Synthesis of Complex Terpenes From Simple Precursors

母公司奖励汇总（R 01 GM 116952） 从Taxol®到青蒿琥酯再到瑞他帕林，复杂的萜烯类化合物对植物的生长和发育都产生了深远的影响。 治疗和了解人类疾病。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的最佳起点， 化学生物学研究，与许多小分子药物发现计划不同， 很容易混合和匹配结构片段。该研究计划旨在发现和 开发简单，模块化的合成途径，以获得复杂的，药用相关的天然萜类化合物 并确定其蛋白质靶点。这项提议的核心是希望大大简化 通过使用简单异戊二烯衍生单元和手性池材料与新的 方法和综合战略。该计划选择的目标代表了两个国家- 复杂分子合成以及潜在的下一代治疗方法的最新挑战 非常适合深入的化学生物学研究。由于其强大的细胞毒性特性， 苦木素类三萜几十年来一直是有吸引力的目标， 分子很长，许多成员还没有屈服于合成。利用新型的交叉- 耦合方法，我们已经制定了一个蓝图，方便访问这个家庭。骑自行车，海洋 西松烷类化合物代表了一类结构迷人的萜烯目标， 了解细胞毒活性。尽管许多实验室做了大量工作，但许多旗舰实验室 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- 的方法和各种自由基环化策略，我们相信许多这样的目标可以访问 利用尖端的蛋白质组学技术， 技术.总的来说，这个项目旨在利用合成化学的进步来构建罕见的， 具有高效率的生物活性萜类，允许探究其抗癌性质 蛋白质靶点在这项工作的过程中，学生将提供严格和 在合成化学方面的智力刺激训练。

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.