NUCLEAR TARGETS FOR NATURAL PRODUCTS DRUG DISCOVERY

天然产物药物发现的核目标

• 批准号: 6352741
• 负责人: Sidney Michael Hecht
• 金额: $ 14.83万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2000-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6352741
• 关键词: DNA damage; DNA directed DNA polymerase; DNA topoisomerases; antineoplastics; aquatic organism; biological products; chromatography; combinatorial chemistry; cytotoxicity; drug discovery /isolation; drug interactions; drug screening /evaluation; enzyme inhibitors; plant extracts; yeasts

The long term objective of this Laboratory Program is the identification of compounds suitable for development as antitumor agents. During the project period, objectives include: (1) utilizing yeast-based screens for DNA damaging agents to identify mechanistically unique species whose behavior suggests potential utility as antitumor agents. (2) utilizing topoisomerase I as a locus for the development of new antitumor agents by isolating additional inhibitors of topoisomerase I function, producing large numbers of structural analogues of identified inhibitors using combinatorial chemistry techniques, and developing several secondary discriminators that can be used to identify those topoisomerase I inhibitors likely to be of utility as antitumor agents. (3) obtaining more potent inhibitors of DNA polymerase beta so that it is possible to complete the testing of the hypothesis that these agents can potentiate the cytotoxic activity of activity of antitumor agents that act by creating DNA lesions, and demonstrate the ability of such inhibitors to potentiate the antitumor activity of agents such as bleomycin, esperamicin and calicheamicin (4) prioritizing the lead compounds identified by the studies outlined above and obtaining the most promising compounds in quantitities sufficient for antitumor evaluation in experimental animal models/initial preclinical development (5) enhancing our prospects for identifying novel antitumor agents by preparing additional plant extracts from plant samples already in hand.

本实验室计划的长期目标是确定 适合开发为抗肿瘤剂的化合物。 在项目 在此期间，目标包括： （一） 利用基于酵母的DNA损伤剂筛选， 机械独特的物种，其行为表明潜在的效用， 抗肿瘤剂。 (2)利用拓扑异构酶I作为开发新的 通过分离附加的拓扑异构酶I抑制剂的抗肿瘤剂 功能，产生大量的结构类似物的鉴定 抑制剂，使用组合化学技术，并开发几个 可用于识别那些拓扑异构酶的二级鉴别器 I抑制剂可能用作抗肿瘤剂。 (3)获得更有效的DNA聚合酶β抑制剂， 有可能完成对假设的测试，即这些代理人可以 增强抗肿瘤剂的细胞毒活性， 通过创建DNA损伤，并证明这种抑制剂的能力， 增强药物如博来霉素、埃斯波霉素 和加利车霉素 (4)优先考虑由概述的研究确定的先导化合物 并获得最有前途的化合物的数量 足以在实验动物模型中进行抗肿瘤评价/初始 临床前开发 (5)通过以下方法提高我们鉴定新型抗肿瘤药物的前景： 从已有的植物样品中制备额外的植物提取物。