Discovery of Potent Indenoisoquinoline Topoisomerase I Poisons Lacking the 3‑Nitro Toxicophore

3-Nitroindenoisoquinoline
human topoisomerase IB (Top1) poisons
have potent antiproliferative effects on cancer cells. The undesirable
nitro toxicophore could hypothetically be replaced by other functional
groups that would retain the desired biological activities and minimize
potential safety risks. Eleven series of indenoisoquinolines bearing
3-nitro bioisosteres were synthesized. The molecules were evaluated
in the Top1-mediated DNA cleavage assay and in the National Cancer
Institute’s 60 cell line cytotoxicity assay. The data reveal
that fluorine and chlorine may substitute for the 3-nitro group with
minimal loss of Top1 poisoning activity. The new information gained
from these efforts can be used to design novel indenoisoquinolines
with improved safety.