Several 6H-indeno[1,2-c]isoquinolin-5,11-diones and 5H-dibenzo[c,h][1,6]naphthyridin-6-ones were synthesized and evaluated for their relative topoisomerase I-targeting activity and cytotoxicity. Comparative studies were performed in P388, RPMI8402, and U937 tumor cell lines, as well as their camptothecin-resistant variants, i.e. P388 / CPT45, CPT-K5, and U937 / CR, respectively. The relative cytotoxic activity of these compounds in cell lines known to overexpress efflux transporters that are associated with multidrug resistance or are known to be resistant to topoisomerase II-targeting agents was also determined. Our results suggest that some of these compounds are highly potent TOP1-specific poisons with cytotoxic activity rivaling that of camptothecin and different drug-resistant profiles.