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: 8398621
• 负责人: Kiel Lazarski
• 金额: $ 4.71万
• 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/8398621
• 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; Screening procedure; 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; 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). PUBLIC HEALTH RELEVANCE: Between 1981-2006, an estimated 60% of new anticancer pharmaceuticals were either natural products, modified natural products, or compounds with a natural product derived pharmacophore. Thus, the exploration of synthetic routes to natural products has had, and will continue to have, an irreplaceable impact on human health. The proposed research will synthesize a suite of macrocarpal natural products and explore the origin of their biological activity, and evaluate their potential as molecular probes to investigate the functional states of enzymes.

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。选择性差可能会导致不必要的副作用，这些副作用可能表现为危险的副作用。相比之下，三维复杂的先导化合物通常具有很强的选择性，成为立体化学丰富或结构复杂的天然产物的非常理想的目标。 psiguadial A、euglobal V 和相关的大果核的核心结构体现了这些有吸引力的特征。拟议的研究旨在根据其假设的生物合成来合成这些理想的天然产物。该路线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已被广泛研究。然而，作为级联多环化反应，引发的性质和所实现的结构架构都是前所未有的。该反应的成功发展将为引发阳离子多环化开辟新的可能性，并挑战化学家利用它们达到新的复杂水平。合成后，已安排合作来彻底研究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 细胞筛选中进行检测，并使用 COMPARE 算法进行分析，以深入了解其活性和可能的​​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得到加强。先进的蛋白质组学技术将用于识别这些天然产物的细胞靶点。详细描述这些天然产物的生物学作用将带来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。这项研究的长期目标是 1) 通过研究邻醌甲基化物对活化烯烃的反应性并开发新型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标，包括 psiguadial A 和 euglobal V 抗癌活性。这些研究将调查大果树作为赖氨酸反应性分子探针的潜力，这将是确定酶功能状态的有力工具。根据这些目标，拟议研究的具体目标是： 1) 从生物合成中汲取灵感，开发 psiguadial A、euglobal V 和相关大腕化合物的合成。 2) 通过建立癌细胞选择性谱、研究其作用机制并通过基于活性的蛋白质分析 (ABPP) 揭示细胞靶标，研究 psiguadial A、euglobal V 和相关大腕天然产物的生物活性。 公共健康相关性：1981 年至 2006 年间，估计 60% 的新型抗癌药物是天然产物、改良天然产物或具有天然产物衍生药效基团的化合物。因此，天然产物合成路线的探索已经并将继续对人类健康产生不可替代的影响。拟议的研究将合成一套大腕天然产物，探索其生物活性的起源，并评估它们作为分子探针研究酶功能状态的潜力。