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: 8710102
• 负责人: Kiel Lazarski
• 金额: $ 2.35万
• 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 2015-02-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8710102
• 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平坦的二维结构，具有较高的效力，但通常缺乏选择性。差的选择性可能导致不必要的侧际交往可能表现为危险的副作用。相比之下，三维复杂的导线通常非常有选择性，从而使立体化学上富含或结构上复杂的天然产物的高度理想的靶标。 Psiguadial A，Euglobal V和相关的大型核心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综合这些理想的天然产品。该路线将利用分子间的O- Ququinone甲基元素引发的环化级联反应。多环化反应已在合成中进行了广泛的研究。但是，开始的开始性质和结构结构的性质都是前所未有的，作为级联多环化反应。这种反应的成功发展将为发起阳离子多环化并挑战化学家以达到新的复杂程度的新可能性。合成后，已经安排了合作，以彻底研究其生物活性的范围和起源。与HE国家癌症研究所合作，将在NCI-60细胞筛选中分析这些天然产品，并使用比较算法进行分析，以深入了解活动和可能的作用机理。这些研究将通过与Skaggs化学生物学研究所的合作努力来增强。晚期蛋白质组学技术将用于识别这些天然产物的细胞靶标。详细说明这些天然产物的生物学作用将导致蛋白质注释中的新发现，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thong-term目标是1）通过研究其对活化烯烃的反应性并开发出新的多环化级联反应的反应性来扩大o-喹酮甲基的实用性，以及2）研究，以调查负责大量果质生物学活性的细胞靶标，包括psiguadial a和euguadial a和eugualobal a和euglobal v抗癌药。这些研究将研究大环丙烷作为赖氨酸反应性分子探针的潜力，该探针将是确定酶功能状态的强大工具。与这些目标一致，拟议的研究的具体目的是：1）开发psiguadial a，euglobal V和相关的大型果实化合物的合成，从其生物合成中汲取灵感。 2）通过建立癌细胞的选择性谱，研究其作用机理并通过基于活性的蛋白质谱（ABPP）来研究癌细胞的选择性谱，研究其作用机理并揭示细胞靶标，来研究psiguadial A，Euglobal V和相关的大橄榄球天然产物的生物学活性。