The indenoisoquinoline noncamptothecin topoisomerase I inhibitors: update and perspectives
2009/04/22 by Yves Pommier, Mark Cushman · 5 citations
Biochemistry, Genetics and Molecular Biology · Medicine · #Cancer therapeutics and mechanisms #Antibiotics Pharmacokinetics and Efficacy #Lung Cancer Research Studies
paper · pdf · doi:10.1158/1535-7163.mct-08-0706
openalex publication_date 2009/04/22 · openalex created_date 2016/06/24 · openalex updated_date 2026/08/01
Abstract
Because camptothecins are effective against previously resistant tumors and are the only class of topoisomerase I (Top1) inhibitors approved for cancer treatment, we developed the indenoisoquinolines. Like camptothecins, the indenoisoquinolines selectively trap Top1-DNA cleavage complexes and have been cocrystallized with the Top1-DNA cleavage complexes. Indenoisoquinolines show antitumor activity in animal models. They have several advantages over the camptothecins: (a) They are synthetic and chemically stable. (b) The Top1 cleavage sites trapped by the indenoisoquinolines have different genomic locations, implying differential targeting of cancer cell genomes. (c) The Top1 cleavage complexes trapped by indenoisoquinolines are more stable, indicative of prolonged drug action. (d) They are seldom or not used as substrates for the multidrug resistance efflux pumps (ABCG2 and MDR-1). Among the >400 indenoisoquinolines synthesized and evaluated, three have been retained as leads for clinical development by the National Cancer Institute: NSC 706744, NSC 725776 (Indimitecan), and NSC 724998 (Indotecan). The trapping of Top1 cleavage complexes by indenoisoquinolines in cells results in the rapid and sustained phosphorylation of histone H2AX (γ-H2AX). We discuss the use of γ-H2AX as a pharmacodynamic biomarker for the clinical development of the indenoisoquinolines.
Citations
- Bisindenoisoquinoline Bis-1,3-(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-6-propylaminopropane bis(trifluoroacetate) (NSC 727357), a DNA Intercalator and Topoisomerase Inhibitor with Antitumor Activity
- Synthesis and antiproliferative evaluation of certain indeno[1,2-c]quinoline derivatives
- Nitrated Indenoisoquinolines as Topoisomerase I Inhibitors: A Systematic Study and Optimization
- Topoisomerase I inhibitors: selectivity and cellular resistance
- Next generation topoisomerase I inhibitors: Rationale and biomarker strategies
- Convenient synthesis of indeno[1,2-c]isoquinolines as constrained forms of 3-arylisoquinolines and docking study of a topoisomerase I inhibitor into DNA–topoisomerase I complex
- Synthesis and Biological Evaluation of Bisindenoisoquinolines as Topoisomerase I Inhibitors
- Design, Synthesis, and Biological Evaluation of Indenoisoquinoline Topoisomerase I Inhibitors Featuring Polyamine Side Chains on the Lactam Nitrogen
- Histone H2A variants H2AX and H2AZ
- Evaluation of indenoisoquinoline topoisomerase I inhibitors using a hollow fiber assay
- Optimization of the Indenone Ring of Indenoisoquinoline Topoisomerase I Inhibitors
- Structures of Three Classes of Anticancer Agents Bound to the Human Topoisomerase I−DNA Covalent Complex
- Cellular Topoisomerase I Inhibition and Antiproliferative Activity by MJ-III-65 (NSC 706744), an Indenoisoquinoline Topoisomerase I Poison
- Synthesis and Mechanism of Action Studies of a Series of Norindenoisoquinoline Topoisomerase I Poisons Reveal an Inhibitor with a Flipped Orientation in the Ternary DNA−Enzyme−Inhibitor Complex As Determined by X-ray Crystallographic Analysis
- Camptothecins and Topoisomerase I; A Foot in the Door. Targeting the Genome Beyond Topoisomerase I with Camptothecins and Novel Anticancer Drugs; Importance of DNA Replication, Repair and Cell Cycle Checkpoints
- Synthesis and Evaluation of Indenoisoquinoline Topoisomerase I Inhibitors Substituted with Nitrogen Heterocycles
- A novel norindenoisoquinoline structure reveals a common interfacial inhibitor paradigm for ternary trapping of the topoisomerase I-DNA covalent complex
- Synthesis of New Indeno[1,2-c]isoquinolines: Cytotoxic Non-Camptothecin Topoisomerase I Inhibitors
- Novel Indenoisoquinolines NSC 725776 and NSC 724998 Produce Persistent Topoisomerase I Cleavage Complexes and Overcome Multidrug Resistance
- Topoisomerase I inhibitors: camptothecins and beyond
- Design, docking, and synthesis of novel indeno[1,2-c]isoquinolines for the development of antitumor agents as topoisomerase I inhibitors
- Stereoselective oxidation by thionyl chloride leading to the indeno[1,2-c]isoquinoline system
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