title: Comparative solution equilibrium studies of antitumor ruthenium(η6-p-cymene) and rhodium(η5-C5Me5) complexes of 8-hydroxyquinolines.
abstract: Complex formation processes of [Ru(η6-p-cymene)(H2O)3]+and [Rh(η5-C5Me5)(H2O)3]+organometallic cations with 8-hydroxyquinoline (HQ) ligands were studied in aqueous solution by the combined use of1H NMR spectroscopy, UV-visible spectrophotometry and pH-potentiometry. Solution stability, chloride ion affinity and lipophilicity of the complexes were characterized together with the in vitro cytotoxicity against a pair of cancer cell lines, responsive and resistant to classic chemotherapy. The solid phase structure of the [Rh(η5-C5Me5)(8-quinolinolato)(Cl)] complex was characterized by single-crystal X-ray diffraction analysis. In addition to the unsubstituted HQ its 7-(1-piperidinylmethyl) (PHQ) and 5-sulfonate (HQS) derivatives were involved. PHQ has a significant preference for targeting multidrug resistant cancer cell lines, while HQS served as a water soluble model compound. The equilibrium studies revealed the formation of mono[M(L)(H2O)] complexes with prominently high solution stability, which predominate at physiological pH even in the micromolar concentration range, and the formation of mixed hydroxido [M(L)(OH)] complexes was characterized by relatively high pKavalues (8.5-10.3). In comparison to the Rh(η5-C5Me5) species the complexation process with Ru(η6-p-cymene) is much slower, and both the pKavalues and the H2O/Cl-co-ligand exchange constants are lower by 1-1.5 orders of magnitude. The stability order obtained for these organometallic complexes is as follows: HQS > HQ > PHQ. The cytotoxicity of the ligands and their Ru(η6-p-cymene) and Rh(η5-C5Me5) complexes was investigated against MES-SA (human uterine sarcoma) cell line and its multidrug resistant counterpart (MES-SA/Dx5). HQ and its complexes show similar cytotoxicity in both cell lines. In contrast, PHQ and its Rh(η5-C5Me5) complex are more potent against MES-SA/Dx5 cells, while this selectivity could not be observed for the Ru(η6-p-cymene) complex.
authors.affiliation: Department of Inorganic and Analytical Chemistry, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary. enyedy@chem.u-szeged.hu and MTA-SZTE Bioinorganic Chemistry Research Group, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary.
authors.forename: Orsolya
authors.initials: O
authors.lastname: Dömötör
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok körútja 2, H-1117 Budapest, Hungary.
authors.forename: Veronika F S
authors.initials: VFS
authors.lastname: Pape
authors.affiliation: Research Centre for Natural Sciences Hungarian Academy of Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary.
authors.forename: Nóra V
authors.initials: NV
authors.lastname: May
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok körútja 2, H-1117 Budapest, Hungary and Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: Gergely
authors.initials: G
authors.lastname: Szakács
authors.affiliation: Department of Inorganic and Analytical Chemistry, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary. enyedy@chem.u-szeged.hu.
authors.forename: Éva A
authors.identifier: http://orcid.org/0000-0002-8058-8128
authors.initials: ÉA
authors.lastname: Enyedy
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002712:Chlorides / Q000737:chemistry; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003517:Cyclopentanes / Q000737:chemistry; D000081007:Cymenes; D055808:Drug Discovery; D006801:Humans; D039821:Monoterpenes / Q000737:chemistry; D009942:Organometallic Compounds; D015125:Oxyquinoline / Q000737:chemistry*; D010880:Piperidines / Q000737:chemistry; D012238:Rhodium / Q000737:chemistry*; D012428:Ruthenium / Q000737:chemistry*; D013451:Sulfonic Acids / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D002712:Chlorides; D056831:Coordination Complexes; D003517:Cyclopentanes; D000081007:Cymenes; D039821:Monoterpenes; D009942:Organometallic Compounds; D010880:Piperidines; D013451:Sulfonic Acids; D014867:Water; C007210:4-cymene; D015125:Oxyquinoline; D012428:Ruthenium; D012238:Rhodium