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: 6269453
• 负责人: LEON H. ZALKOW
• 金额: $ 15.96万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6269453
• 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传导改变的疾病。 这些研究的目的是鉴定和开发新的天然药物， 癌基因信号通路的产物抑制剂， 治疗和预防癌症。 这些信号目标将 使用的酶包括磷脂信号传导酶（磷脂酰肌醇 磷脂酶C、磷脂酰肌醇-3-激酶和磷脂酶D）， 蛋白丝氨酸/苏氨酸激酶（Raf-1激酶、MEK激酶和MAP-1激酶）， 激酶）和调节细胞周期的酶（cdc 26磷酸酶和 cdk 4激酶）。天然产品的来源将是植物， 传统中药，美洲土著药用植物，真菌 提取物和天然产物的组合文库 分子（“祖细胞”）。确定的中国合作者将 透过香港提供覆盖草本植物主要生境的植物， 在中国的增长。容易获得的天然产品， 生物活性，将被用作“生物支架”， 不同的产品混合物（“前体”），通过使用非选择性 试剂、反应和/或反应条件。活跃的潜在客户将 通过生物测定指导的指纹图谱鉴定， 液相色谱法，以获得每种粗提取物或混合物 “前体”，96孔微量滴定板中的级分，其将被 提交筛选。每一部分的指纹都将 以二极管收集的紫外/可见光谱的形式提供 阵列检测器并存储在数据库中。 论主动的识别 分数，将检索原始参比平板，并进行质量分析。 光谱和核磁共振和其他光谱数据将收集在积极的 威尔斯完成指纹鉴定。这个指纹将用于 选择所需材料进行进一步纯化和测试 结构解析将通过有机化学中最先进的方法进行。 化学.具有与活性化合物类似结构的化合物 将通过合成或从其他来源获得，如果可行， 筛选出在生物化学中表现出活性的纯化合物 将评价靶筛选的生长抑制活性， 体外肿瘤细胞和那些具有足够体外活性的化合物 将在体内进一步评估。 有前途的临床前开发 先导化合物将由我们的商业合作者进行。