DNA TOPOISOMERASE II AS A THERAPEUTIC TARGET

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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.