Biomimetic Synthesis of Macrocarpal Natural Products and Biological Evaluation

描述（由申请人提供）：大多数药物化合物是平面的二维结构，具有高效能，但往往缺乏选择性。差的选择性会导致不必要的副作用，这可能表现为危险的副作用。相比之下，三维复杂引线通常是非常有选择性的，使立体化学丰富或结构复杂的天然产物成为非常理想的目标。这些吸引人的特征体现在腕骨的核心结构上。拟议的研究旨在根据其假设的生物合成合成这些理想的天然产物。这条路线将利用分子间邻醌甲基启动环化级联。多环化反应在合成中得到了广泛的研究。然而，无论是引发的性质和所获得的结构结构是前所未有的级联多环化反应。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，以彻底调查其生物活性的范围和来源。与美国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努力得到加强。先进的蛋白质组学技术将用于鉴定这些天然产物的细胞靶点。详细介绍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)通过研究邻醌类化合物对活性烯烃的反应性和开发一种新的多环化级联反应，扩大邻醌类化合物的应用范围；2)研究大腕生物活性的细胞靶点，包括psiigual a和euglobal V抗癌活性。这些研究将探讨大腕骨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，本研究的具体目标是：1)从它们的生物合成中获得灵感，开发一种合成psiguadial a， euglobal V和相关大腕化合物的方法。2)通过建立癌细胞选择性谱，研究其作用机制，并通过活性蛋白谱（activity-based protein profiling， ABPP）揭示细胞靶点，研究psigual A、euglobal V及相关大腕天然产物的生物活性。

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.