Optimization of the Lactam
Side Chain of 7‑Azaindenoisoquinoline Topoisomerase I Inhibitors
and Mechanism of Action Studies in Cancer Cells
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Abstract
Optimization
of the lactam ω-aminoalkyl substituents in a
series of 7-azaindenoisoquinolines resulted in new anticancer agents
with improved Top1 inhibitory potencies and cancer cell cytotoxicities.
The new compounds <b>14–17</b> and <b>19</b> exhibited
mean graph midpoint cytotoxicity (GI<sub>50</sub>) values of 21–71
nM in the NCI panel of 60 human cancer cell cultures. Ternary 7-azaindenoisoquinoline–DNA–Top1
cleavage complexes that persist for up to 6 h were detected in HCT116
colon cancer cells. Ternary complexes containing 7-azaindenoisoquinolines
were significantly more stable than those in which camptothecin was
incorporated. DNA content distribution histograms showed S-phase block
3 h after drug removal. Drug-induced DNA damage in HCT116 cells was
revealed by induction of the histone γ-H2AX marker. The 7-azaindenoisoquinolines
were able to partially overcome resistance in several drug-resistant
cell lines, and they were not substrates for the ABCB1 drug efflux
transporter. Molecular modeling studies indicate that the 7-azaindenoisoquinolines
intercalate at the DNA cleavage site in DNA–Top1 covalent complexes
with the lactam side chain projecting into the major groove. Overall,
the results indicate that the 7-azaindenoisoquinolines are promising
anticancer agents that merit further development