The Total Synthesis of Pleurotin

侧耳素的全合成

• 批准号: 9467893
• 负责人: Andrew Musacchio
• 金额: $ 5.67万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-11 至 2019-09-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9467893
• 关键词: Antibiotics; Binding; Biological; Biological Assay; Biological Testing; Biology; Breast Cancer Cell; Cancer Biology; Carbon; Chemical Structure; Collaborations; Colon Carcinoma; Cyclization; Cyclohexanes; Development; HT29 Cells; Hand; Human; Hypoxia; Investigation; Isotopes; MCF7 cell; Malignant Epithelial Cell; Malignant Neoplasms; Natural Products; Oxidation-Reduction; Pathway interactions; Pleurotus; Polyenes; Prevalence; Property; Proteolysis; Quinones; Reaction; Reporting; Research; Research Proposals; Route; Source; Structure; System; Testing; Vascular Endothelial Growth Factors; activity-based protein profiling; analog; angiogenesis; antitumor agent; base; cancer cell; cancer therapy; cancer type; chemical synthesis; decalin; driving force; effective therapy; fight against; hypoxia inducible factor 1; insight; migration; novel; novel therapeutics; pleuromutilin; pleurotin; scaffold; small molecule inhibitor; thioredoxin reductase; transcription factor; tumor; tumor progression

Project Summary Development of novel cancer therapies that selectively target cancer cells through mechanisms unique to cancer biology remains an important challenge in the fight against cancer. This task is made even more difficult due to the vast number of different cancer types, each with its own unique biology. However, certain biological pathways are common to many different varieties of cancer, providing an opportunity for the development of a general therapy for cancer treatment. One such pathway is hypoxia-induced angiogenesis, which has been suggested to be the driving force for around 70% of human cancer types. Development of a selective small molecule inhibitor of this pathway would represent a major step forward in cancer treatment, enabling effective treatment of a diverse range of different cancer types. Pleurotin is an antibiotic fungal metabolite first isolated in 1947 and found to possess powerful anticancer properties. Despite being known for 70 years, the exact mechanism of pleurotin’s anticancer effect remains unknown, although it is proposed to function through inhibition of hypoxia-induced angiogenesis. This proposed biological mode of action has made pleurotin a high value target for both biological studies and chemical synthesis. This research proposal describes a short chemical synthesis of pleurotin through rapid formation of the challenging trans- hydrindane motif found in the natural product. Due to the prevalence of trans-hydrindane structures in a variety of natural products, this strategy should enable the synthesis of a wealth of molecules with varied biological activity. The research plan also outlines the synthesis and biological testing of novel pleurotin analogs. The combination of analog synthesis and biological assays will allow for the elucidation of the mechanism of pleurotin’s anticancer properties, potentially leading to new general treatments for cancer. Overall, the proposed research will allow for the rapid synthesis of an important natural product and provide valuable information on the mechanism of inhibition of a prevalent driving force in human cancer.

项目概要 开发选择性靶向癌细胞的新型癌症疗法 癌症生物学独特的机制仍然是抗击癌症的重要挑战。 由于存在大量不同的癌症类型，每种癌症类型都有其不同的特点，因此这项任务变得更加困难。 然而，许多不同品种的某些生物途径是共同的。 癌症，为开发癌症治疗的一般疗法提供了机会。 这种途径是缺氧诱导的血管生成，这被认为是驱动力 开发一种选择性小分子抑制剂，用于治疗约 70% 的人类癌症类型。 途径将代表癌症治疗向前迈出的重要一步，能够有效治疗 多种不同的癌症类型。 侧耳素是一种抗生素真菌代谢物，于 1947 年首次分离出来，并被发现具有 尽管其强大的抗癌特性已为人所知 70 年，但其确切机制仍不清楚。 侧耳素的抗癌作用仍不清楚，尽管有人认为它是通过抑制发挥作用 这种所提出的生物学作用模式使侧耳素成为一种低氧诱导的血管生成。 该研究提案对于生物学研究和化学合成都是高价值的目标。 描述了通过快速形成具有挑战性的反式-侧耳素的简短化学合成 由于反式茚烷结构的普遍存在，因此在天然产物中发现了茚烷基序。 在各种天然产物中，这种策略应该能够合成丰富的分子 该研究计划还概述了具有不同生物活性的合成和生物测试。 新型侧耳素类似物的类似物合成和生物测定的结合将允许 阐明侧耳素抗癌特性的机制，可能导致新的通用方法 总体而言，拟议的研究将允许快速合成一种药物。 重要的天然产物，并提供有关抑制机制的有价值的信息 人类癌症的普遍驱动力。