Determinants for Tight and Selective Binding of a Medicinal Dicarbene Gold(I) Complex to a Telomeric DNA G‐Quadruplex: a Joint ESI MS and XRD Investigation

Bazzicalupi, Carla; Ferraroni, Marta; Papi, Francesco; Massai, Lara; Bertrand, Benoît; Messori, Luigi; Gratteri, Paola; Casini, Angela

doi:10.1002/ange.201511999

Cited by 56 publications

(34 citation statements)

References 36 publications

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“…It was already confirmed that [(NHC) 2 Au I ] + complexes show significantly improved inhibition of cancer cell proliferation compared to the respective (NHC)Au I X complexes. 7 , 9 , 12 , 17 , 46 − 49 …”

Section: Introductionmentioning

confidence: 99%

N-Heterocyclic Carbene Gold(I) Complexes: Mechanism of the Ligand Scrambling Reaction and Their Oxidation to Gold(III) in Aqueous Solutions

et al. 2020

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N -Heterocyclic carbene (NHC) gold(I) complexes offer great prospects in medicinal chemistry as antiproliferative, anticancer, and antibacterial agents. However, further development requires a thorough understanding of their reaction behavior in aqueous media. Herein, we report the conversion of the bromido[3-ethyl-4-(4-methoxyphenyl)-5-(2-methoxypyridin-5-yl)-1-propylimidazol-2-ylidene]gold(I) ((NHC)Au I Br, 1 ) complex in acetonitrile/water mixtures to the bis[3-ethyl-4-(4-methoxyphenyl)-5-(2-methoxypyridin-5-yl)-1-propylimidazol-2-ylidene]gold(I) ([(NHC) 2 Au I ] + , 7 ), which is subsequently oxidized to the dibromidobis[3-ethyl-4-(4-methoxyphenyl)-5-(2-methoxypyridin-5-yl)-1-propylimidazol-2-ylidene]gold(III) ([(NHC) 2 Au III Br 2 ] + , 9 ). By combining experimental data from HPLC, NMR, and (LC-)/HR-MS with computational results from DFT calculations, we outline a detailed ligand scrambling reaction mechanism. The key step is the formation of the stacked ((NHC)Au I Br) 2 dimer ( 2 ) that rearranges to the T-shaped intermediate Br(NHC) 2 Au I –Au I Br ( 3 ). The dissociation of Br – from 3 and recombination lead to (NHC) 2 Au I –Au I Br 2 ( 5 ) followed by the separation into [(NHC) 2 Au I ] + ( 7 ) and [Au I Br 2 ] − ( 8 ). [Au I Br 2 ] − is not stable in an aqueous environment and degrades in an internal redox reaction to Au 0 and Br 2 . The latter in turn oxidizes 7 to the gold(III) species 9 . The reported ligand rearrangement of the (NHC)Au I Br complex differs from that found for related silver(I) analogous. A detailed understanding of this scrambling mechanism is of utmost importance for the interpretation of their biological activity and will help to further optimize them for biomedical and other applications.

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Section: Introductionmentioning

confidence: 99%

N-Heterocyclic Carbene Gold(I) Complexes: Mechanism of the Ligand Scrambling Reaction and Their Oxidation to Gold(III) in Aqueous Solutions

et al. 2020

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“…[11,12,17,18] Thisp henomenon can also be explained by the stabilityo ft he complexes. More recently,a lternative targets have been identified for gold(I) NHC complexes, namely telomeric DNA G-quadruplexes [19] and zinc finger proteins such as poly(adenosine diphosphate-ribose) polymerase 1( PARP-1), [20] As tructurally diverse library of 14 gold(I)c ationic bis(NHC)a nd neutralm ono(NHC)c omplexes (NHC: N-heterocyclic carbene) was synthesized andc haracterized in this work. Four of them were new cationic gold(I) complexes containing functionalized NHCs, and their X-ray crystal structures are presented herein.…”

