Biomimetic Synthesis of Macrocarpal Natural Products and Biological Evaluation

大果天然产物的仿生合成及生物学评价

• 批准号: 8572973
• 负责人: Kiel Lazarski
• 金额: $ 4.92万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-17 至 2015-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8572973
• 关键词: Adverse effects; Aldehydes; Algorithms; Alkenes; Amines; Anabolism; Architecture; Area; Binding; Biological; Biological Assay; Biological Factors; Biology; Biomimetics; Breathing; Cancer Cell Growth; Cell Line; Cells; Chemicals; Collaborations; Collection; Complex; Cyclization; Data; Development; Diarrhea; Enzymes; Evaluation; Exhibits; Family; Folk Medicine; Future; Goals; Gram-Positive Bacteria; HIV; Health; Human; Hyperglycemia; Imines; Inhibitory Concentration 50; Institutes; Lead; Light; Lysine; Malignant neoplasm of liver; Methods; Molecular; Molecular Probes; National Cancer Institute; Nature; Parasites; Pathway interactions; Peptides; Pharmacologic Substance; Phloroglucinol; Proteins; Proteomics; Psidium guajava; RNA-Directed DNA Polymerase; Reaction; Research; Role; Route; Scheme; Side; Skeleton; Source; Structure; Study models; Sulfhydryl Compounds; Techniques; Terpenes; Training; Ursidae Family; activity-based protein profiling; anticancer activity; cancer cell; cellular targeting; cytotoxic; cytotoxicity; fungus; insight; interest; novel; pharmacophore; professor; quinone methide; screening; small molecule; tool; trait; two-dimensional

DESCRIPTION (provided by applicant): Most pharmaceutical compounds are flat, two-dimensional structures that have a high potency but often suffer from a lack of selectivity. Poor selectivity can result in unwanted side-interactions that may manifest themselves as dangerous side effects. In contrast, three-dimensionally complex leads are often very selective, making highly desirable targets of stereochemically rich or structurally intricate natural products. The core structure of psiguadial A, euglobal V, and related macrocarpals embodies these attractive traits. The proposed research aims to synthesize these desirable natural products in accordance with their hypothesized biosyntheses. This route will utilize an intermolecular o-quinone methide initiated cyclization cascade. Polycyclization reactions have been extensively studied in synthesis. However, both the nature of initiation and structural architecture achieved are unprecedented as cascade polycyclization reactions. The successful development of this reaction will open new possibilities for initiating cationic polycyclizations and challenge chemist to reach new levels of complexity with them. After synthesis, collaborations have been arranged to thoroughly investigate the scope and origin of their biological activity. In collaboration with he National Cancer Institute, these natural products will be assayed in the NCI-60 cell screen and analyzed with the COMPARE algorithm to give insights into the activity and possible mechanism of action. These studies will be augmented through a collaborative effort with the Skaggs Institute of Chemical Biology. Advanced proteomics techniques will be used to identify the cellular target of these natural products. Detailing the biological role of these natural products will lead to new discoveries in protein annotation and contribute to our understanding of small-molecule-protein interactions. Thelong-term goals of this research are 1) to expand the utility of o-quinone methides by investigating their reactivity towards activated olefins and developing a novel polycycization cascade reaction, and 2) to investigate the cellular targets responsible for macrocarpal biological activity, including psiguadial A and euglobal V anticancer activity. These studies will investigate the potential of macrocarpals as lysine-reactive molecular probes that would be powerful tools for determining the functional state of enzymes. In line with these goals, the Specific Aims of the proposed research are: 1) To develop a synthesis of psiguadial A, euglobal V, and related macrocarpal compounds drawing inspiration from their biosyntheses. 2) Investigate the biological activity of psiguadial A, euglobal V, and related macrocarpal natural products by establishing cancer cell selectivity profiles, investigating its mechanism of action, and uncovering cellular targets via activity-based protein profiling (ABPP).

描述（由申请人提供）：大多数药物化合物是扁平的二维结构，具有高效力，但通常缺乏选择性。选择性差可能导致不需要的副作用，这些副作用可能表现为危险的副作用。相比之下，三维复杂的铅往往是非常有选择性的，立体化学丰富或结构复杂的天然产品的高度理想的目标。psiguadial A，euglobal V和相关的大果类的核心结构体现了这些吸引人的特征。该研究的目的是根据其假设的生物合成来合成这些理想的天然产物。该途径将利用分子间邻醌甲基化物引发的环化级联。多环化反应在合成中得到了广泛的研究。然而，作为级联多环化反应，所实现的引发性质和结构架构都是前所未有的。该反应的成功开发将为引发阳离子多环化开辟新的可能性，并挑战化学家将其复杂性提高到新的水平。合成后，已安排合作彻底调查其生物活性的范围和起源。与国家癌症研究所合作，这些天然产物将在NCI-60细胞筛选中进行分析，并使用COMPARE算法进行分析，以深入了解活性和可能的作用机制。这些研究将通过与斯卡格斯化学生物学研究所的合作来加强。先进的蛋白质组学技术将被用来确定这些天然产物的细胞靶点。详细说明这些天然产物的生物学作用将导致蛋白质注释的新发现，并有助于我们对小分子-蛋白质相互作用的理解。本研究的长期目标是：1）通过研究邻醌甲基化物对活化烯烃的反应性和开发新的多环化级联反应来扩大邻醌甲基化物的用途; 2）研究负责大腕生物活性的细胞靶点，包括psiguadial A和euglobal V抗癌活性。这些研究将探讨大果类作为赖氨酸反应性分子探针的潜力，这将是确定酶的功能状态的有力工具。根据这些目标，所提出的研究的具体目标是：1）从它们的生物合成中获得灵感，开发psiguadial A，euglobal V和相关的大腕化合物的合成。2)研究psiguadial A，euglobal V和相关macrocarpal天然产物的生物活性，通过建立癌细胞选择性图谱，研究其作用机制，并通过基于活性的蛋白质谱（ABPP）揭示细胞靶点。