Pilot-Scale Libraries Based on Nucleoside Templates for the ML Initiative

描述（由申请人提供）：许多大型的、可公开访问的商业文库是基于平面杂环芳香支架的，在三维空间填充和构象迁移方面缺乏药物载体的多样性。因此，美国国立卫生研究院的试点图书馆计划是为了追求目前可用的图书馆无法代表的独特化学多样性而创建的。天然产物已经开采了几个世纪，以满足对生物活性物质的需求，目前在临床使用的药物中占很大比例。根据定义，天然产物本质上偏向于生物可利用性和活性，从天然产物中衍生的文库具有独特的三维结构特征，比从纯合成试剂中衍生的更简单的化合物更复杂。因此，我们计划利用独特的、普遍可用的天然产物模板来制备新的库，这些库在当前的商业库和分子库小分子库（MLSMR）中代表性不足。该计划的具体目标包括易获取的天然产物核苷支架的战略性多样性。我们将从三个特定目标中制备1400个高纯度和新颖的样品，并根据项目要求将每种样品的10至20毫克作为干粉提供给MLSMR。这些样本将被仔细筛选，以确保它们不被专利覆盖，以确保不受阻碍的使用，并且根据NIH资源共享要求，所有样本数据（合成方法和分析）将免费提供给科学界。NIH MLSMR的化学多样性的丰富应提高鉴定的前景

DESCRIPTION (provided by applicant): Many of the large, publicly accessible commercial libraries are based on planar heterocyclic aromatic scaffolds that lack variety as pharmacophores in terms of three dimensional space filling and conformational mobility. As such, the Pilot Library Program of the NIH was created to pursue unique chemical diversity not represented by currently available libraries. Natural products have been mined for centuries to fulfill the need for bioactive substances and currently comprise a large proportion of clinically used drugs. By definition, natural products are inherently biased towards biological availability and activity, and libraries derived there from possess unique three-dimensional structural features and are more complex than simpler compounds derived from purely synthetic reagents. Hence, we plan to take advantage of unique, commonly available natural product templates for the preparation of new libraries that are underrepresented in current commercial libraries and the Molecular Library Small Molecule Repository (MLSMR). The specific aims of this program include strategic diversity-oriented elaboration of readily accessible natural product nucleoside scaffolds. We will prepare 1400 highly pure and novel samples from the three specific aims and supply between 10 to 20 mg of each sample as dry powders to the MLSMR as per program requirements. These samples will be carefully screened to guarantee that they are not covered through patents in order to ensure unencumbered usage, and all data on the samples (synthetic methods and analyses) will be made freely accessible to the scientific community as per NIH Resource Sharing requirements. The enrichment of the chemical diversity of the NIH MLSMR should enhance the prospect of identifying biochemical tools to probe a variety of biological targets of relevance in health and disease. Moreover, the screening of the libraries and free accessibility of those data will stimulate research that should ultimately lead to improvements in our knowledge of systems biology and the living organism. Advances from this effort may eventually lead to new therapeutics, especially for rare or marginalized disorders thus benefiting overall public health.