Diversity Space with Novel Pilot Scale Libraries (RMI)

描述（由申请人提供）：本申请的目标是从一系列新型杂环支架中产生中试规模的文库。我们的目标是为HTS生产“类似药物”和“类似天然产物”的文库，以便最大限度地获得与生物分子靶点相互作用的高可能性化合物。最终，这些文库将通过分子文库筛选网络（MLSCN）进行评估，以发现进一步开发的先导结构。通过采用我们实验室开发的方法，我们可以很好地实现这一目标，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。在许多情况下，拟议的图书馆已被确定为堪萨斯大学（KU）个人研究工作中基于目标的发现计划的一部分。这些努力通过堪萨斯大学的一些卓越中心的专业知识得到加强，包括：(i)组合方法和文库开发中心，（ii）癌症实验治疗中心，（iii）蛋白质结构和功能中心，以及（iv）最先进的高通量筛选实验室。这种基础设施和专业知识的结合使我们能够基于各种各样的新支架生产可扩展的、多样化的图书馆，并使我们能够以动态的方式探索生物和化学空间。为了实现这一目标，将在MLSCN内的许多平台上制作含有60-100种化合物（10-15毫克）的化合物库，以供HTS使用。本文提出的具体工作包括通过计算方法（包括多样性空间映射）对文库进行验证，使用基于高负载romp试剂和其他支持试剂的便利合成方案，以及基于固相和irori的合成方案。许多文库被提议展示各种各样的支架，包括：(i)激发的肽模拟物，（ii）含硫和含磷的杂环，以及（iii）天然产物样杂环支架。

DESCRIPTION (provided by applicant): The goal of this application is to produce pilot-scale libraries derived from an array of novel heterocyclic scaffolds. We aim to produce "drug-like" and "natural product-like" libraries for HTS in order to maximize the probability of procuring compounds that have a high likelihood of interacting with biomolecular targets. 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. In many cases, the proposed libraries have been identified as part of target-based discovery programs within individual research efforts at the University of Kansas (KU). These efforts are augmented by expertise in a number of Centers of Excellence at the University of Kansas, including centers in: (i) Combinatorial Methodologies and Library Development, (ii) Cancer Experimental Therapeutics, (iii) Protein Structure and Function, and (iv) a state-of-the-art High-Throughput Screening Laboratory. This combination of infrastructure and expertise enables us to produce scalable, diverse libraries based on a wide variety of novel scaffolds and allows us to probe biological and chemical space in a dynamic manner. To accomplish this, libraries containing 60-100 compounds in sufficient quantities (10-15 mgs) for HTS on numerous platforms within the MLSCN will be made. Specific efforts proposed herein include library validation by computational methods including diversity-space mapping, the use of facilitated synthetic protocols based on high-load ROMP-reagents and other supported reagents, and both solution-phase and Irori-based solid phase synthetic protocols. A number of libraries are proposed displaying a diverse array of scaffolds, including: (i) turn-inspired peptidomimetics, (ii) sulfur- and phosphorus-containing heterocycles, and (iii) heterocyclic natural product-like scaffolds.