Pilot Scale Libraries Based on Biologically Active Scaffolds

描述(申请人提供)：在本申请中，我们建议基于以下支架、托烷酮类、羟基脯氨酸、2(1H)-吡啶酮环系和1，5-二氧杂八氢吲哚合成文库。选择这些支架的原因有很多，包括它们固有的活性、稳定性、可用性以及可用于合成类似物的常见方法。在合成所建议的每个库时将采取的一般方法是从一个可以合成足够数量的支架开始，以确保对起始核心的访问不会限制合成库的能力。(Dysiherbaine核心的合成更加复杂，因此将在该支架周围合成较小的文库。)因此，我们确信能够提供我们建议的文库，每个核心都具有具有正交反应性的官能团，允许通过可靠的化学作用附着药效团。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，所选择的支架都被发现具有生物活性。此外，我们还与M.D.安德森癌症中心的张树兴博士合作，为不同图书馆的设计提供计算支持。 与公共卫生相关：在项目期间合成的化合物将用于支持国家卫生研究院分子图书馆倡议和国家小分子资料库。这项拟议的工作将为研究生物学创造有价值的研究工具，并支持美国的生物医学研究社区。

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.