Total Synthesis of the Marine Natural Product Leiodelide A

海洋天然产物Leiodelide A的全合成

• 批准号: 7860672
• 负责人: Stephen Shawn Gonzales
• 金额: $ 3.93万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7860672
• 关键词: Anions; Area; Biological; Biological Factors; Biological Testing; Cell Line; Chemicals; Chemistry; Colon Carcinoma; Complex; DNA Sequence Rearrangement; Development; Disease; Drug Kinetics; Exhibits; Gelsemium; Goals; Harvest; Human; Human Development; Inhibitory Concentration 50; Laboratories; Life; Macrolides; Malignant Epithelial Cell; Malignant Neoplasms; Marines; Methodology; Methods; Mission; Nature; Palau; Performance; Pharmaceutical Preparations; Porifera; Property; Protein phosphatase; Public Health; Research; Route; Sea; Squamous cell carcinoma; Structure; Techniques; Testing; analog; chemical synthesis; discodermolide; improved; inhibitor/antagonist; interest; marine natural product; novel; spirastrellolide A

DESCRIPTION (provided by applicant): Leiodelide A is a naturally occurring compound that possesses biological activity against cancer. This natural product, which was obtained from the rare deep sea sponge leiodermatium off the coast of Palau, exhibits impressive activity against the human colon carcinoma cell line HCT-116, with IC50 values of 1.4 ¿g/mL (2.5 ¿M) and 3.8 ¿g/mL (5.6¿M), for leiodolides A and B respectively (J. Org. Chem. 2006, 71, 7245-7251). The depth at which the sponge lives makes harvesting it a difficult, expensive, and dangerous proposition. Therefore, the low natural supply of this compound, combined with its interesting activity and intriguing structure, make it an attractive target for total synthesis. This compound presents opportunities to exploit techniques familiar to the Smith laboratory and to develop new methods, while increasing the supply of material for further testing towards development for human therapy. A synthetic route to leiodelide A has been developed which exploits a Suzuki-Miyaura cross-coupling as a key step, and which makes use of the pool of chiral material as well as catalytic, asymmetric techniques to construct this complex molecule. The synthesis is 18 steps (longest linear sequence) from simple starting materials. This total synthesis effort may also point the way to analogs which could be superior to the natural product itself. Nature provides us with many complex natural products that have interesting medicinal properties. Unfortunately, the amounts of these materials that is isolated is usually quite low, making their development into useful medicinal agents very difficult. The total chemical synthesis of these compounds is therefore an important and crucial part of expanding the lexicon of drugs that are available to us for the treatment of disease. The goal of this project will be to achieve the total synthesis of a naturally occurring compound that posesses biological activity against against cancer, namely, leiodelide A. In doing so, the project will bolster the NIH's mission of sponsoring research that can be applied to expanding the nation's ability to protect and improve public health.

说明(申请人提供)：莱奥地奈德A是一种天然存在的化合物，具有抗癌生物活性。这种天然产物是从帕劳近海罕见的深海海绵Leiodermatum中获得的，对人结肠癌细胞株HCT-116具有令人印象深刻的活性，其IC50值分别为1.4g/mL(2.5M)和3.8g/mL(5.6M)(J.Org)。化学。2006、71、7245-7251)。海绵生活的深度使收获它变得困难、昂贵和危险。因此，该化合物的低天然供应量，再加上其有趣的活性和有趣的结构，使其成为一个有吸引力的全合成目标。这种化合物提供了利用史密斯实验室熟悉的技术和开发新方法的机会，同时增加了材料的供应，以进一步测试人类疗法的开发。以Suzuki-Miyaura交叉偶联为关键步骤，利用手性材料和催化、不对称技术构建了一条合成来碘甲素A的合成路线。从简单的起始原料合成为18步(最长的线性序列)。这种完全的合成努力也可能为开发出比天然产品本身更好的类似物指明了方向。 大自然为我们提供了许多具有有趣药用价值的复杂天然产品。 不幸的是，这些被分离出来的物质的数量通常很少，这使得它们很难开发成有用的药剂。因此，这些化合物的总化学合成是扩大我们可用于治疗疾病的药物词库的重要和关键部分。该项目的目标将是实现一种具有抗癌生物活性的天然化合物的全合成，即Leiodelide A。通过这样做，该项目将支持NIH的使命，即资助可应用于扩大国家保护和改善公共健康能力的研究。