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.

该实验室计划的长期目标是确定 适合发育的化合物作为抗肿瘤剂。 在项目期间 期间，目标包括： （1）利用基于酵母的屏幕来识别DNA破坏剂 机械上独特的物种，其行为表明潜在的效用为 抗肿瘤剂。 （2）利用拓扑异构酶I作为开发新的轨迹 通过分离拓扑异构酶I的其他抑制剂，抗肿瘤剂I 功能，产生大量鉴定的结构类似物 使用组合化学技术的抑制剂，并开发几种 可用于识别那些拓扑异构酶的次级鉴别因子 我的抑制剂可能是抗肿瘤剂的实用性。 （3）获得更有效的DNA聚合酶β抑制剂，以便它是 可以完成这些假设的测试，即这些药物可以 增强作用的抗肿瘤剂活性的细胞毒性活性 通过创建DNA病变，并证明这种抑制剂的能力 增强药物（例如博来霉素）的抗肿瘤活性 和Calicheamicin （4）优先考虑由概述的研究确定的铅化合物 上面并获得数量最有希望的化合物 足以在实验动物模型/初始动物模型中进行抗肿瘤评估 临床前发展 （5）通过通过 从手头准备的植物样品中准备其他植物提取物。