DNA TOPOISOMERASE II AS A THERAPEUTIC TARGET

DNA 拓扑异构酶 II 作为治疗靶点

• 批准号: 2095847
• 负责人: TIMOTHY L MACDONALD
• 金额: $ 14.42万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-03-01 至 1995-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2095847
• 关键词: DNA damage; DNA topoisomerases; antineoplastics; biophysics; chemical cleavage; drug design /synthesis /production; drug metabolism; enzyme substrate complex; molecular dynamics; neoplasm /cancer pharmacology; pharmacokinetics

The goal of this research is to design and synthesize new agents which induce DNA topoisomerase II to form enzyme-bound DNA strand breaks. These studies will be guided by our unifying model for the pharmacophore of drugs with topoisomerase activity. This model pharmacophore has described three structural domains of topoisomerase active agents that are proposed to exhibit intercala- tion and minor groove binding interactions with DNA, dictated the assignment of substructures of several existing classes of agents to each domain, and enabled the prediction of the "active" conformation for conformationally mobile structures. Our primary focus will be directed toward the synthesis of new structural classes that possess conformationally defined relationships between the DNA intercalation and minor groove binding domains of our model pharmacophore. We will also devote effort to the synthesis of structures in which these domains possess a range of spatial relationships, due to the conformational freedom of these domain substructures, and to the construction of molecules that will un- dergo significant structural alteration upon reduction from "inactive" to "active" conformations, in efforts to develop topoisomerase active agents that are activated upon bioreduction.

本研究的目标是设计和合成新的 诱导 DNA 拓扑异构酶 II 形成酶结合 DNA 的试剂 链断裂。 这些研究将以我们的统一模型为指导 用于具有拓扑异构酶活性的药物的药效团。 这 模型药效团描述了三个结构域 拓扑异构酶活性剂被提议表现出嵌入 化和小沟与DNA的结合相互作用，决定了 几个现有代理类别的子结构的分配 到每个域，并启用“活动”的预测 构象移动结构的构象。 我们的小学 重点将转向新结构的合成 具有构象定义关系的类 我们模型的 DNA 嵌入和小沟结合域 药效团。 我们还将致力于综合 这些域拥有一系列空间的结构 由于这些结构域的构象自由度，关系 子结构，以及分子的构建 dergo 减少后会发生重大结构变化 “不活跃”向“活跃”构象，努力发展 在生物还原时被激活的拓扑异构酶活性剂。