CHEMICAL DIVERSITY LIBRARIES FROM MEDICINAL PLANTS (RMI)

描述(由申请人提供)：这项拟议研究的总体目标是生成中试规模的化学多样性文库，该文库将用于分子图书馆筛选中心网络(MLSCN)的高通量筛选(HTS)。这些文库中包含的化合物将来自药用植物--既包括分离的天然产品，也包括合成的修饰衍生物。代表独特化学多样性类别的天然化合物将使用现代化学、物理和光谱技术，包括LC-MSN技术进行分离、纯化和表征。化合物将主要来自三个来源：过去34年来由PI的天然产品实验室(NPL)以前研究过的生物活性天然产品、美国常用药用植物的成分，以及美国以外常用的药用植物成分，特别是在传统中药中。此外，对不溶于水的天然产物进行合理的化学合成改性，将提供更符合HTS的新的水溶性类似物。总共有1200多个化合物将在三年内提交给NIH高温超导知识库，每年有400个化合物。所有提交的化合物的纯度都将超过99%，最初每种化合物的纯度为10毫克。可根据要求提供基于初始HTS的具有良好生物活性的额外数量的化合物。内部数据库将存储信息(来源、结构、生产和表征方法等)。关于所有化合物的信息，将作为资源共享计划的一部分提供。预计不会对提交的化合物提出知识产权索赔。根据来源植物的民俗和临床药用历史，选定用于研究的化合物将具有很高的体内和/或体外生物活性。此外，这些植物物种的成分将覆盖广泛的独特的化学多样性空间，因此很可能影响新型生物大分子的功能。PI的NPL的专业知识和生产力将确保成功地生成化学多样性库，这些库具有产生新的科学知识的良好前景，在新药发现和开发领域为公众健康带来切实的好处。

DESCRIPTION (provided by applicant): The overall goal of this proposed study is the generation of pilot-scale chemical diversity libraries, which will be used for high-throughput screening (HTS) by the Molecular Libraries Screening Center Network (MLSCN). The compounds included in these libraries will be derived from medicinal plants - both isolated natural products and synthetic modified derivatives. Naturally occurring compounds representing unique chemical diversity classes will be isolated, purified, and characterized using modern chemical, physical, and spectral techniques, including LC-MSn technology. Compounds will be obtained from three main sources: bioactive natural products previously investigated by the PI's Natural Product Laboratory (NPL) in the past 34 years, constituents of medicinal plants commonly used in the US, and constituents of medicinal plants commonly used outside of the US, particularly in traditional Chinese medicine (TCM). In addition, rational chemical synthetic modification of water-insoluble natural products will provide new water-soluble analogs that will be more amenable to HTS. Totally, more than 1,200 compounds over three years with 400 compounds per year will be submitted to the NIH Repository for HTS. All submitted compounds will be in greater than 99% purity and, initially, in 10 mg per compound quantity. Additional quantity of compounds with promising biological activity based on the initial HTS might be furnished, upon request. An in-house database will store information (source, structure, production and characterization methods, etc.) on all compounds and will be made available as part of the resource-sharing plan. No intellectual property claims are anticipated on submitted compounds. The compounds chosen for study will have high potential for in vivo and/or in vitro biological activity based on the history of folkloric and clinical medicinal use of the source plants. In addition, the constituents of these plant species will cover a wide range of unique chemical diversity space and, accordingly, be likely to affect the functions of novel classes of biomacromolecules. The expertise and productivity of the PI's NPL will assure the successful generation of chemical diversity libraries that have excellent promise to generate new scientific knowledge with tangible benefits for public health in the areas of new drug discovery and development.