title: Structure-activity relationships and DNA binding properties of apoptosis inducing cytotoxic rhodium(III) polypyridyl complexes containing the cyclic thioether [9]aneS(3).
abstract: 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 RhCl(3).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 [IC(50) values: 12.8 (+/-0.2) and 4.4 (+/-0.1)microM] exhibits significantly higher cytotoxicities towards MCF-7 and HT-29 cells than 4 [IC(50) values: 36.3 (+/-6.0) and 72.2 (+/-8.0)], the activity of complexes in the series 4/6/7 correlates directly with the size of the polypyridyl ligand, as documented by their respective IC(50) 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) [IC(50) values: 1.7 (+/-0.5) and 1.9 (+/-0.1)microM] and tap (5) [IC(50) values: 11.5 (+/-0.6) and 7.6 (+/-4.8)microM] are considerably more potent than their bpy and phen counterparts 2 and 4. Measurement of the lactate dehydrogenase release for lymphoma (BJAB) cells after 1h 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 72h incubation and significant loss of the mitochondrial membrane potential in lymphoma cells indicates that the intrinsic pathway is involved.
authors.affiliation: Lehrstuhl für Analytische Chemie, Ruhr-Universität Bochum, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Bieda
authors.forename: Ingo
authors.initials: I
authors.lastname: Ott
authors.forename: Mara
authors.initials: M
authors.lastname: Dobroschke
authors.forename: Aram
authors.initials: A
authors.lastname: Prokop
authors.forename: Ronald
authors.initials: R
authors.lastname: Gust
authors.forename: William S
authors.initials: WS
authors.lastname: Sheldrick
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000737:chemistry*; D019073:HT29 Cells; D006801:Humans; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D012238:Rhodium / Q000737:chemistry* / Q000494:pharmacology*; D013054:Spectrophotometry, Atomic; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D004247:DNA; D012238:Rhodium