Here we investigated cytotoxicity and DNA and protein binding of an iodido analog of picoplatin, the cis-ammine-diiodido(2-methylpyridine)platinum(II) complex (I-picoplatin). I-picoplatin (IC50 = 3.7-12.4 μM) outperforms picoplatin (IC50 = 11.8-22.6 μM) in the human cancer cell lines used and shows a greater ability to overcome the cisplatin resistance of A2780 ovarian cancer cells than does picoplatin. I-picoplatin also induces different cell cycle changes (reduced S-phase fraction and an increase in the G2/M phase arrest) in HeLa cervical carcinoma cells compared to both picoplatin and cisplatin. Binding of the metal compound to DNA model systems was investigated by ethidium bromide displacement assay and circular dichroism. Its reactivity with lysozyme (HEWL) and pancreatic RNase A was studied by X-ray diffraction and mass spectrometry experiments. I-picoplatin binds the DNA double helix and is able to retain the 2-methylpyridine ligand and at least one of the two iodido ligands when bound to the two proteins. Various Pt-containing moieties, including one based on the isomerized structure of I-picoplatin, coordinate the His and Met residues. A low-resolution structure of the I-picoplatin/human serum albumin (HSA) adduct has also been solved. The side chains of His146, Met289, and Met329 are the primary binding sites of the I-picoplatin moieties on HSA.

Department of Biophysics Faculty of Science Palacký University Olomouc Slechtitelu 27 Olomouc 783 71 Czech Republic

Department of Chemical Sciences University of Naples Federico 2 Complesso Universitario di Monte Sant'Angelo via Cinthia 21 Naples 80126 Italy

Department of Chemistry Ugo Schiff University of Florence via della Lastruccia 3 13 Sesto Fiorentino 50019 Florence Italy

Department of Inorganic Chemistry Faculty of Science Palacký University Olomouc 17 listopadu 1192 12 Olomouc 771 46 Czech Republic

Department of Neuroscience Biomedicine and Movement Sciences Biological Chemistry Section University of Verona Strada Le Grazie 8 Verona 1 37134 Italy

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