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.

项目摘要 通过以下途径选择性靶向癌细胞的新型癌症治疗方法的开发 癌症生物学特有的机制仍然是抗癌斗争中的一个重要挑战。 由于有大量不同的癌症类型，每种癌症都有其各自的特点，这项任务变得更加困难 拥有独特的生物学特性。然而，某些生物途径在许多不同的品种中是共同的 癌症，为开发癌症治疗的一般疗法提供了机会。一 这种途径就是低氧诱导的血管生成，它被认为是驱动力 对于大约70%的人类癌症类型。选择性小分子抗氧化剂的研究进展 途径将代表着癌症治疗向前迈出的重要一步，使有效治疗 各种不同的癌症类型。 侧耳素是一种抗生素真菌代谢物，于1947年首次分离，并被发现具有 强大的抗癌性能。尽管人们已经知道70年了，但它的确切机制 尽管已提出通过抑制来发挥作用，但侧柏木素的抗癌作用尚不清楚 低氧诱导的血管生成。这种被提出的生物学作用模式使胸苷成为一种 生物研究和化学合成的高价值目标。这项研究建议 本文描述了一种通过快速合成具有挑战性的反式侧耳素的简短的化学合成方法。 在天然产品中发现的氢化吲哚基元。由于反式-氢吲哚结构的普遍存在 在各种天然产品中，这一策略应该能够合成丰富的分子。 具有各种各样的生物活性。研究计划还概述了合成和生物测试 新的胸苷类似物。模拟合成和生物检测的结合将允许 阐明柴胡素的抗癌作用机制，可能导致新的一般 癌症的治疗。总体而言，拟议的研究将允许快速合成一个 重要的天然产物，并提供了关于抑制一种 人类癌症的流行驱动力。