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. ? ?
