期刊
JOURNAL OF INORGANIC BIOCHEMISTRY
卷 103, 期 5, 页码 698-708出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jinorgbio.2009.01.008
关键词
Rhodium; Polypyridyl ligands; Thioether complexes; DNA cleavage; Antitumor agents
资金
- Deutsche Forschungsgemeinschaft (DFG) [FOR 630]
- Ruhr-University Research School
- WASAG Foundation
The Rh(III) polypyridyl complexes of the type [RhCl(pp)([9]aneS(3))](2+) [(pp) = 2,2'-bipyridine (bpy), 2,2'-bipyrimidine (bpm),1,10-phenanthroline (phen), pyrazino[2,3-f]quinoxaline (tap), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq), dipyrido[2,3-a:2',3'-c]phenazine (dppz)] 2-7 have been prepared in a stepwise manner by treatment of RhCl3 center dot 3H(2)O with the appropriate polypyridyl ligand (pp) followed by 1,4,7-trithiacyclononane. Interactions of the polypyridyl complexes with DNA were investigated by CD and UV/visible spectroscopy and by gel electrophoresis. The dpq complex 6 cleaves DNA exiguously in the dark, but UV irradiation is required to induce nuclease activity for the bpy complex 2. Whereas 2[IC50 values: 12.8 (+/- 0.2) and 4.4 (+/-0.1) mu M] exhibits significantly higher cytotoxicities towards MCF-7 and HT-29 cells than 4 [IC50 values: 36.3 (+/-6.0) and 72.2 (+/-8.0)], the activity of complexes it) the series 4/6/7 correlates directly with the size of the polypyricly] ligand, as documented by their respective IC50 values of 72.2 (+/-8.0), 20.9 (+/-2.8) and 7.4 (+/-2.2) towards HT-29 cells. Complexes of the nitrogen-rich ligands bpm (3) [IC50 values: 1.7 (+/-0.5) and 1.9 (+/-0.1) mu M] and tap (5) [IC50 values: 11.5 (+/-0.6) and 7.6 (+/-4.8) mu M] are considerably more potent than their bpy and phen counterparts 2 and 4. Measurement of the lactate dehydrogenase release for lymphoma (BJAB) cells after 1 h incubation demonstrates that unspecific necrosis is negligible for the most active compounds 3 and 7. Specific cell death apoptosis via DNA fragmentation was detected for BJAB cells after 72 h incubation and significant loss of the mitochondrial membrane potential in lymphoma cells indicates that the intrinsic pathway is involved. (C) 2009 Elsevier Inc. All rights reserved.
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