Diversity Space with Novel Pilot Scale Libraries (RMI)

描述(申请人提供)：本申请的目标是从一系列新型杂环支架中衍生出中试规模的文库。我们的目标是为HTS建立“类药物”和“类天然产物”文库，以最大限度地增加获得与生物分子靶标相互作用的可能性很高的化合物的可能性。最终，这些文库将通过分子文库筛选网络(MLSCN)进行评估，以揭示进一步开发的铅结构。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。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。堪萨斯大学许多卓越中心的专业知识加强了这些努力，这些中心包括：(I)组合方法学和图书馆开发，(Ii)癌症实验治疗，(Iii)蛋白质结构和功能，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新的支架创建可扩展的、多样化的库，并允许我们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内的许多平台上建立包含60-100个足够数量(10-15毫克)HTS的化合物的库。本文提出的具体努力包括通过包括多样性-空间映射在内的计算方法进行文库验证，使用基于高负载ROMP试剂和其他支持试剂的促进合成方案，以及溶液相和基于irori的固相合成方案。一些文库被提议展示一系列不同的支架，包括：(I)受转折启发的多肽模拟物，(Ii)含硫和磷的杂环，和(Iii)杂环天然产物类支架。

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.