Synthesis of Complex Terpenes From Simple Precursors: Renewal

从简单前体合成复杂萜烯：更新

基本信息

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
项目类别：
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

项目摘要

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.

项目概要从紫杉醇®到青蒿琥酯再到瑞他莫林，复杂的萜烯对然而，尽管它们具有巨大的医学意义，但大多数都是对人类疾病的治疗和理解。复杂的萜烯结构并不是详尽的医学和化学生物研究的最佳起点研究，并且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、药用相关的萜类天然产物并确定其蛋白质靶点。该提案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合成和手性池材料与新颖的方法和合成策略相结合。该计划代表了复杂分子合成的最先进挑战以及潜在的下一步- 由于其有效的细胞毒性特性，新一代疗法是深入化学生物学研究的理想选择。几十年来，复杂的类木犀三萜类化合物一直是有吸引力的目标，但这些化合物的合成途径分子很长，许多成员尚未屈服于使用新颖的交叉偶联进行合成。我们已经开发了一个蓝图，可以轻松获取该家族的环化海洋西松烷内酯。代表了一类结构上令人着迷的萜烯靶标，具有有趣但知之甚少的细胞毒性尽管许多实验室做了很多工作，但许多旗舰成员仍回避了这些活动的实践者。使用基于手性池构建块的方法和各种自由基进行化学合成。环化策略，我们相信许多这样的目标可以被有效地访问，从而允许它们的蛋白质目标总体而言，该计划旨在利用尖端蛋白质组学技术的进步。合成化学以高效率构建稀有的、具有生物活性的萜烯，允许询问在这项工作的过程中，学生将获得严格的抗癌特性和蛋白质目标。以及合成化学方面的智力刺激培训。