New insights in Au-NHCs complexes as anticancer agents

Porchia, Marina; Pellei, Maura; Marinelli, Marika; Tisato, Francesco; Bello, Fabio Del; Santini, Carlo

doi:10.1016/j.ejmech.2018.01.065

Cited by 150 publications

(106 citation statements)

References 130 publications

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“…The potential impact of auranofin triggered the development of new gold compounds. It is known that auranofin and phosphine gold(I) related compounds selectively inhibit the mitochondrial thioredoxin reductase, which leads to the increased production of reactive oxygen species (ROS) and consequent mitochondrial damage followed by the internal induction of apoptosis . Because the mechanisms of action of anticancer gold complexes are likely to be different from those of cisplatin, most of the reported cytotoxic gold complexes are also effective against cisplatin‐resistant cancer cells, thereby revealing the potential of the development of gold chemotherapeutics to resolve the problem of cisplatin resistance .…”

Section: Introductionmentioning

confidence: 99%

The Important Role of the Nuclearity, Rigidity, and Solubility of Phosphane Ligands in the Biological Activity of Gold(I) Complexes

Svahn

Moro

Roma‐Rodrigues

et al. 2018

Chemistry A European J

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A series of 4-ethynylaniline gold(I) complexes containing monophosphane (1,3,5-triaza-7-phosphaadamantane (pta; 2), 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (3), and PR , with R=naphthyl (4), phenyl (5), and ethyl (6)) and diphosphane (bis(diphenylphosphino)acetylene (dppa; 7), trans-1,2-bis(diphenylphosphino)ethene (dppet; 8), 1,2-bis(diphenylphosphino)ethane (dppe; 9), and 1,3-bis(diphenylphosphino)propane (dppp; 10)) ligands have been synthesized and their efficiency against tumor cells evaluated. The cytotoxicity of complexes 2-10 was evaluated in human colorectal (HCT116) and ovarian (A2780) carcinoma as well as in normal human fibroblasts. All the complexes showed a higher antiproliferative effect in A2780 cells, with the cytotoxicity decreasing in the following order 5>6=9=10>8>2>4>7>3. Complex 4 stands out for its very high selectivity towards ovarian carcinoma cells (IC =2.3 μm) compared with colorectal carcinoma and normal human fibroblasts (IC >100 μm), which makes this complex very attractive for ovarian cancer therapy. Its cytotoxicity in these cells correlates with the induction of the apoptotic process and an increase of intracellular reactive oxygen species (ROS). The effects of the nuclearity, rigidity, and solubility of these complexes on their biological activity were also analyzed. X-ray crystal structure determination allowed the identification of short N-H⋅⋅⋅π contacts as the main driving forces for the three-dimensional packing in these molecules.

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Section: Introductionmentioning

confidence: 99%

The Important Role of the Nuclearity, Rigidity, and Solubility of Phosphane Ligands in the Biological Activity of Gold(I) Complexes

Svahn

Moro

Roma‐Rodrigues

et al. 2018

Chemistry A European J

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“…Recently, the N‐heterocyclic carbenes (NHCs) has been developed as substitutes to phosphines as ligands for gold(I) complexes. The interest in gold NHC complexes as anticancer drugs is caused by a number of discoveries such as the great cytotoxic properties, induction of apoptosis, and inhibition of enzyme thioredoxin reductase (TrxR) …”

Section: Introductionmentioning

confidence: 99%

Antiproliferative Activity of Gold(I) N‐Heterocyclic Carbene and Triphenylphosphine Complexes with Ibuprofen Derivatives as Effective Enzyme Inhibitors

