它们可能具有独特的结构。通过新颖的机制发挥各自的作用。 该领域的进展发生在两个层面，即发现改进的方法并利用它们开发全合成的新策略，在全合成的同时，我将继续改进和扩大每种天然产物总方法的范围。上面提到的合成在我的研究小组开发的关键步骤中使用了环化反应。