In vitro anticancer activity and biologically relevant metabolization of organometallic ruthenium complexes with carbohydrate-based ligands.
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).
Berger
Isabella
I
Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna (Austria), Fax: (+43) 1-4277-9526.
Hanif
Muhammad
M
Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna (Austria), Fax: (+43) 1-4277-9526.
Nazarov
Alexey A
AA
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).
Hartinger
Christian G
CG
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).
John
Roland O
RO
Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna (Austria), Fax: (+43) 1-4277-9526.
Kuznetsov
Maxim L
ML
Centro de Química Estrutural, Complexo I, Instituto Superior Técnico, TU Lisbon, Av. Rovisco Pais, 1049-001 Lisbon (Portugal).
Groessl
Michael
M
Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna (Austria), Fax: (+43) 1-4277-9526.
Schmitt
Frederic
F
University Institute of Pathology, Centre Hospitalier Universitaire Vaudois (CHUV), Rue du Bugnon 25, 1011 Lausanne (Switzerland).
Zava
Olivier
O
University Institute of Pathology, Centre Hospitalier Universitaire Vaudois (CHUV), Rue du Bugnon 25, 1011 Lausanne (Switzerland).
Biba
Florian
F
Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna (Austria), Fax: (+43) 1-4277-9526.
Arion
Vladimir B
VB
Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna (Austria), Fax: (+43) 1-4277-9526.
Galanski
Markus
M
Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna (Austria), Fax: (+43) 1-4277-9526.
Jakupec
Michael A
MA
Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna (Austria), Fax: (+43) 1-4277-9526.
Juillerat-Jeanneret
Lucienne
L
University Institute of Pathology, Centre Hospitalier Universitaire Vaudois (CHUV), Rue du Bugnon 25, 1011 Lausanne (Switzerland).
Dyson
Paul J
PJ
Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne (Switzerland).
Keppler
Bernhard K
BK
Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna (Austria), Fax: (+43) 1-4277-9526.
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*
D000970:Antineoplastic Agents; D002241:Carbohydrates; D008024:Ligands; D017975:Ruthenium Compounds