Cyclopentannelation in Total Synthesis

描述（由申请人提供）：天然产品作为新药先导来源的效用得到了重新认识。合成在大小和复杂性方面的实际限制常常使有希望的天然产物不能被考虑作为药物。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来源于链霉菌属，是一种选择性白细胞介素6（IL-6）抑制剂。在肿瘤细胞中，IL-6刺激细胞增殖并且还与恶病质相关。选择性抑制IL-6可以为癌症提供新的治疗方法。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材料。Merrilactone A，分离自八角茴香，具有有效的神经营养活性（在胎鼠皮层神经元中为0.1 μ mol/L），并且作为神经退行性疾病如帕金森氏症和阿尔茨海默氏症的治疗剂是令人感兴趣的，因为它仅占果皮干重的0.004%，供应问题只能通过合成来解决。Terpestacin是一种真菌代谢产物，可抑制与HIV感染相关的合胞体（大的多核细胞）的形成（ID 50 0.46 ug/mL），因此在治疗AIDS方面具有很大的意义。抗血管生成活性与terpestacin有关，使其成为抗癌先导药物。所有这三种天然产物在结构上都是独特的，因此它们可能通过新的机制发挥各自的活性。 在这一领域的进展发生在两个层次，通过发现改进的方法和使用它们来制定新的战略，为全合成。在全面综合的同时，我将继续改进和扩大方法的范围。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。

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.