Section: Introductionmentioning

confidence: 99%

Cationic and Neutral N‐Heterocyclic Carbene Gold(I) Complexes: Cytotoxicity, NCI‐60 Screening, Cellular Uptake, Inhibition of Mammalian Thioredoxin Reductase, and Reactive Oxygen Species Formation

et al. 2018

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A structurally diverse library of 14 gold(I) cationic bis(NHC) and neutral mono(NHC) complexes (NHC: N-heterocyclic carbene) was synthesized and characterized in this work. Four of them were new cationic gold(I) complexes containing functionalized NHCs, and their X-ray crystal structures are presented herein. All of the complexes were investigated for their anticancer activities in four cancer cell lines, including a cisplatin-resistant variant, and a noncancerous cell line. Seven of the cationic gold(I) complexes were found to display high and specific cytotoxic activities toward cancer cells. Two of them were even able to overcome cisplatin resistance. Two highly potent cationic complexes (11 and 15) were also submitted to the NCI-60 cancer panel for further cytotoxicity evaluation. Complex 15 showed a surprisingly high potency toward leukemia among the nine examined cancer subtypes, particularly toward the CCRF-CEM leukemia cell line with a concentration for 50 % inhibition of growth down to 79.4 nm. In addition, cationic complex 13, which demonstrated a remarkable cytotoxicity against hepatocellular carcinoma, was selected to obtain insight into the mechanistic aspects in HepG2 cells. Cellular uptake measurements were indicative of good bioavailability. By various biochemical assays, this complex was found to effectively inhibit thioredoxin reductase and its cytotoxicity toward HepG2 cells was found to be reactive oxygen species dependent.

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“…The main advantage of these compounds against platinum complexes is that they differ in their mechanism of action. Whereas platinum compounds interact with nucleic acids, gold-containing drugs display a higher variety of targets, including non-canonical DNA structures [9,10], zinc finger proteins [11] or the redox enzyme thioredoxin reductase (TrxR). Gold complexes are able to inhibit TrxR via interacting with the selenium atom [12] of the selenocysteine moiety.…”

Section: Introductionmentioning

confidence: 99%

Alkynyl gold(I) complex triggers necroptosis via ROS generation in colorectal carcinoma cells

Mármol

Virumbrales-Muñoz

Medina-Quero

et al. 2017

Journal of Inorganic Biochemistry

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Given the rise of apoptosis-resistant tumors, there exist a growing interest in developing new drugs capable of inducing different types of cell death to reduce colorectal cancer-related death rates. As apoptosis and necroptosis do not share cellular machinery, necroptosis induction may have a great therapeutic potential on those apoptosis-resistant cancers, despite the inflammatory effects associated with it. We have synthesized an alkynyl gold(I) complex [Au(CC-2-NCH)(PTA)] whose anticancer effect was tested on the colorectal adenocarcinoma Caco-2 cell line. With regard to its mechanism of action, this gold complex enters the mitochondria and disrupts its normal function, leading to an increase in ROS production, which triggers necroptosis. Necroptosis induction has been found dependent of TNF-α (Tumor necrosisfactor α) and TNFR1(Tumor necrosisfactor receptor 1) binding, RIP1(Receptor-Interacting Protein 1) activation and NF-κB (Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells) signaling. Moreover, the antitumor potential of [Au(CC-2-NCH)(PTA)] has also been confirmed on the 3D cancer model spheroid. Overall, the obtained data show firstly that gold complexes might have the ability of inducing necroptosis, and secondarily that our compound [Au(CC-2-NCH)(PTA)] is an interesting alternative to current chemotherapy drugs in cases of apoptosis resistance.

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Determinants for Tight and Selective Binding of a Medicinal Dicarbene Gold(I) Complex to a Telomeric DNA G‐Quadruplex: a Joint ESI MS and XRD Investigation

Cited by 56 publications

References 36 publications

N-Heterocyclic Carbene Gold(I) Complexes: Mechanism of the Ligand Scrambling Reaction and Their Oxidation to Gold(III) in Aqueous Solutions

N-Heterocyclic Carbene Gold(I) Complexes: Mechanism of the Ligand Scrambling Reaction and Their Oxidation to Gold(III) in Aqueous Solutions

Cationic and Neutral N‐Heterocyclic Carbene Gold(I) Complexes: Cytotoxicity, NCI‐60 Screening, Cellular Uptake, Inhibition of Mammalian Thioredoxin Reductase, and Reactive Oxygen Species Formation

Alkynyl gold(I) complex triggers necroptosis via ROS generation in colorectal carcinoma cells

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