Pilot Scale Libraries Inspired by Natural Products

描述(由申请人提供)：这项试验规模文库(PSL)提案描述了包含新结构的文库的构建，并将其提交给NIH分子文库小分子文库(MLSMR)。选择项目是为了最大限度地提高(1)提交结构的新颖性，如通过对PubChem数据库的检查和内部多样性分析确定的那样，(2)建议的文库将通过与已知生物活性物质类似的设计在筛选中有用的可能性，以及(3)效率，通过设计基于已建立的支架制备方法(通常在PI的实验室发明)和简单的多样化计划的合成。一旦组装，文库将使用质量定向分馏技术进行纯化，并提交给分子库小分子储存库。 这些图书馆按五个主要主题组织。它们是(1)从Lewis酸促进的烷基叠氮化合物的反应中衍生的生物碱样库，这些反应提供了复杂的酮，这些酮随后被转化为 氨基甲酸酯、胺、吲哚或其他杂环产品，(2)基于最近报道的一类扭曲内酰胺的文库，(3)由合成路线启发的 圆柱菌素/来帕双胺类，(4)豪华胺A类似物，和(5)天然产物马丁内林和核激素受体的共同结构启发的文库。 与公共健康相关：这一试点规模图书馆提案的目标是产生具有与生物活性一致的特性的高质量的新型化合物集合。在将这些化合物提交到分子图书馆小分子储存库后，它们将在与人类健康有关的许多测试中进行筛选。在这些筛查中发现的活性化合物可以导致将加强生物医学研究的探测器。

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.