title: Effect of the piperazine unit and metal-binding site position on the solubility and anti-proliferative activity of ruthenium(II)- and osmium(II)- arene complexes of isomeric indolo[3,2-c]quinoline-piperazine hybrids.
abstract: In this study, the indoloquinoline backbone and piperazine were combined to prepare indoloquinoline-piperazine hybrids and their ruthenium- and osmium-arene complexes in an effort to generate novel antitumor agents with improved aqueous solubility. In addition, the position of the metal-binding unit was varied, and the effect of these structural alterations on the aqueous solubility and antiproliferative activity of their ruthenium- and osmium-arene complexes was studied. The indoloquinoline-piperazine hybrids L(1-3) were prepared in situ and isolated as six ruthenium and osmium complexes [(η(6)-p-cymene)M(L(1-3))Cl]Cl, where L(1) = 6-(4-methylpiperazin-1-yl)-N-(pyridin-2-yl-methylene)-11H-indolo[3,2-c]quinolin-2-N-amine, M = Ru ([1a]Cl), Os ([1b]Cl), L(2) = 6-(4-methylpiperazin-1-yl)-N-(pyridin-2-yl-methylene)-11H-indolo[3,2-c]quinolin-4-N-amine, M = Ru ([2a]Cl), Os ([2b]Cl), L(3) = 6-(4-methylpiperazin-1-yl)-N-(pyridin-2-yl-methylene)-11H-indolo[3,2-c]quinolin-8-N-amine, M = Ru ([3a]Cl), Os ([3b]Cl). The compounds were characterized by elemental analysis, one- and two-dimensional NMR spectroscopy, ESI mass spectrometry, IR and UV-vis spectroscopy, and single-crystal X-ray diffraction. The antiproliferative activity of the isomeric ruthenium and osmium complexes [1a,b]Cl-[3a,b]Cl was examined in vitro and showed the importance of the position of the metal-binding site for their cytotoxicity. Those complexes containing the metal-binding site located at the position 4 of the indoloquinoline scaffold ([2a]Cl and [2b]Cl) demonstrated the most potent antiproliferative activity. The results provide important insight into the structure-activity relationships of ruthenium- and osmium-arene complexes with indoloquinoline-piperazine hybrid ligands. These studies can be further utilized for the design and development of more potent chemotherapeutic agents.
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna , Währinger Strasse 42, A-1090 Vienna, Austria.
authors.forename: Lukas K
authors.initials: LK
authors.lastname: Filak
authors.forename: Danuta S
authors.initials: DS
authors.lastname: Kalinowski
authors.forename: Theresa J
authors.initials: TJ
authors.lastname: Bauer
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Arion
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008670:Metals / Q000737:chemistry*; D008958:Models, Molecular; D017892:Osmium Compounds / Q000737:chemistry* / Q000494:pharmacology*; D010879:Piperazines / Q000737:chemistry*; D017975:Ruthenium Compounds / Q000737:chemistry* / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D008670:Metals; D017892:Osmium Compounds; D010879:Piperazines; D017975:Ruthenium Compounds