title: A novel class of bis- and tris-chelate diam(m)inebis(dicarboxylato)platinum(IV) complexes as potential anticancer prodrugs.
abstract: A novel class of platinum(IV) complexes of the type [Pt(Am)(R(COO)2)2], where Am is a chelating diamine or two monodentate am(m)ine ligands and R(COO)2 is a chelating dicarboxylato moiety, was synthesized. For this purpose, the reaction between the corresponding tetrahydroxidoplatinum(IV) precursors and various dicarboxylic acids, such as oxalic, malonic, 3-methylmalonic, and cyclobutanedicarboxylic acid, was utilized. All new compounds were characterized in detail, using 1D and 2D NMR techniques, ESI-MS, FTIR spectroscopy, elemental analysis, TGA, and X-ray diffraction. Their in vitro cytotoxicity was determined in a panel of human tumor cell lines (CH1, SW480 and A549) by means of the MTT colorimetric assay. Furthermore, the lipophilicity and redox properties of the novel complexes were evaluated in order to better understand their pharmacological behavior. The most promising drug candidate, 4b (Pt(DACH)(mal)2), demonstrated low in vivo toxicity but profound anticancer activity against both the L1210 leukemia and CT-26 colon carcinoma models.
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna , Waehringer Strasse 42, 1090 Vienna, Austria.
authors.forename: Hristo P
authors.initials: HP
authors.lastname: Varbanov
authors.forename: Simone
authors.initials: S
authors.lastname: Göschl
authors.forename: Petra
authors.initials: P
authors.lastname: Heffeter
authors.forename: Sarah
authors.initials: S
authors.lastname: Theiner
authors.forename: Alexander
authors.initials: A
authors.lastname: Roller
authors.forename: Frank
authors.initials: F
authors.lastname: Jensen
authors.forename: Michael A
authors.initials: MA
authors.lastname: Jakupec
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.forename: Mathea Sophia
authors.initials: MS
authors.lastname: Galanski
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002627:Chemistry, Physical; D003110:Colonic Neoplasms / Q000188:drug therapy; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007939:Leukemia L1210 / Q000188:drug therapy; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D016513:Mice, SCID; D008958:Models, Molecular; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010084:Oxidation-Reduction; D010984:Platinum; D011789:Quantum Theory; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D009944:Organoplatinum Compounds; C000595004:diaminocyclohexane)bis(malonato)platinum(IV); D010984:Platinum