| Autor: |
Mulcahy SP; Fachbereich Chemie, Hans-Meerwein-Strasse, 35032, Marburg, Germany., Gründler K, Frias C, Wagner L, Prokop A, Meggers E |
| Jazyk: |
angličtina |
| Zdroj: |
Dalton transactions (Cambridge, England : 2003) [Dalton Trans] 2010 Sep 21; Vol. 39 (35), pp. 8177-82. Date of Electronic Publication: 2010 Aug 05. |
| DOI: |
10.1039/c0dt00034e |
| Abstrakt: |
A strategy for combinatorial parallel coordination chemistry is introduced that provides access to libraries of tris-heteroleptic ruthenium complexes in an economical fashion. Using this method, a library of 560 constitutionally unique, monocationic ruthenium complexes was synthesized, followed by a screening for anticancer activity and resulting in the identification of three hits with promising cytotoxic properties in HeLa cancer cells. A subsequent structure-activity relationship led to the discovery of the surprisingly simple anticancer complex [Ru(tBu(2)bpy)(2)(phox)]PF(6) (complex 1), with tBu(2)bpy = 4,4'-di-tert-buty-2,2'-bipyridine and Hphox = 2-(2'-hydroxyphenyl)oxazoline, displaying an LC(50) value in HeLa cells of 1.3 microM and 0.3 microM after incubation for 24 and 72 h, respectively. Complex 1 also shows remarkable antiproliferative and apoptotic properties at submicromolar concentrations in more clinically relevant Burkitt-like lymphoma cells. A reduction of the mitochondrial membrane potential by 1 indicates the involvement of the intrinsic pathway of programmed cell death. Further investigations reveal that 1 requires caspase-3 for the induction of apoptosis but is insensitive to the proapoptotic and antiapoptotic proteins Smac and Bcl-2, respectively. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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