title: In vitro anticancer activity and biologically relevant metabolization of organometallic ruthenium complexes with carbohydrate-based ligands.
abstract: The synthesis and in vitro anticancer activity of dihalogenido(eta6-p-cymene)(3,5,6-bicyclophosphite-alpha-D-glucofuranoside)ruthenium(II) complexes are described. The compounds were characterized by NMR spectroscopy and ESI mass spectrometry, and the molecular structures of dichlorido-, dibromido- and diiodido(eta6-p-cymene)(3,5,6-bicyclophosphite-1,2-O-isopropylidene-alpha-D-glucofuranoside)ruthenium(II) were determined by X-ray diffraction analysis. The complexes were shown to undergo aquation of the first halido ligand in aqueous solution, followed by hydrolysis of a P--O bond of the phosphite ligand, and finally formation of dinuclear species. The hydrolysis mechanism was confirmed by DFT calculations. The aquation of the complexes was markedly suppressed in 100 mM NaCl solution, and notably only very slow hydrolysis of the P--O bond was observed. The complexes showed affinity towards albumin and transferrin and monoadduct formation with 9-ethylguanine. In vitro studies revealed that the 3,5,6-bicyclophosphite-1,2-O-cyclohexylidene-alpha-D-glucofuranoside complex is the most cytotoxic compound in human cancer cell lines (IC50 values from 30 to 300 microM depending on the cell line).
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna (Austria), Fax: (+43) 1-4277-9526.
authors.forename: Isabella
authors.initials: I
authors.lastname: Berger
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna (Austria), Fax: (+43) 1-4277-9526.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Hanif
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna (Austria), Fax: (+43) 1-4277-9526.|Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne (Switzerland).
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Nazarov
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna (Austria), Fax: (+43) 1-4277-9526.|Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne (Switzerland).
authors.forename: Christian G
authors.initials: CG
authors.lastname: Hartinger
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna (Austria), Fax: (+43) 1-4277-9526.
authors.forename: Roland O
authors.initials: RO
authors.lastname: John
authors.affiliation: Centro de Química Estrutural, Complexo I, Instituto Superior Técnico, TU Lisbon, Av. Rovisco Pais, 1049-001 Lisbon (Portugal).
authors.forename: Maxim L
authors.initials: ML
authors.lastname: Kuznetsov
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna (Austria), Fax: (+43) 1-4277-9526.
authors.forename: Michael
authors.initials: M
authors.lastname: Groessl
authors.affiliation: University Institute of Pathology, Centre Hospitalier Universitaire Vaudois (CHUV), Rue du Bugnon 25, 1011 Lausanne (Switzerland).
authors.forename: Frederic
authors.initials: F
authors.lastname: Schmitt
authors.affiliation: University Institute of Pathology, Centre Hospitalier Universitaire Vaudois (CHUV), Rue du Bugnon 25, 1011 Lausanne (Switzerland).
authors.forename: Olivier
authors.initials: O
authors.lastname: Zava
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna (Austria), Fax: (+43) 1-4277-9526.
authors.forename: Florian
authors.initials: F
authors.lastname: Biba
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna (Austria), Fax: (+43) 1-4277-9526.
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Arion
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna (Austria), Fax: (+43) 1-4277-9526.
authors.forename: Markus
authors.initials: M
authors.lastname: Galanski
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna (Austria), Fax: (+43) 1-4277-9526.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Jakupec
authors.affiliation: University Institute of Pathology, Centre Hospitalier Universitaire Vaudois (CHUV), Rue du Bugnon 25, 1011 Lausanne (Switzerland).
authors.forename: Lucienne
authors.initials: L
authors.lastname: Juillerat-Jeanneret
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne (Switzerland).
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dyson
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna (Austria), Fax: (+43) 1-4277-9526.
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D050260:Carbohydrate Metabolism; D002241:Carbohydrates / Q000737:chemistry*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D055601:Organic Chemistry Phenomena; D017975:Ruthenium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D002241:Carbohydrates; D008024:Ligands; D017975:Ruthenium Compounds