Pilot Scale Libraries Inspired by Natural Products

描述（由申请人提供）：该中试规模文库（PSL）提案描述了包含新结构的文库的构建，并将其提交给NIH分子文库小分子库（MLSMR）。项目的选择是为了最大限度地提高(1)提交的结构的新颖性，这是通过对PubChem数据库的检查和内部多样性分析确定的；(2)通过与已知生物活性剂相似的设计来确定所提议的文库在筛选中有用的可能性；以及(3)效率。通过基于支架制备的既定方法（通常是在Pi的实验室发明的）设计合成，并结合直接的多样化方案。一旦组装完成，文库将使用质量导向分馏技术进行纯化，并提交给Molecular libraries小分子库。

DESCRIPTION (provided by applicant): This Pilot Scale Library (PSL) proposal describes the construction of libraries containing novel structures and their submission to the NIH Molecular Libraries Small Molecule Repository (MLSMR). Projects are chosen to maximize (1) the novelty of the submitted structures, as determined by examination of the PubChem database and through an in-house diversity analysis, (2) the likelihood that the libraries proposed will be useful in screening by designing them in analogy with known bioactive agents, and (3) efficiency, by designing syntheses based on established methods for scaffold preparation (generally invented in the Pi's laboratory) combined with straightforward diversification schemes. Once assembled, libraries will be purified using mass directed fractionation techniques and submitted to the Molecular Libraries Small Molecule Repository. The libraries are organized in five major themes. They are (1) alkaloid-like libraries derived from Lewis acid promoted reactions of alkyl azides that afford complex ketones that are subsequently converted to carbamates, amines, indoles, or other heterocyclic products, (2) libraries based on a recently reported class of twisted lactams, (3) libraries inspired by synthetic routes toward marine alkaloids of the cylindricine/lepadiformine class, (4) haouamine A analogs, and (5) libraries inspired by the natural product martinelline and consensus structures of nuclear hormone receptors. PUBLIC HEALTH RELEVANCE: The goal of this Pilot Scale Library proposal is to generate high-quality collections of novel chemical compounds with properties consistent with biological activity. Following submission of these compounds to the Molecular Libraries Small Molecule Repository, they will be screened in numerous assays relevant to human health. Compounds found to be active in these screens can lead to probes that will enhance biomedical research.