Platinum(II) Complexes with O,S Bidentate Ligands: Biophysical Characterization, Antiproliferative Activity, and Crystallographic Evidence of Protein Binding.
We recently characterized a series of novel platinum(II) compounds bearing a conserved O,S binding moiety as a bifunctional ligand and evaluated their solution behavior and antiproliferative properties in vitro against a representative cancer cell line. On the whole, those platinum compounds showed an appreciable stability in mixed dimethyl sulfoxide-aqueous buffers and promising in vitro cytotoxic effects; yet they manifested a rather limited solubility in aqueous media making them poorly suitable for further pharmaceutical development. To overcome this drawback, four new derivatives of this series were prepared and characterized based on a careful choice of substituents on the O,S bidentate ligand. The solubility and stability profile of these novel compounds in a reference buffer was determined, as well as the ligands' log P(o/w) value (P(o/w) = n-octanol-water partition coefficient) as an indirect measure for the complexes' lipophilicity. The antiproliferative properties were comparatively evaluated in a panel of three cancer cell lines. The protein binding properties of the four platinum compounds were assessed using the model protein hen egg white lysozyme (HEWL), and the molecular structures of two relevant HEWL-metallodrug adducts were solved. Overall, it is shown that a proper choice of the substituents leads to a higher solubility and enables a selective fine-tuning of the antiproliferative properties. The implications of these results are thoroughly discussed.
Institute of Inorganic and Analytical Chemistry, Friedrich-Schiller-University Jena , Humboldtstraße 8, 07743 Jena, Germany.|Inorganic Chemistry I - Bioinorganic Chemistry, Faculty of Chemistry and Biochemistry, Ruhr University Bochum , Universitaetsstrasse 150, 44801 Bochum, Germany.
Carolin
C
Mügge
Laboratory of Metals in Medicine, Department of Chemistry, University of Florence , Via della Lastruccia 3, 50019 Sesto Fiorentino, Firenze, Italy.
Tiziano
T
Marzo
Laboratory of Metals in Medicine, Department of Chemistry, University of Florence , Via della Lastruccia 3, 50019 Sesto Fiorentino, Firenze, Italy.
Lara
L
Massai
Institute of Inorganic and Analytical Chemistry, Friedrich-Schiller-University Jena , Humboldtstraße 8, 07743 Jena, Germany.
Jana
J
Hildebrandt
Department of Chemical Sciences, University of Naples Federico II , via Cintia, Napoli I-80126, Italy.
Giarita
G
Ferraro
Department of Chemistry, Chemistry Research Laboratory, University of Oxford , 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
Pablo
P
Rivera-Fuentes
Inorganic Chemistry I - Bioinorganic Chemistry, Faculty of Chemistry and Biochemistry, Ruhr University Bochum , Universitaetsstrasse 150, 44801 Bochum, Germany.
Nils
N
Metzler-Nolte
Department of Chemical Sciences, University of Naples Federico II , via Cintia, Napoli I-80126, Italy.|CNR Institute of Biostructures and Bioimages , via Mezzocannone 16, Napoli I-80100, Italy.
Antonello
A
Merlino
Laboratory of Metals in Medicine, Department of Chemistry, University of Florence , Via della Lastruccia 3, 50019 Sesto Fiorentino, Firenze, Italy.
Luigi
L
Messori
Institute of Inorganic and Analytical Chemistry, Friedrich-Schiller-University Jena , Humboldtstraße 8, 07743 Jena, Germany.|Jena Center for Soft Matter (JCSM) , Philosophenweg 7, 07743 Jena, Germany.
Wolfgang
W
Weigand
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D009113:Muramidase / Q000737:chemistry*; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology*; D010100:Oxygen / Q000737:chemistry*; D011485:Protein Binding; D011789:Quantum Theory; D013329:Structure-Activity Relationship; D013455:Sulfur / Q000737:chemistry*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D008024:Ligands; D009944:Organoplatinum Compounds; D013455:Sulfur; C421864:hen egg lysozyme; D009113:Muramidase; D010100:Oxygen