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 structureactivity 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 drugDNATop1 cleavage complex than CPT.