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 6 H-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.
Ryckebusch
Adina
A
UMR 8009 Chimie Organique et Macromoléculaire, Laboratoire de Chimie Organique Physique, Bâtiment C3(2), Université des Sciences et Technologies de Lille, 59655 Villeneuve d'Ascq, France. Adina.Ryckebusch@ensc-lille.fr
Garcin
Deborah
D
Lansiaux
Amélie
A
Goossens
Jean-François
JF
Baldeyrou
Brigitte
B
Houssin
Raymond
R
Bailly
Christian
C
Hénichart
Jean-Pierre
JP
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005453:Fluorescence; D006801:Humans; D007192:Indenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008942:Mitoxantrone / Q000494:pharmacology; D009691:Nucleic Acid Denaturation; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; D007192:Indenes; D007546:Isoquinolines; D011804:Quinolines; D059005:Topoisomerase II Inhibitors; D004247:DNA; D008942:Mitoxantrone