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Dalton Transactions

The international journal for inorganic, organometallic and bioinorganic chemistry



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Dalton Trans., 2009, 10882 - 10888, DOI: 10.1039/b917792b

Inert ruthenium half-sandwich complexes with anticancer activity

Eric Meggers, G. Ekin Atilla-Gokcumen, Katharina Gründler, Corazon Frias and Aram Prokop

In this study, we investigate the anticancer properties of an inert half-sandwich metal complex scaffold. UV melting experiments with duplex DNA and 1H-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 IC50 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.

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