title: Novel tetracarboxylatoplatinum(IV) complexes as carboplatin prodrugs.
abstract: It is widely accepted that platinum(IV) complexes act as prodrugs and have to be activated by reduction to the respective platinum(II) analogs. Recently it could be shown that introduction of lipophilic carboxylato ligands in the axial position leads to diaminedichloridoplatinum(IV) compounds with exceptionally high cytotoxicity. With the aim of improving the antiproliferative properties of carboplatin, a series of twenty-one novel Pt(IV) complexes, featuring the equatorial ligand sphere of carboplatin as well as lipophilic axial carboxylato ligands, was synthesized. In depth characterization is based on elemental analysis, ESI-MS, ATR-IR, and multinuclear ((1)H, (13)C, (15)N, and (195)Pt) NMR spectroscopy. Their cytotoxic activity in four cell lines (CH1, SK-OV-3, SW480, and A549), lipophilicity, electrochemistry and additionally the rate of reduction in the presence of ascorbic acid were investigated. In contrast to analogous diaminedicarboxylatodichloridoplatinum(IV) compounds, the cytotoxicity of novel diaminetetracarboxylato counterparts could not substantially be increased by simply enhancing their lipophilic character. It seems that not only the reduction potential, but also the rate of reduction has a tremendous influence on the cytotoxic properties. This has to be taken into account for the development of novel anticancer platinum(IV) agents.
authors.affiliation: University of Vienna, Institute of Inorganic Chemistry, Waehringer Strasse 42, A-1090 Vienna, Austria. mathea.galanski@univie.ac.at.
authors.forename: Hristo P
authors.initials: HP
authors.lastname: Varbanov
authors.affiliation: University of Vienna, Institute of Inorganic Chemistry, Waehringer Strasse 42, A-1090 Vienna, Austria. mathea.galanski@univie.ac.at.
authors.forename: Seied M
authors.initials: SM
authors.lastname: Valiahdi
authors.affiliation: University of Vienna, Institute of Inorganic Chemistry, Waehringer Strasse 42, A-1090 Vienna, Austria. mathea.galanski@univie.ac.at.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Kowol
authors.affiliation: University of Vienna, Institute of Inorganic Chemistry, Waehringer Strasse 42, A-1090 Vienna, Austria. mathea.galanski@univie.ac.at.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Jakupec
authors.affiliation: University of Vienna, Institute of Inorganic Chemistry, Waehringer Strasse 42, A-1090 Vienna, Austria. mathea.galanski@univie.ac.at.
authors.forename: Mathea S
authors.initials: MS
authors.lastname: Galanski
authors.affiliation: University of Vienna, Institute of Inorganic Chemistry, Waehringer Strasse 42, A-1090 Vienna, Austria. mathea.galanski@univie.ac.at.
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D016190:Carboplatin / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D009369:Neoplasms / Q000188:drug therapy; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D011355:Prodrugs; D016190:Carboplatin