Pilot Scale Libraries Based on Biologically Active Scaffolds

描述（由申请人提供）：在本申请中，我们提出基于以下骨架合成文库：托品酮、羟基脯氨酸、2（1H）-吡啶酮环系统和1，5-二氧杂八氢茚。这些支架的选择有多种原因，包括其固有的活性、稳定性、可用性和可用于合成类似物的常用方法。在所提出的每个文库的合成中将采取的一般方法是从可以以足够量合成的支架开始，以确保对起始核心的访问不会限制合成文库的能力。(The dysiherbaine核心的合成更复杂，因此围绕该支架将合成更小的文库。因此，我们确信能够提供我们提出的文库，每个核心具有正交反应性的官能团，允许通过可靠的化学连接药效团。为了帮助确保文库具有所需的物理性质，如溶解性和稳定性，已经选择的支架都被发现具有生物活性。此外，我们还与医学博士张树兴博士合作，安德森癌症中心提供计算支持的设计不同的图书馆。 公共卫生相关性：在项目期间合成的化合物将用于支持美国国立卫生研究院分子图书馆倡议和国家小分子库。拟议的工作将创造有价值的研究工具，以研究生物学和支持美国的生物医学研究界。

DESCRIPTION (provided by applicant): In this application we propose to synthesize libraries based on the following scaffolds, tropinones, hydroxyprolines, 2(1H)-pyridone ring systems and 1,5-dioxaoctahydroindenes. These scaffolds were chosen for a variety of reasons, including their inherent activity, stability, availability and common methods that can be used in the synthesis of analogs. The general approach that will be taken in the synthesis of each of the libraries proposed is to start with a scaffold that can be synthesized in sufficient quantities to ensure that access to the starting core will not limit the ability to synthesize libraries. (The synthesis of the dysiherbaine core is more complicated and consequently smaller libraries will be synthesized around this scaffold.) So that we are assured to being able to provide the libraries we propose, each core has functional groups with orthogonal reactivity that allows for the attachment of pharmacophores by reliable chemistry. To help ensure that the libraries have the desired physical properties such as solubility and stability the scaffolds that have been chosen have all been found to be biologically active. Additionally, we have entered in to a collaboration with Dr. Shuxing Zhang from M.D. Anderson Cancer Center to provide computational support in the design of diverse libraries. PUBLIC HEALTH RELEVANCE: The compounds synthesized during the project period will be used to support the National Institutes of Health Molecular Libraries initiative and the National Small Molecule Repertory. The proposed work will create valuable research tools to study biology and support the biomedical research community in the United States.