Synthesis of Complex Terpenes From Simple Precursors

家长奖摘要(R01GM116952) 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药用价值， 大多数复杂的萜类结构不是穷尽药物和 化学生物学研究，与许多小分子药物发现计划不同，很难 很容易混合搭配结构片段。拟议的研究计划旨在发现和 开发简单、模块化的合成途径来获得复杂的、药用上相关的天然萜类化合物 并确定它们的蛋白质靶标。这项提议的核心是希望大大简化 用简单的异戊二烯衍生单元和手性池材料协同合成萜烯 方法论和综合战略。为该计划选择的目标代表了 复杂分子合成面临的最新挑战以及潜在的下一代疗法 非常适合深入的化学生物学研究。由于其强大的细胞毒特性，络合物 几十年来，四氢类三萜类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。使用新的交叉- 结合方法论，我们已经制定了一张方便地进入这个家庭的蓝图。骑自行车，海军陆战队 西膜类化合物代表了一类结构上令人着迷的萜类目标，虽然耐人寻味，但效果不佳。 明白，是细胞毒活动。尽管许多实验室做了大量工作，但许多旗舰产品 几十年来，成员们一直躲避着化学合成的从业者。使用手性池构建块- 基于方法和各种激进的环化策略，我们相信许多这样的目标可以进入 有效地允许使用尖端蛋白质组学询问他们的蛋白质靶标 技巧。总体而言，这个项目试图利用合成化学的进步来构建稀有的， 高效生物活性萜类化合物的抗癌性能研究 和蛋白质靶标。在这项工作的过程中，将为学生提供严谨和 在合成化学方面的智力激发训练。

Summary of Parent Award (R01GM116952) 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.