Synthesis of Complex Terpenes From Simple Precursors: Renewal

从简单前体合成复杂萜烯：更新

• 批准号: 10366008
• 负责人: Thomas John Maimone
• 金额: $ 28.51万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366008
• 关键词: Amines; Architecture; Biological; Biological Assay; Biology; Breathing; Carbon; Chemicals; Chemistry; Complex; Copper; Coupling; Cyclization; Development; Family; Family member; Glues; Goals; Human; Isoprene; Laboratories; Malignant Neoplasms; Medicine; Methodology; Methods; Molecular; Natural Products; Nature; Organic Chemistry; Paclitaxel; Pathway interactions; Periodicity; Pharmaceutical Chemistry; Process; Property; Protein Inhibition; Proteins; Proteomics; Reaction; Reagent; Research; Route; Structure; Students; Synthesis Chemistry; Techniques; Terpenes; Therapeutic Agents; Training; Triterpenes; Work; anti-cancer; anticancer activity; antiproliferative agents; artesunate; base; bielschowskysin; career; cell type; chemical synthesis; cost; cyclopentenone; cytotoxic; design; drug discovery; exhaustion; fascinate; graduate student; human disease; insight; member; neoplastic cell; novel; novel therapeutics; programs; small molecule; success; wasting

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.

项目摘要 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， 复杂的萜类结构对于详尽的药物和化学生物学来说不是最佳的起点。 与许多小分子药物发现计划不同，很难轻松地混合和匹配结构 片段拟议的研究计划旨在发现和开发简单的模块化合成途径 获取复杂的、与医学相关的萜类天然产物，并确定其蛋白质靶点。在 该建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 以及与新方法和合成策略相一致的手性池材料。选择的目标 该计划代表了复杂分子合成的最新挑战以及潜在的下一个- 是深入化学生物学研究的理想选择。由于它们具有强的细胞毒性， 几十年来，复杂的苦木素类三萜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。使用新型交叉耦合 我们已经制定了一个蓝图，方便进入这个家庭。环化海生西松烷 代表了一类结构迷人的萜烯靶点，具有有趣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，但许多旗舰成员都避开了 化学合成几十年。使用基于手性池构建模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有效地访问，允许其蛋白质目标 用最先进的蛋白质组学技术进行审问总体而言，该计划旨在利用先进的 合成化学，以高效率构建稀有的生物活性萜烯， 它们的抗癌特性和蛋白质靶点。在这项工作的过程中，学生将提供严格的 和智力刺激的合成化学训练。