Indeno[1,2-c]isoquinolin-5,11-diones conjugated to amino acids: Synthesis, cytotoxicity, DNA interaction, and topoisomerase II inhibition properties |
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Authors: | Ahn Gang Lansiaux Amélie Goossens Jean-François Bailly Christian Baldeyrou Brigitte Schifano-Faux Nadège Grandclaudon Pierre Couture Axel Ryckebusch Adina |
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Affiliation: | EA CMF 4478, Université Lille Nord de France-Université Lille 1, Bat C3(2), Cité Scientifique, 59655 Villeneuve d'Ascq Cedex, France. |
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Abstract: | Three series of indeno[1,2-c]isoquinolin-5,11-dione-amino acid conjugates were designed and synthesized. Amino acids were connected to the tetracycle through linkers with lengths of n=2 and 3 atoms using ester (series I), amide (series II), and secondary amine (series III) functions. DNA binding was evaluated by thermal denaturation and fluorescence measurements. Lysine and arginine substituted derivatives with n=3 provided the highest DNA binding. Arginine derivative 32 (n=2, series II) and glycine derivative 34 (n=2, series III) displayed high topoisomerase II inhibition. Incrementing the length of the N-6 side chain from two to three methylene units provided a significant increase in DNA affinity but a substantial loss in topoisomerase II inhibition. The most cytotoxic compounds toward HL60 leukemia cells were 19, 33, and 34 displaying micromolar IC(50) values. When tested with the topoisomerase II-mutated HL60/MX2 cell line, little variation of IC(50) values was found, suggesting that topoisomerase II might not be the main target of these compounds and that additional targets could be involved. |
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