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

Abstract

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.