Design, Synthesis, and Biological Evaluation of O‑2-Modified Indenoisoquinolines as Dual Topoisomerase I–Tyrosyl-DNA Phosphodiesterase I Inhibitors

Tyrosyl-DNA
phosphodiesterase I (TDP1) repairs stalled topoisomerase
I (Top1)–DNA covalent complexes and has been proposed to be
a promising and attractive target for cancer treatment. Inhibitors
of TDP1 could conceivably act synergistically with Top1 inhibitors
and thereby potentiate the effects of Top1 poisons. This study describes
the successful design and synthesis of 2-position-modified indenoisoquinolines
as dual Top1–TDP1 inhibitors using a structure-based drug design
approach. Enzyme inhibition studies indicate that indenoisoquinolines
modified at the 2-position with three-carbon side chains ending with
amino substituents show both promising Top1 and TDP1 inhibitory activity.
Molecular modeling of selected target compounds bound to Top1 and
TDP1 was used to rationalize the enzyme inhibition results and structure–activity
relationship analysis.