Synthesis and Biological Evaluation of Nitrated 7‑, 8‑, 9‑, and 10-Hydroxyindenoisoquinolines as Potential Dual Topoisomerase I (Top1)–Tyrosyl-DNA Phosphodiesterase I (TDP1) Inhibitors

The
structure–activity relationships and hit-to-lead optimization
of dual Top1–TDP1 inhibitors in the indenoisoquinoline drug
class were investigated. A series of nitrated 7-, 8-, 9-, and 10-hydroxyindenoisoquinolines
were synthesized and evaluated. Several compounds displayed potent
dual Top1–TDP1 inhibition. The 9-hydroxy series exhibited potencies
and cytotoxicities vs Top1 that surpassed those of camptothecin (CPT),
the natural alkaloid that is being used as a standard in the Top1-mediated
DNA cleavage assay. One member of this series was a more potent Top1
inhibitor at a concentration of 5 nM and produced a more stable ternary
drug–DNA–Top1 cleavage complex than CPT.