Structural and Sterochemically Diverse Heterocycles for the Small Molecule Reposi

描述（由申请人提供）：具有独特化学结构、形状和物理性质的化合物的合成是多样性导向合成（DOS）的重要目标。通过高通量筛选工作鉴定出干扰生物过程的化合物大大增强了进行基础生物医学研究的能力。获得具有新颖化学性质的分子的一种独特方法是从支架结构构建小分子库。该提案概述了中试规模图书馆 (PSL) 计划的具体计划，该计划旨在合成一系列结构复杂的杂环化合物，以纳入美国国立卫生研究院分子图书馆小分子存储库 (MLSMR)。提案中概述的库项目表明了首席研究员 (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。总共描述了 14 个具有不同结构的库。图书馆的设计已与国家中心进行了比较 生物技术信息分子数据库 PubChem 确保每种化合物都是独特的并具有新颖的化学空间特性。此外，文库设计标准还包括计算的理化性质和溶解度性质，这些性质与生物活性天然产物的特征一致。目标库包括嘧啶酮和相关化合物、天然产物启发的化合物、聚酮衍生的杂环化合物和咔唑衍生的库。 PSL 计划数据共享的关键机制包括将化合物库结构上传到 PubChem 数据库，并将化合物 ID 链接到基于互联网的合成协议数据库，该数据库可公开访问，并且能够为作为 PSL 计划一部分合成的化合物提供详细的合成程序。这项工作中开发的化合物库预计将有助于通过分子库计划发现生物和细胞过程的新化学探针。公共卫生相关性：该项目期间合成的化合物将用于支持美国国立卫生研究院分子图书馆计划和国家小分子存储库资源。拟议的项目将创建有价值的研究工具来研究生物学并支持 NIH 创建的生物医学研究社区。

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.