title: Tetracarboxylatoplatinum(IV) complexes featuring monodentate leaving groups - A rational approach toward exploiting the platinum(IV) prodrug strategy.
abstract: A series of novel symmetrically and unsymmetrically coordinated platinum(IV) complexes with monodentate carboxylato ligands was synthesized. The compounds exhibit a general coordination sphere of [Pt(en)(OCOR)2(OCOR')(OCOR″)], where the carboxylato ligands are represented by acetato and succinic acid monoester ligands. Dicarboxylatoplatinum(II) complexes were synthesized and oxidized symmetrically or unsymmetrically to obtain platinum(IV) complexes, which were subsequently carboxylated with noncyclic anhydrides. The compounds were investigated in detail by elemental analysis, mass spectrometry, infrared and multinuclear ((1)H, (13)C, (15)N, (195)Pt) NMR spectroscopy as well as by X-ray diffraction in some cases. The reduction behavior was followed by NMR spectroscopy, while stability and lipophilicity were examined by analytical reversed phase HPLC measurements. Cytotoxic properties were studied in three human cancer cell lines derived from cisplatin sensitive ovarian teratocarcinoma (CH1/PA-1), cisplatin insensitive colon carcinoma (SW480) and non-small cell lung cancer (A549). Thereby, the most lipophilic (yet water soluble) platinum(IV) complexes showed promising IC50 values in the low micromolar and even nanomolar range, demonstrating the significant advantage of using equatorially coordinated monodentate carboxylato ligands.
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria.
authors.forename: Doris
authors.initials: D
authors.lastname: Höfer
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria; Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015, Lausanne, Switzerland. Electronic address: hristo.varbanov@univie.ac.at.
authors.forename: Hristo P
authors.initials: HP
authors.lastname: Varbanov
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria.
authors.forename: Anton
authors.initials: A
authors.lastname: Legin
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria; Research Platform "Translational Cancer Therapy Research", University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Jakupec
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Roller
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria. Electronic address: markus.galanski@univie.ac.at.
authors.forename: Mathea S
authors.initials: MS
authors.lastname: Galanski
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria; Research Platform "Translational Cancer Therapy Research", University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria. Electronic address: bernhard.keppler@univie.ac.at.
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D011355:Prodrugs
keywords: Characterization; Cytotoxicity; Lipophilicity; Platinum complexes; Reduction; Synthesis