Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 54, Issue 17, Pages 6106-6116Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm200719v
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Funding
- National Institutes of Health (NIH) [UO1 CA89566]
- National Cancer Institute, Center for Cancer Research
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A series of 7-azaindenoisoquinoline topoisomerase I (Top 1) inhibitors have been prepared to investigate the effect of increased electron affinity of the aromatic system on the ability to stabilize the Top1-DNA cleavage complex. Ab initio calculations suggest that introduction of nitrogen into the aromatic system of the indenoisoquinolines would facilitate charge transfer complex formation with DNA, thus improving the pi-pi stacking interactions. The present study shows that 7-azaindenoisoquinolines demonstrate improved water solubility without any decrease in Top1 inhibitory activity or cytotoxicity. Analysis of the biological results reveals that smaller lactam ring substituents enable intercalation into both free DNA and Top1-DNA cleavage complex, whereas larger substituents only allow binding to the cleavage complex but not free DNA. Free DNA binding suppresses Top1-catalyzed DNA cleavage at high drug concentrations, whereas DNA cleavage and inhibition of religation occurs at low drug concentration.
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