Structural and Sterochemically Diverse Heterocycles for the Small Molecule Reposi

描述(申请人提供)：合成具有独特的化学结构、形状和物理性质的化合物是面向多样性合成(DOS)的重要目标。从高通量筛选工作中识别扰乱生物过程的化合物极大地增强了进行基础生物医学研究的能力。从支架结构构建小分子文库是获得具有新化学性质的分子的一种独特的方法。该提案概述了试点规模图书馆(PSL)倡议的具体计划，该倡议旨在合成一系列结构复杂的杂环化合物，以便纳入国家卫生研究院分子图书馆小分子储存库(MLSMR)。建议中概述的文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。总共有14个库被描述为具有不同的结构。图书馆的设计已经与国家图书馆中心进行了比较 生物技术信息分子数据库PubChem，以确保每种化合物都是唯一的，并获得新的化学空间性质。此外，文库设计标准还包括与生物活性天然产物类特征一致的计算的物理化学性质和溶解性性质。目标文库包括嘧啶酮及其相关化合物、天然产物激发的化合物、聚酮衍生的杂环和咔唑衍生的文库。PSL倡议的数据共享的一个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链接到一个基于互联网的合成协议数据库，该数据库可供公众访问，并能够为作为PSL倡议一部分合成的化合物提供详细的合成程序。在这项工作中开发的化合物文库预计将通过分子文库倡议促进发现生物和细胞过程的新化学探针。公共卫生相关性：在该项目期间合成的化合物将用于支持国家卫生研究院分子图书馆倡议和国家小分子资源库。拟议的项目将创造有价值的研究工具来研究生物学，并支持由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.