Synthesis, Cytotoxicity, DNA Interaction, and Topoisomerase II Inhibition Properties of Novel Indeno[2,1-c]quinolin-7-one and Indeno[1,2-c]isoquinolin-5,11-dione Derivatives

Indeno[2,1-c]quinolin-7-ones and 6H-indeno[1,2-c]isoquinolin-5,11-diones, bearing two cationic aminoalkyl side chains, were synthesized and evaluated for DNA interaction, topoisomerases inhibition, and cytotoxicity against human cancer cell lines. They displayed strong interaction with DNA and one i...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2008-06, Vol.51 (12), p.3617-3629
Main Authors: Ryckebusch, Adina, Garcin, Deborah, Lansiaux, Amélie, Goossens, Jean-François, Baldeyrou, Brigitte, Houssin, Raymond, Bailly, Christian, Hénichart, Jean-Pierre
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Biological and medical sciences
Cell Line, Tumor
DNA - chemistry
Drug Resistance, Neoplasm
Drug Screening Assays, Antitumor
Fluorescence
General aspects
Humans
Indenes - chemical synthesis
Indenes - chemistry
Indenes - pharmacology
Isoquinolines - chemical synthesis
Isoquinolines - chemistry
Isoquinolines - pharmacology
Medical sciences
Mitoxantrone - pharmacology
Nucleic Acid Denaturation
Pharmacology. Drug treatments
Quinolines - chemical synthesis
Quinolines - chemistry
Quinolines - pharmacology
Structure-Activity Relationship
Topoisomerase II Inhibitors
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Summary:Indeno[2,1-c]quinolin-7-ones and 6H-indeno[1,2-c]isoquinolin-5,11-diones, bearing two cationic aminoalkyl side chains, were synthesized and evaluated for DNA interaction, topoisomerases inhibition, and cytotoxicity against human cancer cell lines. They displayed strong interaction with DNA and one indeno[1,2-c]isoquinolin-5,11-dione bearing side chains at N-6 and C-8 positions (6a) was a potent human topoisomerase II inhibitor with high cytotoxicity toward HL60 cells. An increased topoisomerase II inhibition is found with (a) a cationic aminoalkyl side chain at the C-8 rather than at the C-9 position, (b) a dimethylaminoethoxy side chain at the C-8 position introduced on the N-6 monosubstituted derivative, going with suppression of topoisomerase I poisoning, and (c) a dimethylaminoethyl rather than a dimethylaminopropyl side chain at the N-6 position. The cytotoxicity was only partially reduced when using the topoisomerase II-mutated mitoxantrone-resistant HL60/MX2 cell line, suggesting that additional targets are involved in their mechanism of action. These indeno[1,2-c]isoquinolin-5,11-dione derivatives represent new DNA−topoisomerase II interfering anticancer molecules.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm800017u