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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• 作者：Gang Ahn ; Amé ; lie Lansiaux ; Jean-Franç ; ois Goossens ; Christian Bailly ; Brigitte Baldeyrou ; Nadè ; ge Schifano-Faux ; Pierre Gr ; claudon ; Axel Couture ; Adina Ryckebusch
• 关键词：Cancer ; DNA ligand ; Topoisomerases ; Cytotoxicity ; Amino acid conjugate ; Indenoisoquinolin-5 ; 11-dione
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2010
• 出版时间：15 November 2010
• 年：2010
• 卷：18
• 期：22
• 页码：8119-8133
• 全文大小：751 K

文摘

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 IC₅₀ values. When tested with the topoisomerase II-mutated HL60/MX2 cell line, little variation of IC₅₀ values was found, suggesting that topoisomerase II might not be the main target of these compounds and that additional targets could be involved.