Inert ruthenium half-sandwich complexes with anticancer activity.
In this study, we investigate the anticancer properties of an inert half-sandwich metal complex scaffold. UV melting experiments with duplex DNA and (1)H-NMR experiments with 9-ethylguanine reveal that the apoptotic ruthenium complex DW12 does not interact with DNA. On the other hand, diminishing the kinase inhibition properties of DW12 by methylating the maleimide nitrogen (DW12-Me) abolishes the anticancer activity. Furthermore, the incorporation of a fluorine into the pyridine moiety (NP309) improves the IC(50) value for glycogen synthase kinase 3 (GSK-3) and at the same time the cytotoxicity, implying that the anticancer activity correlates with the inhibition of GSK-3 and maybe other not yet identified kinases. We demonstrate in Burkitt-like lymphoma (BJAB) cells that NP309 is not necrotic but induces apoptosis and that this apoptosis is mediated by a loss of the mitochondrial membrane potential, caspase-9 processing, and is partly dependent on Bcl-2 expression. In addition, NP309 efficiently induces apoptosis in vincristine- and cytarabine-resistant human B-cell precursor cell lines.
Meggers
Eric
E
Department of Chemistry, University of Pennsylvania, 231 S. 34th Street, Philadelphia, PA 19104, USA. meggers@chemie.uni-marburg.de
Atilla-Gokcumen
G Ekin
GE
Gründler
Katharina
K
Frias
Corazon
C
Prokop
Aram
A
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000633:toxicity; D017209:Apoptosis; D053453:Caspase 9 / Q000378:metabolism; D002460:Cell Line; D056831:Coordination Complexes / Q000737:chemistry* / Q000633:toxicity; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012428:Ruthenium / Q000737:chemistry*
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D019253:Proto-Oncogene Proteins c-bcl-2; D012428:Ruthenium; D038362:Glycogen Synthase Kinase 3; D053453:Caspase 9