Probing Diversity Space with Novel Pilot Scale Libraries

描述（由申请人提供）：本申请的目标是设计和构建由新型杂环组成的中试规模文库，重点是骨架、立体化学和外周官能团（FG）多样性。特别地，我们将把我们的初步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，我们通常将其称为S-和P-杂环。我们的目标是使用“关键到支架到库”范式设计和构建以下库，其中关键设计、反应歧管和计算机多样性筛选（PubChem）的组合将指导我们以动态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的一系列便利合成方案的整合将使中试规模的图书馆建设成为可能。在所有情况下，将使用通过质量导向分馏的高通量纯化来验证化合物纯度和鉴别。合成的文库将包含约40-100个单独的亚文库。 在MLSCN内的许多平台上，每个关键点的化合物以足够的量（10-15 mg）和高纯度（>90%）用于HTS。我们计划每年交付750种化合物。最终，这些 将通过分子文库筛选网络（MLSCN）对文库进行评估，以揭示先导结构，用于进一步开发。我们有能力通过采用我们实验室开发的方法来实现这一目标，这些方法专注于根据药物化学原理设计的支架，并使用有效的支架生成/多样化策略和促进文库生产的合成方案。总的来说，这个平台将使我们能够基于多种新型支架产生可扩展的，多样化的文库，并使我们能够以动态的方式探测生物和化学空间。

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.