期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 14, 期 16, 页码 4816-4822出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.200800294
关键词
antitumor agents; bioorganometallic chemistry; kinase inhibitors; osmium; ruthenium
资金
- NCI NIH HHS [P01 CA114046-01A2, P01 CA114046] Funding Source: Medline
- NIGMS NIH HHS [R01 GM071695, GM071695] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [P01CA114046] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM071695] Funding Source: NIH RePORTER
In this study, we probe and verify the concept of designing unreactive bioactive metal complexes, in which the metal possesses a purely structural function, by investigating the consequences of replacing ruthenium in a bioactive half-sandwich kinase inhibitor scaffold by its heavier congener osmium. The two isostructural complexes are compared with respect to their anticancer properties in 1205 Lu melanoma cells, activation of the Wnt signaling pathway, IC50 values against the protein kinases GSK-3 beta and Pim-1, and binding modes to the protein kinase Pim-1 by protein crystallography. It was found that the two congeners display almost indistinguishable biological activities, which can be explained by their nearly identical three-dimensional structures and their identical mode of action as protein kinase inhibitors. This is a unique example in which the replacement of a metal in an anticancer scaffold by its heavier homologue does not alter its biological activity.
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