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

Based on the central role of the ubiquitin–proteasome system (UPS) in the degradation of cellular proteins, proteasome inhibition has been considered an attractive approach for anticancer therapy. Deubiquitinases (DUBs) remove ubiquitin conjugates from diverse substrates; therefore, they are essential regulators of the UPS. DUB inhibitors, especially the inhibitors of proteasomal DUBs are becoming a research hotspot in targeted cancer therapy. Previous studies have shown that metal complexes, such as copper and zinc complexes, can induce cancer cell apoptosis through inhibiting UPS function. Moreover, we have found that copper pyrithione inhibits both 19S proteasome-associated DUBs and 20S proteasome activity with a mechanism distinct from that of the classical 20S proteasome inhibitor bortezomib. In the present study, we reveal that (i) nickel pyrithione complex (NiPT) potently inhibits the UPS via targeting the 19S proteasome-associated DUBs (UCHL5 and USP14), without effecting on the 20S proteasome; (ii) NiPT selectively induces proteasome inhibition and apoptosis in cultured tumor cells and cancer cells from acute myeloid leukemia human patients; and (iii) NiPT inhibits proteasome function and tumor growth in nude mice. This study, for the first time, uncovers a nickel complex as an effective inhibitor of the 19S proteasomal DUBs and suggests a potentially new strategy for cancer treatment.

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“…These observations are consistent with the previous findings that nickel complex could not inhibit the 20S proteasome. 26,27 …”

Section: Resultsmentioning

confidence: 99%

A novel nickel complex works as a proteasomal deubiquitinase inhibitor for cancer therapy

et al. 2016

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“…A Zn(II) complex, along with a zinc salt, showed CT-like inhibitory effects when studied in vitro with purified 20S proteasome. Additionally, the zinc complex caused proteasome inhibition and apoptosis in C4-2B cancer cells, and also showed specificity towards cancer cells over normal MCF-10A breast cells [124]. Gallium(III)-containing compounds are also apoptosis inducers and can inhibit CT-like activity in prostate cancer cells; in one study, they demonstrated a 70% reduction in tumor growth [125].…”

Section: Natural Compounds and Repurposed Drugs With Proteasome-inhmentioning

confidence: 99%

Targeting the ubiquitin-proteasome system for cancer treatment: discovering novel inhibitors from nature and drug repurposing

Soave

Guerin

Liu

et al. 2017

Cancer Metastasis Rev

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In the past fifteen years, the proteasome has been validated as an anticancer drug target and 20S proteasome inhibitors (such as bortezomib and carfilzomib) have been approved by the FDA for the treatment of multiple myeloma and some other liquid tumors. However, there are shortcomings of clinical proteasome inhibitors, including severe toxicity, drug resistance and no effect in solid tumors. At the same time, extensive research has been conducted in the areas of natural compounds and old drug repositioning toward the goal of discovering effective, economical, low toxicity proteasome-inhibitory anticancer drugs. A variety of dietary polyphenols, medicinal molecules, metallic complexes and metal-binding compounds have been found to be able to selectively inhibit tumor cellular proteasomes and induce apoptotic cell death in vitro and in vivo, supporting the clinical success of specific 20S proteasome inhibitors bortezomib and carfilzomib. Therefore, the discovery of natural proteasome inhibitors and researching old drugs with proteasome inhibitory properties may provide an alternative strategy for improving the current status of cancer treatment and even prevention.

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“…The angles around the Zn II atom are from 81.53(7) to 120.79(5)°. The Zn-N [2.0469(2) and 2.1085(2) Å] bond lengths in the title structure are slightly shorter than those [2.149(6)-2.259(7) Å] in a similar complex [3]. The N-H···Cl hydrogen bonds link the complexes into one-dimensional chains which run along b.…”

mentioning

confidence: 84%

“…All other H-atoms were placed in calculated positions and treated as riding: C-H = 0.93 or 0.97 Å, with U iso (H) = 1.2 U eq (C). Discussion a-amino-pyridines metal complexes, in particular those of gallium(III), nickel(II) and zinc(II), have a great potential to be developed into novel anticancer drugs [1][2][3], and its cationic palladium complexes can catalyze the copolymerization of ethylene and norbornene [4]. The title complex was prepared by the reaction of ZnCl 2 with the potentially bidentate ligand N-(pyridin-2-ylmethyl)aniline.…”

Section: Methodsmentioning

confidence: 99%

Crystal structure of dichlorido[N-(pyridin-2-ylmethyl)aniline]zinc(II), C12H12Cl2N2Zn

Lei

Chen

et al. 2013

Zeitschrift Für Kristallographie - New Crystal Structures

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Source of materialPicolinaldehyde (1.07 g, 10 mmol) and aniline (0.93 g, 10 mmol) in methanol (50 mL) were heated to reflux for 1 h. After the mixture was cooled to room temperature, NaBH 4 (0.074 g, 20 mmol) was added slowly with vigorous stirring. Then the solvent was removed in a rotary evaporator and the solid residue treated with 50 mL of water. The mixture was neutralized with glacial acetic acid and then extracted three times with 50 mL of diethyl ether. The combined extracts were washed with water (50 mL), evaporated to dryness in vacuo. Afterwards ZnCl 2 and one molar equivalents of N-(pyridin-2-ylmethyl)aniline were dissolved in methanol with stirring. After allowing the clear purple solution obtained to stand at room temperature in air for 3 days, large colourless block-shaped crystals were formed at the bottom of the vessel on slow evaporation of the solvent. Experimental detailsThe hydrogen atom H2A was located in a difference Fourier map and the positional parameters were refined with U iso (H) = 1.2 U eq (N). All other H-atoms were placed in calculated positions and treated as riding: C-H = 0.93 or 0.97 Å, with U iso (H) = 1.2 U eq (C). Discussion a-amino-pyridines metal complexes, in particular those of gallium(III), nickel(II) and zinc(II), have a great potential to be developed into novel anticancer drugs [1][2][3], and its cationic palladium complexes can catalyze the copolymerization of ethylene and norbornene [4]. The title complex was prepared by the reaction of ZnCl 2 with the potentially bidentate ligand N-(pyridin-2-ylmethyl)aniline. The molecular structure of the title compound is shown in the figure with ellipsoids drawn at the 50% probability level. The Zn II ion is in a distorted tetrahedral coordination environment. The angles around the Zn II atom are from 81.53(7) to 120.79(5)°. The Zn-N [2.0469(2) and 2.1085(2) Å] bond lengths in the title structure are slightly shorter than those [2.149(6)-2.259(7) Å] in a similar complex [3]. The N-H···Cl hydrogen bonds link the complexes into one-dimensional chains which run along b.

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

Cited by 59 publications

References 67 publications

A novel nickel complex works as a proteasomal deubiquitinase inhibitor for cancer therapy

A novel nickel complex works as a proteasomal deubiquitinase inhibitor for cancer therapy

Targeting the ubiquitin-proteasome system for cancer treatment: discovering novel inhibitors from nature and drug repurposing

Crystal structure of dichlorido[N-(pyridin-2-ylmethyl)aniline]zinc(II), C12H12Cl2N2Zn

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