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Luigi Messori - One of the best experts on this subject based on the ideXlab platform.
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antiproliferative properties of a few auranofin related Gold i and silver i complexes in leukemia cells and their interferences with the ubiquitin proteasome system
Molecules, 2020Co-Authors: Damiano Cirri, Luigi Messori, Lara Massai, Tanja Schirmeister, Eanjeong Seo, Thomas Efferth, Nicola MicaleAbstract:A group of triethylphosphine Gold(I) and silver(I) complexes, structurally related to auranofin, were prepared and investigated as potential anticancer drug candidates. The antiproliferative properties of these metal Compounds were assessed against two leukemia cell lines, i.e., CCRF-CEM and its multidrug-resistant counterpart, CEM/ADR5000. Interestingly, potent cytotoxic effects were disclosed for both series of Compounds against leukemia cells, with IC50 values generally falling in the low-micromolar range, the Gold derivatives being on the whole more effective than the silver analogues. Some initial structure-function relationships were drawn. Subsequently, the ability of the study Compounds to inhibit the three main catalytic activities of the proteasome was investigated. Different patterns of enzyme inhibition emerged for the various metal complexes. Notably, Gold Compounds were able to inhibit effectively both the trypsin-like and chymotrypsin-like proteasome activities, being less effective toward the caspase-like catalytic activity. In most cases, a significant selectivity of the study Compounds toward the proteasome proteolytic activities was detected when compared to other proteases. The implications of the obtained results are discussed.
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Structural and solution chemistry, antiproliferative effects, and serum albumin binding of three pseudohalide derivatives of auranofin
BioMetals, 2019Co-Authors: Damiano Cirri, Luigi Messori, Lara Massai, Maria Giulia Fabbrini, Serena Pillozzi, Annalisa Guerri, Alessio Menconi, Tiziano Marzo, Alessandro PratesiAbstract:Three pseudohalide analogues of the established Gold drug auranofin (AF hereafter), of general formula Au(PEt_3)X, i.e. Au(PEt_3)CN, Au(PEt_3)SCN and Au(PEt_3)N_3 (respectively denoted as AFCN, AFSCN and AFN_3), were prepared and characterized. The crystal structure was solved for Au(PEt_3)SCN highlighting the classical linear geometry of the 2-coordinate Gold(I) center. The solution behaviour of the Compounds was then comparatively analysed through ^31PNMR providing evidence for an acceptable stability under physiological-like conditions. Afterward, the reaction of these Gold Compounds with bovine serum albumin (BSA) and consequent adduct formation was investigated by ^31PNMR. For all the studied Gold Compounds, the [Au(PEt_3)]^+ moiety was identified as the reactive species in metal/protein adducts formation. The cytotoxic effects of the complexes were subsequently measured in comparison to AF against a representative colorectal cancer cell line and found to be still relevant and roughly similar in the three cases though far weaker than those of AF. These results show that the nature of the anionic ligand can modulate importantly the pharmacological action of the Gold-triethylphosphine moiety, affecting the cytotoxic potency. These aspects may be further explored to improve the pharmacological profiles of this family of metal complexes.
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auranofin and its analogues show potent antimicrobial activity against multidrug resistant pathogens structure activity relationships
ChemMedChem, 2018Co-Authors: Damiano Cirri, Tiziano Marzo, Simona Pollini, Marco Prato, Stefania Fallani, Maria Iris Cassetta, Andrea Novelli, Gian Maria Rossolini, Luigi MessoriAbstract:Due to the so-called "antibiotic resistance crisis" new antibacterial agents are urgently sought to treat multidrug-resistant pathogens. A group of Gold- or silver-based complexes, of general formula [M(PEt3 )X] (with M=Au or Ag, and X=Cl, Br or I), alongside with three complexes bearing a positive or negative charge-[Au(PEt3 )2 ]Cl, K[Au(CN)2 ] and [Ag(PEt3 )2 ]NO3 -were prepared and comparatively tested with auranofin on a representative panel of pathogens including Gram-positive, Gram-negative and Candida strains. Interestingly, all the Gold and silver complexes tested were active on Gram-positive strains, with the Gold complexes having greater efficacy. The effects of the Gold Compounds were potentiated to a larger extent than silver Compounds when tested in combination with a permeabilizing agent. A number of relevant structure-activity relationships emerged from the comparative analysis of the observed antibacterial profiles, shedding new light on the underlying molecular mechanisms of the action of these Compounds.
