Synthesis and Study of Cyclotryptamine and Diketopiperazine Alkaloids

环色胺和二酮哌嗪生物碱的合成与研究

• 批准号: 8628952
• 负责人: Mohammad Movassaghi
• 金额: $ 44.68万
• 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 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8628952
• 关键词: Alkaloids; Architecture; Biogenesis; Biological; Biological Factors; Biology; Carbonates; Chemicals; Chemistry; Complement 3a; Complex; Development; Ensure; Evaluation; Family; Future; Generations; Grant; Human; Investigation; Link; Longitudinal Studies; Methodology; Molecular; Play; Positioning Attribute; Preparation; Reaction; Research; Research Activity; Role; Route; Sampling; Secure; Staging; Structure; Therapeutic; Tryptamines; Tryptophan; Validation; asperazine; base; chemical synthesis; chetomin; design; diazene; diketopiperazine; insight; interest; multidisciplinary; novel strategies; oxidation; programs; public health relevance; tool

DESCRIPTION (provided by applicant): The detailed study of the chemistry and biology of complex natural products at a fundamental level provides critical insight to understanding their mode of action and enables development of new approaches for treatment of various human ailments. This research program focuses on the development of efficient and concise total chemical syntheses of structurally complex and biologically active natural products through the systematic discovery, development, and application of new synthetic strategies and methodologies. A key feature of the planned syntheses is the development of highly chemoselective and stereoselective transformations that enable the implementation of new generalizable synthetic strategies, often inspired by biogenetic consideration, for the rapid generation of molecular complexity. The development of concise and unified approaches to families of natural products, a continuing theme of this program, requires the concurrent development of new methodologies allowing advanced stage functionalization in complex settings. The targets are selected based on novelty of molecular architecture, paucity of prior synthetic studies, abundance of opportunities for development of new strategies and methodologies, possession of significant biological activity, and the potential for future chemical and biological studies. This program will focus on synthetic studies of the rich family of cyclotryptamine and diketopiperazine alkaloids. Of central interest is the directed, regioselective stereoselective, and efficient adjoining of cyclotryptamine substructures providing late stage unions to secure challenging quaternary stereocenters. With this program's particular focus on the potently bioactive epidithiodiketopiperazine, a concurrent effort is the development of new efficient methodologies to enable regioselective and stereoselective sulfidation of complex diketopiperazines. This program will continue to provide synthetic samples of rare and precious compounds for structure validation and detailed examination of their chemistry and biology. The well recognized biological activity of the entire family of compounds under investigation ensure that the many related intermediates and derivatives accessed through these efforts will also behold great promise both as mechanistic tools and as new bioactive compounds, and thus they will be subject to continuous evaluation through our multidisciplinary and collaborative engagements.

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为理解其作用方式提供了关键的见解，并能够开发新方法来治疗各种人类疾病。该研究计划着重于通过系统的发现，开发和应用新的合成策略和方法论的结构复杂和生物活性天然产物的有效和简洁的总化学合成。计划合成的一个关键特征是发展高度化学选择性和立体选择性转换，从而实现了新的可概括的合成策略，通常是受生物遗传学考虑的启发，以快速生成分子复杂性。为该计划的持续主题开发简洁而统一的方法，它需要同时开发新方法，从而允许在复杂的环境中进行高级舞台功能化。基于分子结构的新颖性，先前的合成研究的匮乏，新策略和方法论的大量机会，拥有重要的生物学活动以及未来化学化学的潜力，选择了目标 和生物学研究。该计划将重点介绍富含环丙胺和二酮替嗪的生物碱的合成研究。核心感兴趣的是邻近的环状晶体结构的指示，区域选择性的立体选择性，有效的，可提供晚期工会以确保具有挑战性的第四纪立体中心。该计划特别关注有效的生物活性表流二甲苯嗪，同时努力是开发新的有效方法，以使复杂的二甲苯吡嗪的区域选择性和立体选择性硫化。该程序将继续提供稀有和珍贵化合物的合成样本，以验证结构验证并详细研究其化学和生物学。整个正在调查的化合物全家的认可的生物学活动可确保通过这些努力访问的许多相关中间体和衍生物也将成为机械工具和新的生物活性化合物的巨大希望，因此它们将通过我们的多学科和协作参与进行持续评估。