title: {Ru(CO)x}-Core complexes with benzimidazole ligands: synthesis, X-ray structure and evaluation of anticancer activity in vivo.
abstract: The reaction of [Ru(CO)6Cl2], 1, with N[combining low line]3-methylbenzimidazole (MBI) and 5,6-dimethylbenzimidazole (DMBI) afforded two new complexes with the general formula fac-[RuII(CO)3Cl2L], L = MBI (2) or DMBI (4). Crystals of cis,trans-[RuII(CO)2Cl2(N[combining low line]3-MBI)2], 3, were also obtained from the mother liquor that produced 2. In the presence of water, the dissociation of Ru-N, Ru-Cl and Ru-CO bonds occurred as a function of time, water content and pH. Density functional theory structure simulations/optimizations were carried out at the Becke3LYP level of theory for evaluating the relative stability of possible conformers. ESI-MS studies revealed the ability of the complexes to link model proteins, such as lysozyme, bovine pancreatic ribonuclease and cytochrome c, with the partial release of the heteroaromatic base, chlorido and carbonyl ligands. X-ray diffraction studies on crystals grown from a solution of HEWL and 2 showed the partial removal of chloride and CO. Cytotoxicity tests yielded two-digit micromolar IC50values in CH1/PA-1 and SW480 cancer cells. In contrast to CORM-3 and 2, a significantly reduced tumor growth was observed with 4 in the murine colon cancer CT-26 model in vivo.
authors.affiliation: Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy. tamasi@unisi.it.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Tamasi
authors.affiliation: Department of Chemical Sciences, University of Naples Federico II, Via Cintia, 80126, Napoli, Italy and Institute of Biostructure and Bioimaging, CNR, Via Mezzocannone 16, 80120, Napoli, Italy.
authors.forename: Antonello
authors.identifier: http://orcid.org/0000-0002-1045-7720
authors.initials: A
authors.lastname: Merlino
authors.affiliation: Department of Chemistry, University of Florence, Via della Lastruccia 3-13, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Scaletti
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria and Research Platform "Translational Cancer Therapy Research", University of Vienna, Währinger Straße 42, 1090 Vienna, Austria.
authors.forename: Petra
authors.initials: P
authors.lastname: Heffeter
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Währinger Straße 42, 1090 Vienna, Austria. bernhard.keppler@univie.ac.at.
authors.forename: Anton A
authors.initials: AA
authors.lastname: Legin
authors.affiliation: Research Platform "Translational Cancer Therapy Research", University of Vienna, Währinger Straße 42, 1090 Vienna, Austria and Institute of Inorganic Chemistry, University of Vienna, Währinger Straße 42, 1090 Vienna, Austria. bernhard.keppler@univie.ac.at.
authors.forename: Michael A
authors.identifier: http://orcid.org/0000-0001-7945-1426
authors.initials: MA
authors.lastname: Jakupec
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria and Research Platform "Translational Cancer Therapy Research", University of Vienna, Währinger Straße 42, 1090 Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.affiliation: Department of Chemistry, University of Florence, Via della Lastruccia 3-13, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Messori
authors.affiliation: Research Platform "Translational Cancer Therapy Research", University of Vienna, Währinger Straße 42, 1090 Vienna, Austria and Institute of Inorganic Chemistry, University of Vienna, Währinger Straße 42, 1090 Vienna, Austria. bernhard.keppler@univie.ac.at.
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
authors.affiliation: Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy. tamasi@unisi.it.
authors.forename: Renzo
authors.initials: R
authors.lastname: Cini
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry*; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D009113:Muramidase / Q000737:chemistry / Q000378:metabolism; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D012428:Ruthenium / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D008024:Ligands; D009942:Organometallic Compounds; D012428:Ruthenium; C031000:benzimidazole; D009113:Muramidase