Synthesis of Complex Terpenes From Simple Precursors: Renewal

项目总结 从紫杉醇®到青蒿琥酯再到瑞帕蛋白，复杂的萜类化合物对 对人类疾病的治疗和理解。然而，尽管它们具有巨大的医学意义，但大多数 复杂的萜类结构不是穷尽药物和化学生物学的最佳起点 研究，与许多小分子药物发现程序不同，很难容易地混合和匹配结构 碎片。拟议的研究计划寻求发现和开发简单、模块化的合成途径 获取复杂的、药用相关的萜类天然产物，并确定它们的蛋白质靶标。在 这一提议的核心是希望通过使用简单的异戊二烯衍生单元来大大简化萜烯的合成 和手性池材料与新的方法和合成策略相协调。为其选择的目标 这个项目既代表了复杂分子合成的最新挑战，也代表了潜在的下一步- 世代疗法是深入化学生物学研究的理想选择。由于它们具有强大的细胞毒性， 几十年来，复杂的类三萜化合物一直是有吸引力的目标，但合成路线是这样的 分子很长，许多成员还没有完全屈服于合成。使用新型交叉耦合 方法论我们已经制定了一张方便地进入这个家庭的蓝图。环化的海洋西门冬青 代表了一类结构上令人着迷的萜类目标，具有耐人寻味但知之甚少的细胞毒性 活动。尽管许多实验室做了大量工作，但许多旗舰成员都躲过了实践者 化学合成已经有几十年了。使用基于手性池构建块的方法和各种自由基 环化策略，我们相信许多这样的靶点可以有效地进入它们的蛋白质靶点 使用尖端的蛋白质组学技术进行讯问。总体而言，该计划寻求使用先进的 合成化学以高效的方式构建稀有的生物活性萜类化合物 它们的抗癌特性和蛋白质靶标。在这项工作的过程中，将为学生提供严格的 以及在合成化学方面的智力刺激训练。

PROJECT SUMMARY From Taxol® to artesunate to retapamulin, complex terpenes have had a profound impact on both the treatment and understanding of human disease. Despite their enormous medicinal relevance, however, most complex terpene architectures are not optimal starting points for exhaustive medicinal and chemical biological studies, and unlike many small molecule drug discovery programs, it is difficult to easily mix- and-match structural fragments. The proposed research program seeks to discover and develop simple, modular synthetic pathways to access complex, medicinally relevant terpenoid natural products and determine their protein targets. At the core of this proposal is the desire to greatly simplify terpene synthesis by using simple isoprene-derived units and chiral pool materials in concert with novel methodologies and synthetic strategies. The targets chosen for this program represent both state-of-the-art challenges for complex molecule synthesis as well as potential next- generation therapeutics ideal for in-depth chemical biological studies. Owing to their potent cytotoxic properties, complex quassinoid triterpenes have remained attractive targets for decades, yet synthetic routes to these molecules are lengthy and many members have yet to succumb to syntheses at all. Using novel cross-coupling methodology we have developed a blueprint for facile access to this family. Cyclized, marine cembranoids represent a structurally fascinating class of terpene targets with intriguing, yet poorly understood, cytotoxic activities. Despite much work from numerous laboratories, many flagship members have eluded practitioners of chemical synthesis for decades. Using a chiral pool building block-based approach and various radical cyclization strategies, we believe many such targets can be accesses efficiently allowing for their protein targets to be interrogated using cutting-edge proteomics techniques. Overall this program seeks to use advances in synthetic chemistry to construct rare, biologically active terpenes with high efficiency allowing interrogation of their anti-cancer properties and protein targets. In the process of this work, students will be provided with rigorous and intellectually stimulating training in synthetic chemistry.