Synthesis and Study of Dimeric Diketopiperazine Alkaloids

二聚二酮哌嗪生物碱的合成与研究

• 批准号: 8211014
• 负责人: Mohammad Movassaghi
• 金额: $ 38.87万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8211014
• 关键词: Alkaloids; Architecture; Biological; Biological Factors; Biology; Breathing; Chemicals; Chemistry; Collaborations; Complement 3a; Complex; Development; Dimerization; Evaluation; Family; Future; Grant; Human; Hydroxyl Radical; Investigation; Link; Longitudinal Studies; Methodology; Molecular; Play; Preparation; Reaction; Research; Research Activity; Role; Route; Sampling; Secure; Solutions; Staging; Structure; Testing; Therapeutic; Tryptophan; Validation; asperazine; base; chaetocin; design; diketopiperazine; insight; interest; men; migration; novel therapeutics; oxidation; programs; public health relevance; stereochemistry; tool; verticillin A

DESCRIPTION (provided by applicant): The detailed study of the chemistry and biology of complex natural products at a fundamental level provides insight that is key to understanding their mode of action and development of new therapeutics for treatment of various human ailments. This research program aims to develop efficient and concise total syntheses of structurally complex and biologically active natural products through the discovery, development, and application of new strategies and methodologies. In this program, biogenetic considerations provide inspiration for development of new generalizable strategies to rapidly build molecular complexity. A key feature of the planned syntheses is the development of new highly chemoselective and stereoselective transformations. Of particular interest is development of new methodologies allowing advanced stage functionalization using the inherent reactivity of intermediates. Targets are selected based on novelty of molecular architecture, paucity of prior synthetic studies, ample opportunities for development of new strategies and methodologies, possession of significant biological activity, and the potential for future chemical and biological mechanistic studies. This program will focus on synthetic studies of the rich family of dimeric diketopiperazine alkaloids. The core structures of these alkaloids are adjoined by either Csp3-alkyl (sp3-sp3) or Csp3-aryl (sp3-sp2) bond connectivity at quaternary stereocenters. The program will focus on potently bioactive epidithiodiketopiperazines, including the verticillin alkaloids, and will develop generalizable methodologies for rapid assembly and functionalization of dimeric diketopiperazines containing vicinal quaternary stereocenters connected via a Csp3-Csp3 bond. We will also study a late stage highly stereoselective oxidation-migration sequence using bisindole structures to access the Csp3-aryl (sp3-sp2) bond connectivity found in a variety of alkaloids. This program will result in synthetic samples of rare and precious compounds for structure validation and exploration of their chemistry and biology. Given the rich biological activity of diketopiperazines and epidithiodiketopiperazines under investigation, related intermediates and derivatives also hold great promise as mechanistic tools and new bioactive compounds, and thus will be subject to various tests through our collaborative activities. PUBLIC HEALTH RELEVANCE: The study of the fundamental chemical and biological mechanism of action of natural products continues to play an important role in the development of new treatments for a variety of human ailments. This program aims to discover, develop, and apply new and unique strategies and methodologies for preparation of bioactive and complex natural molecules and related designed derivatives. While the immediate result is direct access to samples of extremely rare and precious compounds for structure validation, collaborative biological evaluation, and mechanistic studies, the longer term and broader impact of this program is the establishment of precedence for the application of these new chemistries to other targets and potential therapeutics both natural or rationally designed.

描述（由申请人提供）：基本层面上复杂天然产品的化学和生物学的详细研究提供了洞察力，这是了解其作用方式和新疗法以治疗各种人类疾病的关键。该研究计划旨在通过发现，开发和应用新的策略和方法论，开发有效，简洁的结构复杂和生物活性天然产品的总合成。在该计划中，生物遗传学的考虑为发展新的可概括策略的发展提供了灵感，以快速建立分子复杂性。计划合成的一个关键特征是开发新的高度化学选择性和立体选择性转换。特别有趣的是开发新方法，允许使用中间体的固有反应性进行高级阶段功能化。基于分子结构的新颖性，先前的合成研究的匮乏，新策略和方法论的充足机会，拥有重要的生物学活性以及未来化学和生物学机械研究的潜力。该计划将重点介绍二聚体二哌嗪生物碱的丰富家族的合成研究。这些生物碱的核心结构与第四纪立体中心处的CSP3-烷基（SP3-SP3）或CSP3-ARYL（SP3-SP2）键连接相邻。该计划将重点放在包括肉黄霉素生物碱在内的有效的生物活性二硫代二甲苯嗪，并将开发可推广的方法，用于快速组装和功能化含有含有阴道季季立体体的二聚体二季型哌嗪。我们还将研究晚期高度立体选择性氧化式迁移序列，使用双层结构来访问在多种生物碱中发现的CSP3-ARYL（SP3-SP2）键连接性。该程序将导致稀有和珍贵化合物的合成样品，以验证其化学和生物学。鉴于正在研究的二酮哌嗪和流行生二甲苯吡嗪的丰富生物学活性，相关的中间体和衍生物也具有巨大的希望，作为机械工具和新的生物活性化合物，因此将通过我们的协作活动进行各种测试。 公共卫生相关性：对天然产品作用的基本化学和生物生物学机制的研究在开发各种人类疾病的新疗法中继续发挥重要作用。该计划旨在发现，开发和应用新的和独特的策略和方法，以制备生物活性和复杂的自然分子以及相关设计的衍生物。虽然直接的结果是直接访问具有结构验证，协作生物学评估和机理研究的极稀有和宝贵化合物的样品，但该计划的长期和更广泛的影响是将这些新化学物质应用于其他靶标以及潜在的自然或自然设计的潜在治疗方法的优先级。