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Bulky N(,N)‑(Di)alkylethane-1,2-diamineplatinum(II) Compounds as Precursors for Generating Unsymmetrically Substituted Platinum(IV) Complexes

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posted on 15.07.2013, 00:00 by Verena Pichler, Simone Göschl, Samuel M. Meier, Alexander Roller, Michael A. Jakupec, Markus Galanski, Bernhard K. Keppler
Investigations of the influence of bulky groups in the equatorial ligand sphere of platinum­(IV) compounds on the complexes’ stability and reaction pattern were performed. Four dihydroxidoplatinum­(IV) complexes were reacted with anhydrides, cinnamoyl chloride, and n-propyl isocyanate and yielded the symmetric dicarboxylated products or, if steric hindrance was observed, unsymmetrically substituted monocarboxylated analogues. With the aim of raising the steric demand, the following ligands were chosen: N-cyclohexylethane-1,2-diamine, N,N-dimethylethane-1,2-diamine, N,N-diethylethane-1,2-diamine, and N,N-diisopropylethane-1,2-diamine. All of the novel complexes were characterized by electrospray ionization mass spectrometry (ESI-MS), one- and two-dimensional NMR spectroscopy, elemental analysis, and reversed-phase HPLC; complexes B3, C3, C6, and D4 were also analyzed by X-ray diffraction. Additionally, the cytotoxicities of 10 compounds toward the cisplatin-sensitive cell line CH1 and the intrinsically cisplatin-resistant cell lines A549 and SW480 were investigated, and IC50 values down to the nanomolar range were found. To aid in the interpretation of structure–activity relationships, log kw values as a measure for the lipophilicity were determined for all of the new complexes, and the rates of reduction of C1, C3, and C4 relative to satraplatin were determined by means of NMR spectroscopy and ESI-MS.