Design and Synthesis of Chlorinated and Fluorinated 7‑Azaindenoisoquinolines as Potent Cytotoxic Anticancer Agents That Inhibit Topoisomerase I

The
7-azaindenoisoquinolines are cytotoxic topoisomerase I (Top1)
inhibitors. Previously reported representatives bear a 3-nitro group.
The present report documents the replacement of the potentially genotoxic
3-nitro group by 3-chloro and 3-fluoro substituents, resulting in
compounds with high Top1 inhibitory activities and potent cytotoxicities
in human cancer cell cultures and reduced lethality in an animal model.
Some of the new Top1 inhibitors also possess moderate inhibitory activities
against tyrosyl-DNA phosphodiesterase 1 (TDP1) and tyrosyl-DNA phosphodiesterase
2 (TDP2), two enzymes that are involved in DNA damage repair resulting
from Top1 inhibitors, and they produce significantly more DNA damage
in cancer cells than in normal cells. Eighteen of the new compounds
had cytotoxicity mean-graph midpoint (MGM) GI50 values
in the submicromolar (0.033–0.630 μM) range. Compounds 16b and 17b are the most potent in human cancer
cell cultures with MGM GI50 values of 0.063 and 0.033 μM,
respectively. Possible binding modes to Top1 and TDP1were investigated
by molecular modeling.