"Drug-Like" Marine Natural Products Library

“类药”海洋天然产物库

• 批准号: 7192660
• 负责人: Lyndon Michael West
• 金额: $ 31.76万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7192660
• 关键词: Cnidaria; NIH Roadmap Initiative tag; Porifera; Tunicata; amphiphilicity; aquatic organism; biological products; biomedical resource; biotechnology; biotherapeutic agent; chemical registry /resource; chemical structure; cytotoxicity; drug discovery /isolation; high performance liquid chromatography; high throughput technology; liquid chromatography; molecular polarity; nuclear magnetic resonance spectroscopy; saltwater environment

DESCRIPTION (provided by applicant): Marine organisms are a rich source of compounds with unprecedented chemical structures and biological activity. My long-term research goals are to isolate new biologically active compounds from marine organisms that can be used as molecular probes or drug leads relevant to human diseases. The overall objective of this research proposal is to generate a pilot-scale library of marine natural products with "drug like" properties. The specific hypothesis of this proposal is that we can exploit the amphiphilic nature of most biological active compounds (cytotoxic and non-cytotoxic) and the separation efficiency of polymeric resin to isolate compounds with a high probability of exhibiting in vitro and in vivo activity. The hypothesis is based on the following observations. First, by necessity, most bioactive compounds are required to be at least partially soluble in both hydrophilic and hydrophobic environments in order to reach the intended site of their activity and consequently are neither extremely polar nor non-polar in character (intermediate polarity). Second, crude organic extracts of marine organisms are comprised largely of water soluble salts, proteins and carbohydrates and very non-polar fats and steroids. Third, the use of the polymeric resin to fractionate the crude extract, instead of traditional silica based stationary phases, results in the efficient separation of biologically active compounds of intermediate polarity from the polar and non-polar compounds. The specific aims of this proposal are to 1) make additional targeted collections of marine organisms, 2) concentrate compounds from the crude extract with a high potential for being biologically active, and 3) isolate and characterize the "drug-like" compounds from the medium polarity fractions. The compounds provided to the Molecular Libraries Screening Center Network (MLSCN) will be accompanied by analytical purity and structural elucidation data together with record of the organism's collection and isolation scheme to permit re-isolation of the compounds. Achieving the specific aims outlined in this proposal will allow the generation of a structurally diverse "drug-like" marine natural products library that can be used by the MLSCN for high throughput screening to explore function at the molecular, cellular, and in vivo level to treat diseases. This study is also likely to yield many previously reported compounds of undetermined activity or mechanism that can be added to the MLSCN Library for screening.

描述（由申请人提供）：海洋生物是具有前所未有的化学结构和生物活性的化合物的丰富来源。我的长期研究目标是从海洋生物中分离出新的生物活性化合物，这些化合物可以用作与人类疾病相关的分子探针或药物先导物。 该研究计划的总体目标是建立一个具有“类药物”特性的中试规模海洋天然产物库。 该提案的具体假设是，我们可以利用大多数生物活性化合物（细胞毒性和非细胞毒性）的两亲性质和聚合树脂的分离效率来分离很有可能表现出体外和体内活性的化合物。 该假设基于以下观察。 首先，大多数生物活性化合物必须至少部分溶解在亲水和疏水环境中，以便到达其活性的预期位点，因此在性质上既不是极端极性也不是非极性（中等极性）。 其次，海洋生物的粗有机提取物主要由水溶性盐、蛋白质和碳水化合物以及非常非极性的脂肪和类固醇组成。 第三，使用聚合物树脂代替传统的基于二氧化硅的固定相来分馏粗提物，导致中等极性的生物活性化合物与极性和非极性化合物的有效分离。 该提案的具体目标是 1) 收集更多有针对性的海洋生物，2) 浓缩粗提物中具有高生物活性潜力的化合物，以及 3) 分离和表征来自海洋生物的“类药物”化合物。中等极性分数。 提供给分子库筛选中心网络（MLSCN）的化合物将附有分析纯度和结构阐明数据以及生物体收集和分离方案的记录，以允许重新分离化合物。实现该提案中概述的具体目标将能够生成结构多样化的“类药物”海洋天然产物库，MLSCN 可以使用该库进行高通量筛选，以探索分子、细胞和体内水平的功能，从而治疗疾病。 这项研究还可能产生许多先前报道的活性或机制未确定的化合物，这些化合物可以添加到 MLSCN 库中进行筛选。