Biomimetic Synthesis of Macrocarpal Natural Products and Biological Evaluation

描述(申请人提供)：大多数药物化合物是平面的二维结构，具有很高的效力，但往往缺乏选择性。较差的选择性可能会导致不必要的副作用，这可能会表现为危险的副作用。相比之下，三维复杂的铅往往具有非常高的选择性，使其成为立体化学丰富或结构复杂的天然产品的非常理想的目标。冠状A、真球状V和相关的大型腕骨的核心结构体现了这些吸引人的特征。这项拟议的研究旨在根据假想的生物合成来合成这些理想的天然产物。这条路线将利用分子间邻苯二酚甲基引发的环化级联反应。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，所获得的引发性质和结构构型都是前所未有的。这一反应的成功发展将为引发阳离子多环化反应开辟新的可能性，并挑战化学家对它们的复杂性达到新的水平。在合成之后，已经安排了合作来彻底调查它们的生物活性的范围和来源。在国家癌症研究所的合作下，这些天然产物将在NCI-60细胞筛查中进行检测，并使用比较算法进行分析，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被用来确定这些天然产品的细胞靶点。详细了解这些天然产物的生物学作用将导致蛋白质注释方面的新发现，并有助于我们理解小分子-蛋白质相互作用。这项研究的长期目标是：1)通过研究邻醌甲基化合物对活性烯烃的反应性和开发一种新的多环级联反应来扩大其用途；2)研究与宏腕骨生物学活性有关的细胞靶点，包括Piguadial A和Euglobal V抗癌活性。这些研究将探索大心脏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强大工具。根据这些目标，拟议研究的具体目标是：1)开发从其生物合成中获得灵感的Psiguadial A、euglobal V和相关的大腕骨化合物的合成。2)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图谱(ABPP)揭示细胞靶点，研究psiguadial A、euglobal V和相关的巨腕骨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).