Design, Synthesis, and BiologicalEvaluation of O-2-ModifiedIndenoisoquinolines as Dual Topoisomerase I–Tyrosyl-DNA PhosphodiesteraseI Inhibitors.

Tyrosyl-DNAphosphodiesterase I (TDP1) repairs stalled topoisomeraseI (Top1)–DNA covalent complexes and has been proposed to bea promising and attractive target for cancer treatment. Inhibitorsof TDP1 could conceivably act synergistically with Top1 inhibitorsand thereby potentiate the effects of Top1 poisons. This study describesthe successful design and synthesis of 2-position-modified indenoisoquinolinesas dual Top1–TDP1 inhibitors using a structure-based drug designapproach. Enzyme inhibition studies indicate that indenoisoquinolinesmodified at the 2-position with three-carbon side chains ending withamino substituents show both promising Top1 and TDP1 inhibitory activity.Molecular modeling of selected target compounds bound to Top1 andTDP1 was used to rationalize the enzyme inhibition results and structure–activityrelationship analysis. [ABSTRACT FROM AUTHOR]