Gold(I) Carbene Complexes Causing Thioredoxin 1 and Thioredoxin 2 Oxidation as Potential Anticancer Agents

Esther Schuh; Carolin Pflueger; Anna Citta; Alessandra Folda; Maria Pia Rigobello; Alberto Bindoli; Angela Casini; Fabian Mohr

doi:10.1021/jm300428v

Gold(I) Carbene Complexes Causing Thioredoxin 1 and Thioredoxin 2 Oxidation as Potential Anticancer Agents

Esther Schuh, Carolin Pflueger, Anna Citta, Alessandra Folda, Maria Pia Rigobello, Alberto Bindoli, Angela Casini^*, Fabian Mohr^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

226 Citations (Scopus)

Abstract

Gold(I) complexes with 1,3-substituted imidazole-2-ylidene and benzimidazole-2-ylidene ligands of the type NHC-Au-L (NHC = N-heterocyclic carbene L = Cl or 2-mercapto-pyrimidine) have been synthesized and structurally characterized. The compounds were evaluated for their antiproliferative properties in human ovarian cancer cells sensitive and resistant to cisplatin (A2780S/R), as well in the nontumorigenic human embryonic kidney cell line (HEK-293T), showing in some cases important cytotoxic effects. Some of the complexes were comparatively tested as thioredoxin reductase (TrxR) and glutathione reductase (GR) inhibitors, directly against the purified proteins or in cell extracts. The compounds showed potent and selective TrxR inhibition properties in particular in cancer cell lines. Remarkably, the most effective TrxR inhibitors induced extensive oxidation of thioredoxins (Trxs), which was more relevant in the cancerous cells than in HEK-293T cells. Additional biochemical assays on glutathione systems and reactive oxygen species formation evidenced important differences with respect to the classical cytotoxic Au(I)-phosphine compound auranofin.

Original language	English
Pages (from-to)	5518-5528
Number of pages	11
Journal	Journal of Medicinal Chemistry
Volume	55
Issue number	11
DOIs	https://doi.org/10.1021/jm300428v
Publication status	Published - 14-Jun-2012

Keywords

N-HETEROCYCLIC CARBENE
MITOCHONDRIAL PERMEABILITY TRANSITION
IN-VITRO CYTOTOXICITY
CELL-DEATH
THERAPEUTIC AGENTS
METAL-COMPLEXES
REDUCTASE
GLUTATHIONE
CANCER
LIGANDS

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Gold(I) Carbene Complexes Causing Thioredoxin 1 and Thioredoxin 2 Oxidation
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CCDC 922328: Experimental Crystal Structure Determination
Schuh, E. (Contributor), Pflüger, C. (Contributor), Citta, A. (Contributor), Folda, A. (Contributor), Rigobello, M. P. (Contributor), Bindoli, A. (Contributor), Casini, A. (Contributor) & Mohr, F. (Contributor), University of Groningen, 28-Jan-2013
DOI: 10.5517/cczyrj5
Dataset
CCDC 922327: Experimental Crystal Structure Determination
Schuh, E. (Contributor), Pflüger, C. (Contributor), Citta, A. (Contributor), Folda, A. (Contributor), Rigobello, M. P. (Contributor), Bindoli, A. (Contributor), Casini, A. (Contributor) & Mohr, F. (Contributor), University of Groningen, 28-Jan-2013
DOI: 10.5517/cczyrh4
Dataset
CCDC 922326: Experimental Crystal Structure Determination
Schuh, E. (Contributor), Pflüger, C. (Contributor), Citta, A. (Contributor), Folda, A. (Contributor), Rigobello, M. P. (Contributor), Bindoli, A. (Contributor), Casini, A. (Contributor) & Mohr, F. (Contributor), University of Groningen, 28-Jan-2013
DOI: 10.5517/cczyrg3
Dataset

Cite this

@article{a5589cc52cb34998b231de1777acf5d7,

title = "Gold(I) Carbene Complexes Causing Thioredoxin 1 and Thioredoxin 2 Oxidation as Potential Anticancer Agents",

abstract = "Gold(I) complexes with 1,3-substituted imidazole-2-ylidene and benzimidazole-2-ylidene ligands of the type NHC-Au-L (NHC = N-heterocyclic carbene L = Cl or 2-mercapto-pyrimidine) have been synthesized and structurally characterized. The compounds were evaluated for their antiproliferative properties in human ovarian cancer cells sensitive and resistant to cisplatin (A2780S/R), as well in the nontumorigenic human embryonic kidney cell line (HEK-293T), showing in some cases important cytotoxic effects. Some of the complexes were comparatively tested as thioredoxin reductase (TrxR) and glutathione reductase (GR) inhibitors, directly against the purified proteins or in cell extracts. The compounds showed potent and selective TrxR inhibition properties in particular in cancer cell lines. Remarkably, the most effective TrxR inhibitors induced extensive oxidation of thioredoxins (Trxs), which was more relevant in the cancerous cells than in HEK-293T cells. Additional biochemical assays on glutathione systems and reactive oxygen species formation evidenced important differences with respect to the classical cytotoxic Au(I)-phosphine compound auranofin.",

