title: The role of the equatorial ligands for the redox behavior, mode of cellular accumulation and cytotoxicity of platinum(IV) prodrugs.
abstract: The current study aims to elucidate the possible reasons for the significantly different pharmacological behavior of platinum(IV) complexes with cisplatin-, carboplatin- or nedaplatin-like cores and how this difference can be related to their main physicochemical properties. Chlorido-containing complexes are reduced fast (within hours) by ascorbate and are able to unwind plasmid DNA in the presence of ascorbate, while their tri- and tetracarboxylato analogs are generally inert under the same conditions. Comparison of the lipophilicity, cellular accumulation and cytotoxicity of the investigated platinum compounds revealed the necessity to define new structure-property/activity relationships (SPRs and SARs). The higher activity and improved accumulation of platinum(IV) complexes bearing Cl(-) in equatorial position cannot only be attributed to passive diffusion facilitated by their lipophilicity. Therefore, further platinum accumulation experiments under conditions where active/facilitated transport mechanisms are suppressed were performed. Under hypothermic conditions (4°C), accumulation of dichloridoplatinum(IV) complexes is reduced down to 10% of the amount determined at 37°C. These findings suggest the involvement of active and/or facilitated transport in cellular uptake of platinum(IV) complexes with a cisplatin-like core. Studies with ATP depletion mediated by oligomycin and low glucose partially confirmed these observations, but their feasibility was severely limited in the adherent cell culture setting.
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria.
authors.forename: Simone
authors.initials: S
authors.lastname: Göschl
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; Research Platform "Translational Cancer Therapy Research", University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria.
authors.forename: Sarah
authors.initials: S
authors.lastname: Theiner
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: michael.jakupec@univie.ac.at.
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: 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.
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
mesh_terms: D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001692:Biological Transport; D016190:Carboplatin / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000737:chemistry; D003080:Cold Temperature; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000494:pharmacology*; D005947:Glucose / Q000172:deficiency / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D009840:Oligomycins / Q000494:pharmacology; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010984:Platinum / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D008024:Ligands; D009840:Oligomycins; D009944:Organoplatinum Compounds; D011355:Prodrugs; D010984:Platinum; D000255:Adenosine Triphosphate; C053989:nedaplatin; D016190:Carboplatin; D005947:Glucose; D002945:Cisplatin
keywords: Cellular accumulation; Cytotoxicity; Facilitated/active transport; Lipophilicity; Platinum(IV) complexes; Redox behavior