ArticleJournal of medicinal chemistry2014
Optimization of the lactam side chain of 7-azaindenoisoquinoline topoisomerase I inhibitors and mechanism of action studies in cancer cells.
Article in Journal of medicinal chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 46 citations in OpenAlex.
- Design, Synthesis and Bioactive Evaluation of Topo I/Molecules (Basel, Switzerland) · 2025Article
- Design, Synthesis, and Investigation of the Pharmacokinetics and Anticancer Activities of Indenoisoquinoline Derivatives That Stabilize the G-Quadruplex in theJournal of medicinal chemistry · 2024Article
- Rh-Catalyzed Cascade C-H Activation/Annulation ofMolecules (Basel, Switzerland) · 2022Article
- Indenoisoquinoline Topoisomerase Inhibitors Strongly Bind and Stabilize theJournal of the American Chemical Society · 2019Article
- Discovery, Synthesis, and Evaluation of Oxynitidine Derivatives as Dual Inhibitors of DNA Topoisomerase IB (TOP1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1), and Potential Antitumor Agents.Journal of medicinal chemistry · 2018Article
- Interlinked DNA nano-circles for measuring topoisomerase II activity at the level of single decatenation events.Nucleic acids research · 2017Article
- Design and Synthesis of Chlorinated and Fluorinated 7-Azaindenoisoquinolines as Potent Cytotoxic Anticancer Agents That Inhibit Topoisomerase I.Journal of medicinal chemistry · 2017Article
- Synthesis and Biological Evaluation of the First Triple Inhibitors of Human Topoisomerase 1, Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), and Tyrosyl-DNA Phosphodiesterase 2 (Tdp2).Journal of medicinal chemistry · 2017Article
- Design, Synthesis, and Biological Evaluation of Potential Prodrugs Related to the Experimental Anticancer Agent Indotecan (LMP400).Journal of medicinal chemistry · 2016Article
- Investigation of the Structure-Activity Relationships of Aza-A-Ring Indenoisoquinoline Topoisomerase I Poisons.Journal of medicinal chemistry · 2016Article
- Synthesis of indolo[4,3-Synthetic communications · 2016Article
- Discovery of potent indenoisoquinoline topoisomerase I poisons lacking the 3-nitro toxicophore.Journal of medicinal chemistry · 2015Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
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 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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