Total Synthesis of Oxo-Bridged Taxoids and Evaluation of their Anticancer Properties

项目总结/摘要 癌症是一种严重的健康危机，每年有数百万新的诊断。作为回应，研究人员经常转向 大自然在寻找分子，往往结构复杂，这可以作为可行的抗癌疗法。 一种这样的分子是紫杉醇（紫杉醇），一种属于紫杉醇家族的高度氧化的二萜类化合物。 天然产品。虽然紫杉醇已被证明是一种有效的化疗剂，但其高亲脂性和低毒性是一种有效的化疗剂。 耐药癌细胞的出现带来了许多治疗挑战，并迫切需要研究 结构上不同的紫杉烷类，如taxagifine。与紫杉醇一样，紫杉醇及其同系物（统称为 作为氧桥紫杉烷）具有显著的抗癌特性，但仍然相对未被开发， 这些化合物在合成和生物学上都有很大的优势，特别是在克服耐药性的潜力方面。 鉴于迫切需要解决与紫杉醇相关的治疗挑战，该提案旨在建立 第一种从原料化学品（S）-香芹酮合成氧桥紫杉烷的方法，这将使 对这些分子进行全面的生物学评价，并深入了解它们作为 紫杉醇的替代疗法。这些研究将通过三个具体目标来完成： 完成了taxagifine的全合成，2）合成另外的氧桥紫杉烷，包括类似物， （3）通过合作评估其生物活性。 taxagifine和其他氧桥紫杉烷的全合成将通过进行位点- 关键中间体的选择性后期官能化，其由两个（S）- 香芹酮衍生的偶联配偶体使用C-C键裂解/交叉偶联策略。的研制 有效和稳健的taxagifine合成路线将为紫杉烷类似物的合成奠定基础， 最终，本文提出的合成工作不仅能够制备天然和非天然紫杉烷， 而且也将为其它高度氧化的萜类化合物的合成提供新的策略。总体而言，合成 氧桥紫杉烷的生物学研究将为这些未充分探索的 分子，为下一代潜在的抗癌疗法打开了大门。

PROJECT SUMMARY/ABSTRACT Cancer is a major health crisis with millions of new diagnoses each year. In response, researchers often turn to nature in search of molecules, often structurally sophisticated, which can serve as viable anticancer therapeutics. One such molecule is paclitaxel (TaxolÒ), a highly oxygenated diterpenoid belonging to the taxoid family of natural products. While paclitaxel has proven to be an effective chemotherapeutic, its high lipophilicity and the emergence of resistant cancer cells pose many therapeutic challenges and create an urgency to study structurally distinct taxoids, such as taxagifine. Like paclitaxel, taxagifine and its congeners (collectively known as the oxo-bridged taxoids) possess significant anticancer properties but remain relatively underexplored both synthetically and biologically, especially with regard to their potential to overcome drug resistance. Given the urgency to address therapeutic challenges associated with paclitaxel, this proposal aims to establish the first synthetic approach to oxo-bridged taxoids from the feedstock chemical (S)-carvone, which will enable comprehensive biological evaluation of these molecules and provide insight into their potential to serve as alternative treatments to paclitaxel. These studies will be accomplished through three specific aims: 1) completing the total synthesis of taxagifine, 2) synthesizing additional oxo-bridged taxoids, including analogues, and 3) assessing their biological activity through collaborative efforts. The total synthesis of taxagifine and other oxo-bridged taxoids will be pursued through the execution of site- selective, late-stage functionalizations of a key intermediate, which is prepared convergently from two (S)- carvone-derived coupling partners using a C–C bond cleavage/cross-coupling strategy. Development of an efficient and robust synthetic route to taxagifine will set the stage for the synthesis of taxoid analogues, and ultimately, synthetic work proposed herein will enable not only the preparation of natural and unnatural taxoids, but will offer new strategies for the synthesis of other highly oxygenated terpenoids as well. Overall, synthetic and biological investigation of the oxo-bridged taxoids will provide significant insight into these underexplored molecules, opening the door to the next generation of potential anticancer therapeutics.