title: Comparative activities of nickel(II) and zinc(II) complexes of asymmetric [NN'O] ligands as 26S proteasome inhibitors.
abstract: In this study, we compare the proteasome inhibition capabilities of two anticancer candidates, [Ni(L(IA))(2)] (1) and [Zn(L(IA))(2)] (2), where L(IA-) 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 NiCl(2) and ZnCl(2), 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 NiCl(2) nor 1 have the ability to inhibit the proteasome activity at any sustained levels. However, ZnCl(2) and 2 showed superior inhibitory activity versus the chymotrypsin-like activity of both the 26S proteasome (IC(50) = 5.7 and 4.4 micromol/L, respectively) and the purified 20S proteasome (IC(50) = 16.6 and 11.7 micromol/L, respectively) under cell-free conditions. Additionally, inhibition of proteasomal activity in cultured prostate cancer cells by 2 was associated with higher levels of ubiquitinated proteins and apoptosis. Treatment with either the metal complex or the salt was relatively nontoxic toward human normal cells. These results strengthen the current working hypothesis that fast ligand dissociation is required to generate an [ML(IA)](+) pharmacophore, capable of interaction with the proteasome. This interaction, possibly via N-terminal threonine amino acids present in the active sites, renders the proteasome inactive. Our results present a compelling rationale for 2 along with its gallium(III) and copper(II) congeners to be further investigated as potential anticancer drugs that act as proteasome inhibitiors.
authors.affiliation: The Prevention Program, Barbara Ann Karmanos Cancer Institute, and Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan 48201, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Frezza
authors.forename: Sarmad Sahiel
authors.initials: SS
authors.lastname: Hindo
authors.forename: Dajena
authors.initials: D
authors.lastname: Tomco
authors.forename: Marco M
authors.initials: MM
authors.lastname: Allard
authors.forename: Qiuzhi Cindy
authors.initials: QC
authors.lastname: Cui
authors.forename: Mary Jane
authors.initials: MJ
authors.lastname: Heeg
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.forename: Q Ping
authors.initials: QP
authors.lastname: Dou
authors.forename: Cláudio N
authors.initials: CN
authors.lastname: Verani
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D009532:Nickel / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000473:pathology; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D021241:Spectrometry, Mass, Electrospray Ionization; D054875:Ubiquitination; D015032:Zinc / Q000737:chemistry*
chemical_list: D008024:Ligands; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D009532:Nickel; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D015032:Zinc