title: Highly cytotoxic substitutionally inert rhodium(III) tris(chelate) complexes: DNA binding modes and biological impact on human cancer cells.
abstract: The antiproliferative properties and cellular impact of novel substitutionally inert rhodium(III) complexes of the types [Rh{(CH₃)₂ NCS₂}₂(pp)]Cl 3-5 (pp=5,6-Me₂phen, dpq, dppz) and OC-6-23-[Rh(2-S-py)₂(pp)]Cl 6 and 7 (2-S-py=pyridine-2-thiolate; pp=dpq, dppz) have been investigated for the adherent human cancer cell lines MCF-7 and HT-29 and for non-adherent Jurkat cells. Whereas CD and viscosity measurements indicate that the polypyridyl ligands of 4 and 5 intercalate into CT DNA, this is not the case for the analogous pyridine-2-thiolate complexes 6 and 7. Complexes 3-7 all exhibit a high antiproliferative activity towards MCF-7 and HT-29 cells, with IC(50) values in the range 0.055-0.285 μM. As established by online monitoring with a cell-based sensor chip, the highly cytostatic complex 6 (IC(50)=0.059 and 0.078 μM) invokes an immediate concentration-dependent reduction of MCF-7 cell respiration and a time-delayed decrease in cellular impedance, which can be ascribed to the induction of cell death. Annexin V/PI assays demonstrated that 6 also has a pronounced antiproliferative activity towards Jurkat cells and that it invokes extensive apoptosis and high concentrations of reactive oxygen species in these leukemia cells. The observation of a dose-dependent inhibition of the oxygen consumption of isolated mice mitochondria indicates the involvement of an intrinsic mitochondrial pathway in this process.
authors.affiliation: Fakultät für Chemie und Biochemie, Ruhr-Universität Bochum, Bochum, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Hackenberg
authors.forename: Luciano
authors.initials: L
authors.lastname: Oehninger
authors.forename: Hamed
authors.initials: H
authors.lastname: Alborzinia
authors.forename: Suzan
authors.initials: S
authors.lastname: Can
authors.forename: Igor
authors.initials: I
authors.lastname: Kitanovic
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Geldmacher
authors.forename: Malte
authors.initials: M
authors.lastname: Kokoschka
authors.forename: Stefan
authors.initials: S
authors.lastname: Wölfl
authors.forename: Ingo
authors.initials: I
authors.lastname: Ott
authors.forename: William S
authors.initials: WS
authors.lastname: Sheldrick
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry; D004125:Dimethyldithiocarbamate / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005583:Fourier Analysis; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D010101:Oxygen Consumption / Q000187:drug effects; D012238:Rhodium / Q000737:chemistry*; D044366:Transition Temperature
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D004125:Dimethyldithiocarbamate; D004247:DNA; C427203:calf thymus DNA; D012238:Rhodium