Structural and Sterochemically Diverse Heterocycles for the Small Molecule Reposi

描述（由申请人提供）：合成具有独特化学结构、形状和物理性质的化合物是多样性定向合成（DOS）的一个重要目标。从高通量筛选工作中识别干扰生物过程的化合物大大提高了进行基础生物医学研究的能力。获得具有新化学性质的分子的一种独特方法是从支架结构中构建小分子文库。该提案概述了中试规模文库（PSL）倡议的具体计划，以合成一系列结构复杂的杂环化合物，并将其纳入美国国立卫生研究院分子文库小分子库（MLSMR）。提案中概述的图书馆项目说明了首席研究员（PI）和联合首席研究员（Co-PI）对设计和合成具有独特形状、立体化学排列和化学性质的复杂分子的兴趣。共描述了14个具有不同结构的库。图书馆的设计已经与国家中心进行了比较

DESCRIPTION (provided by applicant): The synthesis of compounds that possess unique chemical structures, shapes, and physical properties is an important objective of diversity-oriented synthesis (DOS). The identification of compounds that perturb biological processes from high-throughput screening efforts greatly enhance the ability to perform fundamental biomedical research. A distinct approach to obtain molecules with novel chemical properties is the construction of small molecule libraries from scaffold structures. This proposal outlines specific plans for a Pilot Scale Libraries (PSL) initiative to synthesize a selection of structurally complex heterocyclic compounds for inclusion into the National Institutes of Health Molecular Library Small Molecule Repository (MLSMR). The library Projects outlined in the proposal illustrate the Principal Investigator's (PI's) and Co-Principal Investigator's (Co-PI's) interest in the design and synthesis of complex molecules possessing unique shapes, stereochemical arrangements, and chemical properties. A total of 14 libraries are described with distinct structures. The library designs have been compared against the National Center for Biotechnology Information molecular database PubChem to ensure that each compound is unique and accesses novel chemical space properties. Furthermore, library design criteria has also included calculated physiochemical properties and solubility properties that are consistent with bioactive natural product-like characteristics. Target libraries include pyrimidones and related compounds, natural product-inspired compounds, polyketide-derived heterocycles, and carbazole-derived libraries. A key mechanism for data sharing for the PSL initiative includes uploading the compound library structures to the PubChem database and linking the compound IDs to an Internet-based Synthesis Protocol Database that is publicly accessible and capable of providing detailed synthetic procedures for the compounds synthesized as a part of the PSL initiative. The compound libraries developed in this effort are anticipated to facilitate the discovery of new chemical probes of biological and cellular processes through the Molecular Libraries Initiative. PUBLIC HEALTH RELEVANCE: The compounds synthesized during this project will be used to support the National institutes of Health Molecular Libraries initiative and National Small Molecule Repository Resource. The proposed projects will create valuable research tools to study biology and support the biomedical research community created by the NIH.