keywords = "N-HETEROCYCLIC CARBENE, MITOCHONDRIAL PERMEABILITY TRANSITION, IN-VITRO CYTOTOXICITY, CELL-DEATH, THERAPEUTIC AGENTS, METAL-COMPLEXES, REDUCTASE, GLUTATHIONE, CANCER, LIGANDS",

author = "Esther Schuh and Carolin Pflueger and Anna Citta and Alessandra Folda and Rigobello, {Maria Pia} and Alberto Bindoli and Angela Casini and Fabian Mohr",

year = "2012",

month = jun,

day = "14",

doi = "10.1021/jm300428v",

language = "English",

volume = "55",

pages = "5518--5528",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "AMER CHEMICAL SOC",

number = "11",

}

TY - JOUR

T1 - Gold(I) Carbene Complexes Causing Thioredoxin 1 and Thioredoxin 2 Oxidation as Potential Anticancer Agents

AU - Schuh, Esther

AU - Pflueger, Carolin

AU - Citta, Anna

AU - Folda, Alessandra

AU - Rigobello, Maria Pia

AU - Bindoli, Alberto

AU - Casini, Angela

AU - Mohr, Fabian

PY - 2012/6/14

Y1 - 2012/6/14

N2 - Gold(I) complexes with 1,3-substituted imidazole-2-ylidene and benzimidazole-2-ylidene ligands of the type NHC-Au-L (NHC = N-heterocyclic carbene L = Cl or 2-mercapto-pyrimidine) have been synthesized and structurally characterized. The compounds were evaluated for their antiproliferative properties in human ovarian cancer cells sensitive and resistant to cisplatin (A2780S/R), as well in the nontumorigenic human embryonic kidney cell line (HEK-293T), showing in some cases important cytotoxic effects. Some of the complexes were comparatively tested as thioredoxin reductase (TrxR) and glutathione reductase (GR) inhibitors, directly against the purified proteins or in cell extracts. The compounds showed potent and selective TrxR inhibition properties in particular in cancer cell lines. Remarkably, the most effective TrxR inhibitors induced extensive oxidation of thioredoxins (Trxs), which was more relevant in the cancerous cells than in HEK-293T cells. Additional biochemical assays on glutathione systems and reactive oxygen species formation evidenced important differences with respect to the classical cytotoxic Au(I)-phosphine compound auranofin.

AB - Gold(I) complexes with 1,3-substituted imidazole-2-ylidene and benzimidazole-2-ylidene ligands of the type NHC-Au-L (NHC = N-heterocyclic carbene L = Cl or 2-mercapto-pyrimidine) have been synthesized and structurally characterized. The compounds were evaluated for their antiproliferative properties in human ovarian cancer cells sensitive and resistant to cisplatin (A2780S/R), as well in the nontumorigenic human embryonic kidney cell line (HEK-293T), showing in some cases important cytotoxic effects. Some of the complexes were comparatively tested as thioredoxin reductase (TrxR) and glutathione reductase (GR) inhibitors, directly against the purified proteins or in cell extracts. The compounds showed potent and selective TrxR inhibition properties in particular in cancer cell lines. Remarkably, the most effective TrxR inhibitors induced extensive oxidation of thioredoxins (Trxs), which was more relevant in the cancerous cells than in HEK-293T cells. Additional biochemical assays on glutathione systems and reactive oxygen species formation evidenced important differences with respect to the classical cytotoxic Au(I)-phosphine compound auranofin.

KW - N-HETEROCYCLIC CARBENE

KW - MITOCHONDRIAL PERMEABILITY TRANSITION

KW - IN-VITRO CYTOTOXICITY

KW - CELL-DEATH

KW - THERAPEUTIC AGENTS

KW - METAL-COMPLEXES

KW - REDUCTASE

KW - GLUTATHIONE

KW - CANCER

KW - LIGANDS

U2 - 10.1021/jm300428v

DO - 10.1021/jm300428v

M3 - Article

SN - 0022-2623

VL - 55

SP - 5518

EP - 5528

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 11

ER -

Gold(I) Carbene Complexes Causing Thioredoxin 1 and Thioredoxin 2 Oxidation as Potential Anticancer Agents

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Datasets

CCDC 922328: Experimental Crystal Structure Determination

CCDC 922327: Experimental Crystal Structure Determination

CCDC 922326: Experimental Crystal Structure Determination

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