The Total Synthesis of Pleurotin

项目摘要 通过以下途径选择性靶向癌细胞的新型癌症疗法的开发 癌症生物学特有的机制仍然是对抗癌症的重要挑战。 这项任务变得更加困难，因为有大量不同的癌症类型，每一种都有其独特的特点。 独特的生物学。然而，某些生物学途径对于许多不同种类的肿瘤是共同的。 癌症，为癌症治疗的一般疗法的发展提供了机会。一 这种途径是缺氧诱导的血管生成，这被认为是驱动力 大约70%的人类癌症类型。开发选择性小分子抑制剂， 途径将代表癌症治疗向前迈出的重要一步， 不同类型的癌症。 Pleurotin是一种抗生素真菌代谢物，1947年首次分离， 强大的抗癌特性。尽管人们已经知道了70年， pleurotin的抗癌作用仍然是未知的，尽管它被认为是通过抑制 缺氧诱导的血管新生这种生物学作用模式使pleurotin成为一种 生物学研究和化学合成高价值目标。本研究提案 描述了通过快速形成具有挑战性的反式- 在天然产物中发现的氢化茚基序。由于反式氢化茚结构的普遍存在， 在各种天然产物中，这种策略应该能够合成大量的分子 具有不同的生物活性。该研究计划还概述了合成和生物测试 新的侧耳素类似物。类似物合成和生物测定的组合将允许 阐明了pleurotin的抗癌特性的机制，可能导致新的一般性 癌症的治疗方法总的来说，拟议的研究将允许快速合成一种 重要的天然产物，并提供有价值的信息，抑制机制， 人类癌症的主要驱动力。

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.