Structural features and antiproliferative activity of Pd(II) complexes with halogenated ligands: a comparative study between Schiff base and reduced Schiff base complexes

In order to investigate the structural features and antiproliferative activity of Pd(II) complexes containing halogenated ligands with different flexibility, several Schiff base and reduced Schiff base Pd(II) complexes, namely X1X2PicPd, X1X2PyPd, X1X2Pic(R)Pd, and X1X2Py(R)Pd (where X1 = X2 = Cl, Br and I; Pic: 2-picolylamine; Py = 2-(2-pyridyl)ethylamine), were synthesized and characterized by spectroscopic methods and, in the case of Br2PyPd, Cl2Py(R)Pd and ClBrPy(R)Pd, also by X-ray crystallography. The results of the X-ray crystallography showed that in both series of complexes the Pd(II) ion has a distorted square-planar geometry, although the coordination modes of the two ligands are different. In the Schiff base-type complexes the ligand acts as a tridentate chelate with NN’O donor atoms, whereas in the reduced Schiff base-type complexes the ligand acts as a bidentate chelate with NN’ donor atoms. In both series of complexes, the chloride ions occupy the residual coordination sites of the Pd(II) ion. TD-DFT calculations were performed for a better understanding of the UV-Vis spectra. From these calculations it was found that the signal appearing at ∼400 nm in the complexes with reduced Schiff base ligands (X1X2Pic(R)Pd and X1X2Py(R)Pd) is mainly due to a HOMO → LUMO transition, while for the Schiff base complex ClBrPyPd the signal is due to a HOMO → LUMO+1 transition. For the complex I2PicPd, combinations of HOMO−4 → LUMO and HOMO−2 → LUMO transitions were found to be responsible for that signal. In regard to the biological activity profile, all complexes were first investigated as proteasome inhibitors by fluorometric methods. From these enzymatic assays, it emerged that they are good inhibitors with IC50 values in the low-micromolar range and that their inhibitory activity is strictly related to the presence of the metal ion. Subsequently they were also subjected to cell-based assays (the resazurin method) to assess their antiproliferative properties by using two leukemic cell lines, namely the drug-sensitive CCRF-CEM cell line and its multidrug-resistant sub-cell line CEM/ADR5000. In this test they displayed IC50 values in the submicromolar and low-micromolar range determined for a selected metal complex (Br2Pic(R)Pd) and ligand (Cl2Pic(R)), respectively. Moreover, docking studies were performed on the two expected molecular targets, i.e. proteasome and DNA, to shed light on the mechanisms of action of these types of Pd(II) complexes.