title: Cytotoxicity and cellular impact of dinuclear organoiridium DNA intercalators and nucleases with long rigid bridging ligands.
abstract: The DNA binding modes and cleavage properties of novel dinuclear Ir(III) polypyridyl (pp) complexes [{(η(5)-C(5)Me(5))Ir(pp)}(2)(μ-B)](CF(3)SO(3))(4) depend on the lengths of their rigid bridging dipyridinyl ligands B. Mono-intercalation and strong DNA cleavage properties were observed for the dipyrido[2,3-a:2',3'-c]phenazine (dppz) complexes 1 (B = 4-[(E)-2-(4-pyridinyl)ethenyl]pyridine) and 3 (B = 4-(2-pyridin-4-ylethynyl)pyridine), whose intracationic Ir···Ir' distances are about 13.1 and 13.3 Å, respectively. In contrast, UV/Vis and CD spectra were in accordance with a stable intertwined bis-intercalation mode for pairs of cations of 5 (B = 1,4-di(2-pyridin-4-ylethynyl)benzene), whose much longer Ir···Ir' distance of 20.6 Å allows a stack of five aromatic chromophores to be sandwiched between its effectively parallel dppz ligands. Whereas both 1 and 3 cleaved DNA in the dark, complex 5 exhibited only photoinduced nuclease activity. A significantly higher antiproliferative activity towards MCF-7 breast carcinoma cells was observed for the nucleases 1 and 3, whose IC(50) values of 0.61 and 0.49 were much lower than that of 2.2 μM for bis-intercalator 5. Values of 3.8 μM, only slightly higher than that of 5, were recorded for the 5,6-dimethylphenanthroline complexes 4 and 6, whose bridging ligands are identical to those of 3 and 5, respectively. Marked antileukemic activity (IC(50) = 6-7 μM) associated with increased levels of reactive oxygen species and apoptosis induction was recorded for both 3 and 5 towards Jurkat cells at concentrations of 5 μM and above. Online studies with a sensor chip system indicated that 5 μM solutions of these complexes invoke a rapid and massive reduction in MCF-7 cell respiration.
authors.affiliation: Fakultät für Chemie und Biochemie, Ruhr-Universität-Bochum, Bochum, Germany.
authors.forename: Mhd Ali
authors.initials: MA
authors.lastname: Nazif
authors.forename: Riccardo
authors.initials: R
authors.lastname: Rubbiani
authors.forename: Hamed
authors.initials: H
authors.lastname: Alborzinia
authors.forename: Igor
authors.initials: I
authors.lastname: Kitanovic
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: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002942:Circular Dichroism; D004247:DNA / Q000378:metabolism; D053837:DNA Cleavage; D003851:Deoxyribonucleases / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents / Q000378:metabolism; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology*; D007495:Iridium / Q000737:chemistry / Q000494:pharmacology*; D019169:Jurkat Cells; D008024:Ligands; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D007202:Indicators and Reagents; D007364:Intercalating Agents; D008024:Ligands; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D007495:Iridium; D004247:DNA; C427203:calf thymus DNA; D003851:Deoxyribonucleases