title: Cytotoxic rhodium(III) and iridium(III) polypyridyl complexes: structure-activity relationships, antileukemic activity, and apoptosis induction.
abstract: Meridional rhodium(III) polypyridyl complexes of the type mer-[RhX(3)(DMSO)(pp)] (X=Cl, pp=phen 1, dpq 2, dppz 3; X=Br, pp=phen 4) represent a promising class of potent cytostatic agents for the treatment of lymphoma and leukemia. Exposure of their DMSO solutions to light leads to slow isomerization to mixtures of the mer and the generally less active fac isomers. As a result, the IC(50) values of 1 and 2 toward HT-29 cells increase from 0.19 and 0.069 microM on immediate use in the dark to 0.66 and 0.312 microM, respectively, after exposure of their DMSO stock solutions to light for 7 days. In striking contrast, the complexes mer-[IrX(3)(DMSO)(phen)] (X=Cl 7, Br 8) are significantly less cytotoxic than their facial Ir(III) polypyridyl counterparts: IC(50)=20.3 microM for 7 and 4.6 microM for fac-[IrCl(3)(DMSO)(phen)] 5 toward MCF-7 cells. The IC(50) values for the complexes fac-[IrX(3)(L)(pp)] 9-13 decrease in the orders: a) Cl>Br for X and b) H(2)O>DMSO for L. Specific apoptotic cell death by DNA fragmentation was detected for leukemia (NALM-6) and lymphoma (BJAB) cells after incubation with 2, 3, and 11 (X=Br, L=H(2)O, pp=phen) for 72 h. Loss of the mitochondrial membrane potential in lymphoma cells indicates that apoptosis is mediated via the intrinsic mitochondrial pathway. LDH release assays after 1 or 3 h demonstrate that necrotic damage is negligible.
authors.affiliation: Department of Pediatric Oncology/Hematology, University Medial Center Charité Berlin, Germany.
authors.forename: Mara
authors.initials: M
authors.lastname: Dobroschke
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Geldmacher
authors.forename: Ingo
authors.initials: I
authors.lastname: Ott
authors.forename: Melanie
authors.initials: M
authors.lastname: Harlos
authors.forename: Lisa
authors.initials: L
authors.lastname: Kater
authors.forename: Laura
authors.initials: L
authors.lastname: Wagner
authors.forename: Ronald
authors.initials: R
authors.lastname: Gust
authors.forename: William S
authors.initials: WS
authors.lastname: Sheldrick
authors.forename: Aram
authors.initials: A
authors.lastname: Prokop
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007495:Iridium / Q000737:chemistry* / Q000494:pharmacology*; D007938:Leukemia / Q000473:pathology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D012238:Rhodium / Q000737:chemistry* / Q000494:pharmacology*; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
chemical_list: D007495:Iridium; D012238:Rhodium