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In Vitro Anticancer Activity and Biologically Relevant Metabolization of Organometallic Ruthenium Complexes with Carbohydrate‐Based Ligands
Author(s) -
Berger Isabella,
Hanif Muhammad,
Nazarov Alexey A.,
Hartinger Christian G.,
John Roland O.,
Kuznetsov Maxim L.,
Groessl Michael,
Schmitt Frederic,
Zava Olivier,
Biba Florian,
Arion Vladimir B.,
Galanski Mathea Sophia,
Jakupec Michael A.,
JuilleratJeanneret Lucienne,
Dyson Paul J.,
Keppler Bernhard K.
Publication year - 2008
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200801032
Subject(s) - aquation , ruthenium , chemistry , ligand (biochemistry) , hydrolysis , stereochemistry , medicinal chemistry , in vitro , nuclear magnetic resonance spectroscopy , reactivity (psychology) , kinetics , organic chemistry , biochemistry , reaction rate constant , catalysis , physics , receptor , quantum mechanics , medicine , alternative medicine , pathology
The synthesis and in vitro anticancer activity of dihalogenido(η 6 ‐ p ‐cymene)(3,5,6‐bicyclophosphite‐α‐ 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(η 6 ‐ p ‐cymene)(3,5,6‐bicyclophosphite‐1,2‐ O ‐isopropylidene‐α‐ 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 PO 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 m M NaCl solution, and notably only very slow hydrolysis of the PO 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‐α‐ D ‐glucofuranoside complex is the most cytotoxic compound in human cancer cell lines (IC 50 values from 30 to 300 μ M depending on the cell line).