Synthesis of Complex Terpenes From Simple Precursors

从简单前体合成复杂萜烯

基本信息

批准号：
9901555
负责人：
Thomas John Maimone
金额：
$ 27.75万
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 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9901555
关键词：
Anti-Bacterial Agents Antibiotics Apoptotic Architecture Artemisinins Biological Biological Assay Breathing Cellular biology Chemicals Chemistry Collaborations Complex Coupled Cyclization Development Disease Diterpenes Drug resistance Effectiveness Event Family Family member Goals Immunosuppressive Agents Lead Malaria Manganese Medicine Metals Methods Modification Molecular Molecular Biology National Institute of Allergy and Infectious Disease Natural Products Organic Chemistry Organic Synthesis Oxygen Paclitaxel Pathway interactions Pattern Peroxides Pharmaceutical Chemistry Process Property Reaction Research Route Sesquiterpenes Structure Students Synthesis Chemistry System Technology Terpenes Thapsigargin Therapeutic Therapeutic Agents Training United States National Institutes of Health Work anti-cancer anticancer activity antiproliferative agents career cell type chemical synthesis cost design drug discovery exhaustion graduate student human disease member neoplastic cell novel novel therapeutics ophiobolins prenyl programs public health relevance scaffold sesterterpenes small molecule success wasting

项目摘要

DESCRIPTION (provided by applicant): From Taxol(tm) to artemisinin, 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. At the core of this proposal is the desire to greatly simplify terpene synthesis by using simple prenyl-derived units and chiral pool materials in concert with controlled, non-biomimetic cyclization events and polyoxygenation 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. Complex terpenes featuring 5/8/n-fused ring systems (n = 5,6) have attractive and potent anticancer, antibacterial, and immunesuppressant properties, yet the lack of efficient synthetic methods to construct such systems has greatly hampered in-depth structure/function studies. The ophiobolin family of sesterterpenes in particular has resisted efficient chemical synthesis for several decades and new strategies are needed to efficiently construct this diverse and growing class of natural products. This work will undoubtedly lead to an enhanced SAR picture with respect to structure and function relating to their anticancer properties. Periconicin represent an emerging (and largely unexplored) class of antibacterial agents with activity against both gram positive and negative strains. Despite effort, the complex immunosuppressant variecolin has not been synthesized signifying a gap in current technologies. Highly oxygenated guaianolide terpenes represent state of the art challenges for organic synthesis and potential next generation therapeutics. Finally, terpenoid peroxides represent proven therapeutics for the treatment of malaria and are emerging as a promising class of pro-apoptotic agents for the treatment of various diseases. We have developed a remarkably simple way to construct terpene peroxide scaffolds using efficient, metal-catalyzed tandem reactions. Overall this program seeks to use advances in synthetic chemistry coupled with the inspiration of natural product architectures to construct biologically active small molecules with unprecedented efficiency and diversity. In the process of this work, students will be provided with rigorous and intellectually stimulating training in synthetic chemistry.

描述（由申请人提供）：从紫杉醇（tm）到青蒿素，复杂萜烯对人类疾病的治疗和理解产生了深远的影响。然而，尽管它们具有巨大的医学相关性，但大多数复杂的萜烯结构并不是详尽的医学和化学生物学研究的最佳起点，并且与许多小分子药物发现计划不同，它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，以获取复杂的、药用相关的萜类天然产物。该提案的核心是希望通过使用简单的异戊烯基衍生单元和手性库材料，结合受控的非仿生环化事件和多氧化策略，大大简化萜烯合成。该计划选择的靶标既代表了复杂分子合成的最先进挑战，也代表了潜在的下一代疗法。具有5/8/n稠合环系统（n = 5,6）的复杂萜烯具有有吸引力且有效的抗癌、抗菌和免疫抑制特性，但缺乏构建此类系统的有效合成方法极大地阻碍了深入结构/功能研究。特别是二联萜的蛇草酚家族几十年来一直难以有效地进行化学合成，因此需要新的策略来有效地构建这种多样化且不断增长的天然产物类别。这项工作无疑将增强其抗癌特性相关结构和功能的 SAR 图像。 Periconicin 代表了一类新兴的（且很大程度上未经探索的）抗菌剂，对革兰氏阳性和阴性菌株均具有活性。尽管付出了努力，复杂的免疫抑制剂 variecolin 尚未合成，这表明当前技术存在差距。高度氧化的愈创木酚内酯代表了有机合成和潜在的下一代疗法的最新挑战。最后，萜类过氧化物代表了治疗疟疾的行之有效的疗法，并且正在成为一类有前途的用于治疗各种疾病的促凋亡剂。我们开发了一种非常简单的方法，利用高效的金属催化串联反应构建萜烯过氧化物支架。总体而言，该计划旨在利用合成化学的进步以及天然产物结构的灵感，以前所未有的效率和多样性构建生物活性小分子。在这项工作的过程中，学生将接受严格且刺激智力的合成化学培训。