Noncovalent interactions of antitumor cycloplatinated complexes containing trifluoroacetate ligands as the leaving group with bovine serum albumin. Implications for drug design

The biomolecular interactions of two previously reported cycloplatinated complexes, [Pt(C^N)(SMe2)(OCOCF3)] (C^N = deprotonated benzo[h]quinoline (bhq), 1, or deprotonated 2-phenylpyridine (ppy), 2), with bovine serum albumin (BSA) were investigated using various spectroscopic techniques. Structural characterization of 1 and 2 by NMR, UV-vis spectroscopies and conductivity measurements in aqueous media revealed that the TFAc functions as a leaving group ligand and is rapidly replaced by water molecules to form cationic cycloplatinated complexes having an aqua ligand, [Pt(C^N)(SMe2)(H2O)]+[CF3COO]−. Fluorescence titration of BSA indicated a strong binding interaction between Pt(II) compounds and protein with a static quenching mechanism. The thermodynamic parameters (ΔH°, ΔG° and ΔS°) showed that the binding was exothermic, involving main noncovalent hydrophobic forces and ionic interactions. As revealed by the displacement experiment, while 1 could bind to subdomain IIIA (site II) of albumin, the binding sites of 2 were mostly located at subdomain IIA (site I). The synchronous fluorescence spectra indicate that the cycloplatinated compounds induce structural changes in the protein structure. Moreover, far-UV CD spectroscopy is in agreement with a reduction of the α-helix content of albumin through binding. Further evidence for noncovalent association was obtained from inductively coupled plasma-optical emission spectroscopy (ICP-OES). In addition, the cytotoxicity investigation of 1 as a model complex against two human leukemic cancer cell lines (K562 and HL-60), MCF-7 (human breast adenocarcinoma), U-87MG (human glioblastoma cell line) and HT-29 (human colorectal adenocarcinoma cell line) suggested that 1 is more cytotoxic than cisplatin against HL-60 and generally toxic toward K562, MCF-7 and U-87MG. Finally, the quantitative structure–activity relationship (QSAR) was applied to correlate the structure of some cycloplatinated complexes including 1 and 2 with the SA albumin binding constant.