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Download fileOptimization of the Lactam Side Chain of 7‑Azaindenoisoquinoline Topoisomerase I Inhibitors and Mechanism of Action Studies in Cancer Cells
journal contribution
posted on 17.12.2015, 00:48 authored by Evgeny Kiselev, Dhriti Sooryakumar, Keli Agama, Mark Cushman, Yves PommierOptimization
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 14–17 and 19 exhibited
mean graph midpoint cytotoxicity (GI50) 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.
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Keywords
Lactam Side Chaingraph midpoint cytotoxicityABCB 1 drug efflux transporterGI2AXMolecular modeling studiescancer cell culturesHCT 116 cellsHCT 116 colon cancer cellsanticancer agentslactam side chaincancer cell cytotoxicitiesDNA cleavage sitecomplexDNA content distribution histogramsazaindenoisoquinolineNCI