Probing Diversity Space with Novel Pilot Scale Libraries

描述(申请人提供)：本申请的目标是设计和构建由新型杂环组成的中试规模的文库，重点是骨架、立体化学和外周官能团(FG)的多样性。特别是，我们将把最初的努力集中在由含硫和含磷的小分子及其类似物组成的文库上，我们通常称之为S杂环和P-杂环。我们的目标是使用“关键到支架再到库”的范例来设计和构建以下文库，其中关键设计、反应流形和电子多样性筛选(PubChem)的结合将指导我们以动态的方式挖掘独特的化学空间。利用我们实验室开发的固定化试剂和技术，整合一系列便利的合成方案，将能够进行中试规模的图书馆建设。所有情况下都将使用通过质量定向分馏进行的高通量纯化，以验证化合物的纯度和身份。合成的文库将由约40-100个单独的亚文库组成 在MLSCN内的多个平台上，为HTS提供足够数量(10-15 mg)和高纯度(&gt；90%)的每个关键化合物。我们预计每年交付750种化合物。最终，这些 将通过分子图书馆筛选网络(MLSCN)对文库进行评估，以发现进一步发展的铅结构。通过采用我们实验室开发的方法来实现这一目标，我们处于有利地位，这些方法侧重于根据药物化学原理设计的支架，并使用高效的支架生成/多样化策略和便于库生产的合成方案。总体而言，这个平台将使我们能够基于多种新型支架制作可扩展的、多样化的文库，并允许我们以动态的方式探索生物和化学空间。

DESCRIPTION (provided by applicant): The goal of this application is to design and construct pilot scale libraries comprised of novel heterocycles with an emphasis on skeletal, stereochemical and peripheral functional group (FG) diversity. In particular, we will focus our initial efforts on libraries comprised of sulfur and phosphorus-containing small molecules and analogues thereof, we term generally as S- and P-heterocycles. We aim to design and construct the following libraries using a "linchpin to scaffolds to library" paradigm where a combination of linchpin design, reaction manifolds and in silico diversity screening (PubChem) will guide our efforts in mining unique chemical space in a dynamic manner. Integration of an array of facilitated synthetic protocols utilizing immobilized reagents and technologies developed in our laboratory will enable pilot-scale libraries construction. High-throughput purification via mass-directed fractionation will be used in all cases to verify compound purity and identity. The libraries synthesized will comprise of individual sublibraries of ~40-100 compounds per linchpin in sufficient quantities (10-15 mg) and high purity (>90%) for HTS on numerous platforms within the MLSCN. We are projecting delivery of 750 compounds per year. Ultimately, these libraries will be evaluated via the Molecular Library Screening Network (MLSCN) in order to uncover lead structures for further development. We are well positioned to meet this goal by employing methodologies developed in our laboratories that focus on scaffolds that are designed according to medicinal chemistry principles, and use efficient scaffold generation/diversification strategies and facilitated synthetic protocols for library production. Overall, this platform will enable us to produce scalable, diverse libraries based on multiple novel scaffolds and allow us to probe both biological and chemical space in a dynamic manner.