Indeno[1,2-c]isoquinolin-5,11-diones conjugated to amino acids: Synthesis, cytotoxicity, DNA interaction, and topoisomerase II inhibition properties.
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.
Ahn
Gang
G
EA CMF 4478, Université Lille Nord de France-Université Lille 1, Bât C3(2), Cité Scientifique, 59655 Villeneuve d'Ascq Cedex, France.
Lansiaux
Amélie
A
Goossens
Jean-François
JF
Bailly
Christian
C
Baldeyrou
Brigitte
B
Schifano-Faux
Nadège
N
Grandclaudon
Pierre
P
Couture
Axel
A
Ryckebusch
Adina
A
D000596:Amino Acids / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001120:Arginine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007192:Indenes / Q000737:chemistry*; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D009154:Mutation; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D044366:Transition Temperature
C556011:6-(arginyl-aminoethyl)-6H-indeno(1,2-c)isoquinolin-5,11-dione; D000596:Amino Acids; D000970:Antineoplastic Agents; D007192:Indenes; D007546:Isoquinolines; D059005:Topoisomerase II Inhibitors; C093581:indene; D004247:DNA; D001120:Arginine; D004250:DNA Topoisomerases, Type II