DNA TOPOISOMERASE II AS A THERAPEUTIC TARGET

这项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 链子断了。这些研究将在我们统一模型的指导下进行 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 拓扑异构酶活性物质被建议显示为- 与DNA的凹槽和小槽结合作用，决定了 几类现有智能体的子结构分配 到每个领域，并使预测的“活跃” 构象活动结构的构象。我们的初选 重点将集中在新结构的合成上 类之间具有构造定义的关系 我们模型的DNA嵌入和小槽结合结构域 药效团。我们还将致力于合成 这些域具有一系列空间范围的结构 关系，由于这些结构域的构象自由 子结构，以及分子的构造将不会- 德尔戈显著的结构变化 从“不活跃”构象到“活跃”构象，努力发展 在生物还原过程中被激活的拓扑异构酶活性物质。

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.