A Novel Class of Bis- and Tris-Chelate Diam(m)inebis(dicarboxylato)platinum(IV) Complexes as Potential Anticancer Prodrugs
datasetposted on 2014-08-14, 00:00 authored by Hristo P. Varbanov, Simone Göschl, Petra Heffeter, Sarah Theiner, Alexander Roller, Frank Jensen, Michael A. Jakupec, Walter Berger, Markus Galanski, Bernhard K. Keppler
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.
DiammonodentateoxalicligandTGABisvivo toxicity4 bcompoundFTIR spectroscopydicarboxylic acidsPtredox propertieschelating diaminemodeltumor cell linesComplexepanelprecursoranticancer activitychelating dicarboxylato moietyNovel ClassL 1210 leukemiacyclobutanedicarboxylic acidlipophilicitytypeCHtetrahydroxidoplati1 DCTMTT colorimetric assaydrug candidateSWmethylmalonic2 D NMR techniquesdiffractionmaloniccarcinomacytotoxicitynovel complexesAmanalysisPotential Anticancer ProdrugsA novel class