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

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• 作者：Adina Ryckebusch ; Deborah Garcin ; Am&#xe9 ; lie Lansiaux ; Jean-Fran&#xe7 ; ois Goossens ; Brigitte Baldeyrou ; Raymond Houssin ; Christian Bailly ; Jean-Pierre H&#xe9 ; nichart
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：June 26, 2008
• 年：2008
• 卷：51
• 期：12
• 页码：3617 - 3629
• 全文大小：371K
• 年卷期：v.51,no.12(June 26, 2008)
• ISSN：1520-4804

文摘

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.