Comparative Activities of Nickel(II) and Zinc(II) Complexes of Asymmetric [NN'O] Ligands as 26S Proteasome Inhibitors

In this study, we compare the proteasome inhibition capabilities of two anticancer candidates, [Ni(LIA)2] (1) and [Zn(LIA)2] (2), where LIA− is the deprotonated form of the ligand 2,4-diiodo-6-(((2-pyridinylmethyl)amino)methyl)phenol. Species 1 contains nickel(II), a considerably inert ion that favors covalency, whereas 2 contains zinc(II), a labile transition metal ion that favors predominantly ionic bonds. We report on the synthesis and characterization of 1 and 2 using various spectroscopic, spectrometric, and structural methods. Furthermore, the pharmacological effects of 1 and 2, along with those of the salts NiCl2 and ZnCl2, were evaluated in vitro and in cultured human cancer cells in terms of their proteasome-inhibitory and apoptotic cell-death-inducing capabilities. It is shown that neither NiCl2 nor 1 have the ability to inhibit the proteasome activity at any sustained levels. However, ZnCl2 and 2 showed superior inhibitory activity versus the chymotrypsin-like activity of both the 26S proteasom...