The Prevention Program, Barbara Ann Karmanos Cancer Institute, and Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan 48201, USA.
Inorg Chem. 2009 Jul 6;48(13):5928-37. doi: 10.1021/ic900276g.
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.
在这项研究中，我们比较了两种抗癌候选物，[Ni(L(IA))(2)]（1）和[Zn(L(IA))(2)]（2）的蛋白酶体抑制能力，其中 L(IA-)是配体 2,4-二碘-6-(((2-吡啶甲基)氨基)甲基)苯酚的去质子形式。物种 1 含有镍（II），这是一种相当惰性的离子，有利于共价键；而 2 含有锌（II），这是一种不稳定的过渡金属离子，主要有利于离子键。我们使用各种光谱、光谱和结构方法报告了 1 和 2 的合成和表征。此外，还评估了 1 和 2 以及盐 NiCl2 和 ZnCl2 的药理学效应，以评估它们在体外和培养的人类癌细胞中抑制蛋白酶体和诱导细胞凋亡的能力。结果表明，NiCl2 或 1 都没有以任何持续水平抑制蛋白酶体活性的能力。然而，ZnCl2 和 2 对 26S 蛋白酶体（IC50 = 5.7 和 4.4 μmol/L，分别）和纯化的 20S 蛋白酶体（IC50 = 16.6 和 11.7 μmol/L，分别）的胰凝乳蛋白酶样活性均表现出优越的抑制活性。在无细胞条件下。此外，2 抑制培养的前列腺癌细胞中蛋白酶体活性与泛素化蛋白和细胞凋亡水平升高有关。金属配合物或盐对人正常细胞的毒性相对较低。这些结果加强了当前的工作假设，即快速配体解离是产生能够与蛋白酶体相互作用的ML(IA)药效团所必需的。这种相互作用可能通过存在于活性部位的 N 末端苏氨酸氨基酸使蛋白酶体失活。我们的结果为 2 及其镓（III）和铜（II）同系物提供了强有力的理由，进一步研究它们作为作用于蛋白酶体的潜在抗癌药物。
