Platinum(II) Complexes with O,S Bidentate Ligands: Biophysical Characterization, Antiproliferative Activity, and Crystallographic Evidence of Protein Binding
The authors recently characterized a series of novel platinum(II) compds. bearing a conserved O,S binding moiety as a bifunctional ligand and evaluated their soln. behavior and antiproliferative properties in vitro against a representative cancer cell line. On the whole, those platinum compds. showed an appreciable stability in mixed DMSO-aq. buffers and promising in vitro cytotoxic effects; yet they manifested a rather limited soly. in aq. media making them poorly suitable for further pharmaceutical development. To overcome this drawback, four new derivs. of this series, [Pt(DMSO)Cl(L)] (HL = β-hydroxydithiocinnamic alkyl ester ligand), were prepd. and characterized based on a careful choice of substituents on the O,S bidentate ligand. The soly. and stability profile of these novel compds. in a ref. buffer was detd., as well as the ligands' log Po/w value (Po/w = n-octanol-water partition coeff.) 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 compds. were assessed using the model protein hen egg white lysozyme (HEWL), and the mol. structures of two relevant HEWL-metallodrug adducts were solved. Overall, a proper choice of the substituents leads to a higher soly. and enables a selective fine-tuning of the antiproliferative properties. The implications of these results are thoroughly discussed.
2015
54
8560
8570
REVIEWED