Production of Pilot Scale Libraries of Marine Natural Products

描述(由申请人提供)：该项目的目标是通过向分子图书馆小分子储存库(MLSMR)提供一个中试规模的文库(PSL)，每年有10-25种新颖或稀有的结构复杂的海洋天然产物，从而扩大分子图书馆探针生产中心网络(MLPCN)可用的化学多样性。这些化合物将来自HBOI冰冻生物库中的海洋大型生物，包括海绵、海鞘动物、海鞘动物和藻类，重点是从较难获得的深水海洋环境中收集的生物。该项目的主要重点将是提供在结构上对科学来说是新的化合物，但除此之外，还将提供具有不寻常结构的稀有天然产品，这些产品目前在MLSMR中无法获得。所有提供的化合物都将符合MLSMR的标准，即10 mg，90%的纯度和在氯仿：甲醇9：1或DMSO中的溶解度。HBOI拥有超过15,000种海洋生物的特殊收藏，可用于建立中试规模的图书馆，其中许多生物是HBOI收藏所独有的。我们的研究小组最近进行了一个项目，创建了一个与高通量筛选相兼容的富集组分峰文库，在检测过去没有进行过化学研究的生物体中的不寻常化学类型方面取得了巨大的成功。峰库中的大多数馏分只需要一个额外的纯化步骤就可以提供纯物质，初始分级(中压液相色谱)的规模很容易导致分离出更大数量的物质。我们最近扩大了HBOI筛选平台，并观察到在Peak文库中发现的许多新的化学类型影响独特的生物靶点，并代表着新的铅结构和用于研究生物过程的优秀探针。我们将在用于生产我们的Peak库的方法的基础上，创建一个独特的纯不寻常天然产品的中试规模库，以扩大MLSMR目前可用的化学多样性空间。 与公共健康相关：拟议的研究项目将向分子库小分子库提供一个独特的新的和稀有天然产物的中试规模库，并扩大库中化学物质的多样性。这将增加分子路线图实现其目标的机会，即发现与人类健康有关的生物机制以及具有独特生物活性的化合物的新探测器。

DESCRIPTION (provided by applicant): The goal of this project is expand the chemical diversity available to the Molecular Library Probe Production Center Network (MLPCN) by providing the Molecular Libraries Small-Molecule Repository (MLSMR) a pilotscale library (PSL) of 10-25, novel or rare, structurally complex marine natural products per year. The compounds will be derived from marine macro-organisms in the HBOI Frozen Organism Repository including sponges, ascidians, cnidarians, and algae with an emphasis on organisms collected from less accessible deep-water marine environments. The primary focus of the project will be to provide compounds that are structurally new to science but in addition to these, rare natural products with unusual structures that are not currently available to the MLSMR will also be provided. All compounds provided will meet the MLSMR's criteria of 10 mg, > 90% purity and solubility in either chloroform:methanol 9:1 or DMSO. HBOI has an exceptional collection of over 15,000 marine organisms that can be used in generation of the pilot-scale library with many of the organisms being unique to the HBOI collection. A recent project conducted by our research group to create a "Peak Library" of enriched fractions compatible with high throughput screening, has been highly successful in detecting unusual chemotypes in organisms which had not been chemically investigated in the past. The majority of the fractions in the Peak Library require only one additional purification step to provide pure materials and the scale of the initial fractionation (medium pressure liquid chromatography) leads readily to the isolation of larger quantities of materials. We have recently expanded the HBOI screening platform and have observed that many of the novel chemotypes found in the Peak Library affect unique biological targets and represent novel lead structures and excellent probes for studying biological processes. We will build upon the methods used to produce our Peak Library to create a unique pilot scale library of pure unusual natural products that expands the chemical diversity space currently available in the MLSMR. PUBLIC HEALTH RELEVANCE: The proposed research project will provide a unique pilot scale library of new and rare natural products to the Molecular Libraries Small Molecule Repository and expand the chemical diversity of the library. This will enhance the Molecular Roadmap's opportunities for meeting their goal of discovering new probes of biological mechanisms as well as compounds with unique biological activities relative to human health.