DIVERSE NATURAL PRODUCTS FROM ISOLATION AND CHEMICAL MODIFICATION

通过分离和化学改性获得多种天然产品

• 批准号: 6237153
• 负责人: LEON H. ZALKOW
• 金额: $ 15.36万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-20 至 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6237153
• 关键词: alkaloids; analytical chemistry; antineoplastics; bioassay; biological products; biological signal transduction; cell cycle proteins; chemical fingerprinting; chemical registry /resource; chemical structure function; cooperative study; drug design /synthesis /production; drug screening /evaluation; enzyme inhibitors; flavones; high performance liquid chromatography; medicinal plants; microorganism culture; phosphatidylinositol 3 kinase; phospholipase C; phospholipase D; plant extracts; protein kinase; yeasts

Cancer can be considered a disease of altered intercellular signalling. The goal of these studies is to identify and develop novel natural product inhibitors of oncogene signalling pathways for the effective treatment and prevention of cancer. The signalling targets which will be used include enzymes of phospholipid signaliing (phosphatidylinositol phospholipase C, phosphatidylinositol-3-kinase and phospholipase D), protein serine/threonine kinases (Raf-1 kinase, MEK kinase and MAP- kinase) and enzymes that regulate the cell Cycle (cdc26 phosphatase and cdk4 kinase). The sources of the natural products will be plants used in traditional Chinese medicine, native Americans' medicinal plants, fungal extracts, and combinatorial libraries of natural product derived molecules ("progenomers"). Identified collaborators in China will provide, via Hong Kong, plants which cover the major habitats of herbal growth in China. Readily available natural products with interesting biological activities, will be used as "biological scaffolds" to prepare diverse mixtures of products ("progenomers") by use of non-selective reagents, reaction and/or reaction conditions. Active leads will be identified by bioassay-directed fingerprinting using high performance liquid chromatography to obtain for each crude extract or mixture of "progenomers", fractions in 96 well microtiter plates, which will be submitted for screening. Fingerprints of each of these fractions will be available in the form of ultraviolet/visible spectra collected by a diode array detector and stored in a data bank. On identification of active fractions, the original reference plate will be retrieved and mass spectra and NMR and other spectral data will be collected on the active wells to complete the fingerprinting. This fingerprint will be used to recollect the desired material for further purification and testing Structure elucidation will be done by state of the art methods in organic chemistry. Compounds of analogous structures to those found to be active will be obtained by synthesis or from other sources, where practical, and screened. The pure compounds exhibiting activity in the biochemical target screens will be evaluated for growth inhibitory activity against tumor cells in vitro and those compounds of sufficient in vitro activity will be further evaluated in vivo. Preclinical development of promising lead compounds will be carried out by our commercial collaborator.

癌症可以被认为是细胞间信号改变的疾病。 这些研究的目的是识别和发展新颖的自然 有效的癌基信号通路的产品抑制剂 治疗和预防癌症。 信号目标将 使用包括磷脂信号的酶（磷脂酰肌醇 磷脂酶C，磷脂酰肌醇-3-激酶和磷脂酶D），D） 蛋白质丝氨酸/苏氨酸激酶（RAF-1激酶，MEK激酶和MAP- 激酶）和调节细胞周期的酶（CDC26磷酸酶和 CDK4激酶）。天然产品的来源将用于使用 中医，美洲原住民的药用植物，真菌 衍生的自然产品的提取物和组合库 分子（“祖细胞”）。确定的中国合作者将 通过香港提供覆盖草药主要栖息地的植物 中国的增长。随时可用的天然产品，有趣 生物活动将用作“生物支架”来准备 通过使用非选择性的产品（“祖细胞”）的多种混合物（“祖细胞”） 试剂，反应和/或反应条件。活跃的线索将是 通过使用高性能的生物测定指纹指纹标识 液相色谱，以获取每种原油提取物或混合物的混合物 “祖细胞”，96个井板板中的分数，这将是 提交筛选。这些分数的指纹将是 以二极管收集的紫外线/可见光谱的形式获得 数组检测器并存储在数据库中。 在识别活动 分数，原始参考板将被检索并质量 光谱和NMR以及其他光谱数据将在活动上收集 井来完成指纹。该指纹将用于 回顾所需的材料以进一步纯化和测试 结构阐明将通过有机状态的最新方法进行 化学。与发现活性的类似结构的化合物 将通过综合或其他来源（实际和其他来源）获得 筛选。在生化中表现活性的纯化合物 目标筛查将评估针对生长抑制活性 体外肿瘤细胞和足够体外活性的化合物 将进一步评估体内。 有前途的临床前发展 铅化合物将由我们的商业合作者进行。