Tabrizi

Romanova

2020

Applied Organom Chemis

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A series of gold(I) complexes of ligand ibuprofen‐alkynyl (but‐3‐yn‐1‐yl 2‐(4‐isobutylphenyl)propanoate, LE) with N‐heterocyclic carbene (LC: 1,3‐dimethylimidazol‐2‐ylidene) and triphenylphosphine (PPh3) ligands with formula (LE)Au (LC) (complex 1) and (LE)Au (PPh3) (complex 2) were synthesized and fully characterized by spectroscopic methods. In order to reveal the cytotoxicity mechanism, the interaction of complex 1 or 2 with cysteine (HCys) has been studied by experimental and density functional theory (DFT) methods. The compounds were investigated for their anticancer activity against MCF‐7, MDAMB 231 breast cancer cells, HT‐29 colon cancer cells and MCF‐10A non‐tumor breast cell line. The results were compared with cisplatin and auranofin as reference drugs. The complex 2 showed more cytotoxic activity than complex 1. The complex 2 was 4.2, 3.7, and 1.7 fold more active than cisplatin against HT‐29, MDA‐MB‐231, MCF‐7 cancer cell lines, respectively. The inhibition of thioredoxin reductase of complexes 1 and 2 including cytosolic (TrxR1) and mitochondrial (TrxR2) thioredoxin reductase and also the inhibition of glutathione reductase (GR) were studied in detail. Moreover, the cellular uptake and reactive oxygen species (ROS) generation of compounds were investigated. Based on the DFT calculations a relationship between the σ‐donor ability of the isolated ligands and cytotoxicity is suggested.

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“…Another class of molecules, cationic N-heterocyclic carbene (NHC) gold(I) complexes show also solid anticancer activities and the main mechanism of action discussed concerns apoptosis due to an antimitochondrial activity of such complexes 9,10,11,12 . During the last few years we focused our research on the optimization of NHC gold(I) complexes for anticancer activities 13,14,15 .…”

Section: Introductionmentioning

confidence: 99%

Artemisinin-Derivative-NHC-gold(I)-Hybrid with Enhanced Cytotoxic Activity Through Inhibiting NRF2 Transcriptional Activity

Zhang¹,

Fortin²,

Barnoin³

et al. 2020

Preprint

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<div><div><div><p>A family of original bis(artemisinin-NHC)gold(I) complexes have been synthesized. These hybrid molecules combine two biological active motifs, an artemisinin derivative (DHA) and a cationic bis(NHC)gold(I) unit. One of these complexes, complex 2a, has been analyzed by single-crystal X-ray diffraction and tested in depth for its anticancer properties. Complex 2a shows strong anticancer activities on a representative panel of human cancer cell models from 8 different localizations (prostate, breast, lung, liver, bladder, bone, acute and chronic myeloid leukemias). Complex 2a shows anticancer activity to a much better degree than Auranofin and DHA standards with GI50 values in nM range, together with a superior selectivity in regard to non-cancer cell models. Next to expected ROS formation and TrxR inhibition, an original and distinctive mechanism of action through inhibition of NRF2 - a transcription factor strongly associated with aggressiveness and resistance to cancer therapies - with an IC50 value at nM range has been evidenced. Importantly, the NRF2 inhibitory effect of complex 2a could remarkably sensitize to sorafenib in HepG2 liver cells, in which dysregulated NRF2 signaling is known to be associated with primary and acquired drug resistance. Moreover, complex 2a also inhibited NF-κB and HIF transcriptional activities, which are also linked to progression and resistance in cancer. Our findings provide experimental evidence that hybrid (NHC)gold(I) molecules - such as complex 2a - represent a new class of organometallic hybrid molecules that may yield new therapeutic agents.</p></div></div></div>

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New insights in Au-NHCs complexes as anticancer agents

Cited by 150 publications

References 130 publications

The Important Role of the Nuclearity, Rigidity, and Solubility of Phosphane Ligands in the Biological Activity of Gold(I) Complexes

The Important Role of the Nuclearity, Rigidity, and Solubility of Phosphane Ligands in the Biological Activity of Gold(I) Complexes

Antiproliferative Activity of Gold(I) N‐Heterocyclic Carbene and Triphenylphosphine Complexes with Ibuprofen Derivatives as Effective Enzyme Inhibitors

Artemisinin-Derivative-NHC-gold(I)-Hybrid with Enhanced Cytotoxic Activity Through Inhibiting NRF2 Transcriptional Activity

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