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selection and characterization of a human ovarian cancer cell line resistant to auranofin
Oncotarget, 2017Co-Authors: Ida Landini, Enrico Mini, Luigi Messori, Andrea Lapucci, Alessandro Pratesi, Lara Massai, Cristina Napoli, Gabriele Perrone, Pamela Pinzani, Stefania NobiliAbstract:// Ida Landini 1 , Andrea Lapucci 1 , Alessandro Pratesi 2 , Lara Massai 2 , Cristina Napoli 3 , Gabriele Perrone 1 , Pamela Pinzani 4 , Luigi Messori 2, * , Enrico Mini 1, * and Stefania Nobili 3, * 1 Department of Experimental and Clinical Medicine, University of Florence, Firenze, Italy 2 Department of Chemistry “Ugo Schiff”, University of Florence, Firenze, Italy 3 Department of Health Sciences, University of Florence, Firenze, Italy 4 Department of Experimental and Clinical Biomedical Sciences, University of Florence, Firenze, Italy * These authors have contributed equally to this work Correspondence to: Enrico Mini, email: enrico.mini@unifi.it Stefania Nobili, email: stefania.nobili@unifi.it Luigi Messori, email: luigi.messori@unifi.it Keywords: auranofin; tumour drug resistance; human tumour cell lines; drug effects; gene expression Received: March 24, 2017 Accepted: August 08, 2017 Published: October 09, 2017 ABSTRACT The anti-arthritic drug auranofin exerts also potent antitumour activity in in vitro and in vivo models, whose mechanisms are not yet well defined. From an auranofin-sensitive human ovarian cancer cell line A2780, a highly resistant (>20-fold) subline (A2780/AF-R) was developed and characterized. Marked reduction of Gold accumulation occurred in auranofin-resistant A2780 cells. Also, moderately higher thioredoxin reductase activity in A2780/AF-R cells was observed while no changes in intracellular glutathione content occurred. Resistance to auranofin was associated with a low level of cross-resistance to some investigational Gold Compounds as well as to oxaliplatin and other anticancer drugs with different mode of action (i.e. melphalan, vinblastine, doxorubicin, etoposide, and paclitaxel). Reduced Gold accumulation was associated to substantial gene expression changes in various influx (e.g. SLC22A1, SLC47A1, SLCO1B1 ) and efflux (e.g. ABCB1, ABCC2, ABCC3 ) transporters. The expression levels of selected proteins (i.e. SLC22A1, SLC47A1, P-gp) were also changed accordingly. These data provide evidence that multiple drug transporters may act as mediators of transport of auranofin and other Gold Compounds in cancer cells. Further investigation into the molecular mechanisms mediating transport of auranofin and new Gold complexes in view of their potential clinical application in the treatment of cancer is warranted.
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metal based Compounds as prospective antileishmanial agents inhibition of trypanothione reductase by selected Gold complexes
ChemMedChem, 2013Co-Authors: Gianni Colotti, Maria Agostina Cinellu, Chiara Gabbiani, Federica Scaletti, Laura Maiore, Andrea Ilari, Annarita Fiorillo, Paola Baiocco, Luigi MessoriAbstract:Leishmaniasis is a set of severe parasitic diseases for which only a limited number of effective drugs are available, including two antimony-based agents (sodium stibogluconate and meglumine antimoniate). Furthermore, resistance toward clinically established drugs is rapidly emerging and spreading. Thus, there is an urgent need for the discovery of new antileishmanial agents. Trypanothione reductase (TR) is a crucial redox enzyme in Leishmania, trypanosomatid protozoa that are the causative agents of Leishmaniasis ; TR plays a pivotal role in maintaining an intracellular reducing environment in trypanosomatids. More precisely, TR is a 54.68 kDa NADPH-dependent flavoprotein oxidoreductase; it is enzymatically active as a homodimer in which there are two active sites, each formed by residues from both subunits. TR requires NADPH as a co-substrate and FAD as a flavin cofactor. 3] Studies have validated TR as a reliable and druggable target for the development of antileishmanial agents. Like most enzymes involved in polyamine metabolism in Leishmania, TR contains a number of functional cysteine residues in its active site and can be potently inhibited by a variety of thiophilic metal-containing species. Accordingly, many of the drugs currently used to treat trypanosomatid infections are metal-based Compounds, containing either arsenic or antimony. Nonetheless, Compounds containing other metals, such as silver, palladium, and platinum, have also been shown to inhibit TR and prevent parasite growth. In recent years, the development of several new Gold complexes for a variety of medicinal applications and the identification of novel uses for existing Gold-based drugs have attracted the attention of researchers toward this family of metal Compounds as potential antiparasitic agents. A study by Baiocco et al. provided valuable insight into the molecular basis for the antileishmanial action of antimonial drugs. The crystal structure of reduced TR in complex with NADPH and Sb was solved, showing an Sb ion sitting in the active site. The Sb ion was reported to be tightly bound to the two redox-active catalytic cysteine residues (Cys52 and Cys57), to a threonine residue (Thr335), and to His461’ of the twofold-symmetry-related subunit in the dimer; these are the main residues of the trypanothione binding site. These findings indicate that thiophilic metal-based Compounds in general can potentially serve as inhibitors of TR, and in turn, these Compounds could constitute prospective antileishmanial agents. Recently, the interaction of the clinically established antirheumatic agent auranofin with TR was investigated, and a low-resolution crystal structure was obtained for an auranofin–TR complex. Again, the Gold center was found to be tightly bound to two cysteine residues in the active site of the enzyme, thereby hampering hydride transfer from the protein to trypanothione. The thiosugar of auranofin also contributes to TR inhibition by occupying the trypanothione binding site within TR (Figure 1). This structure proves that Au binds with high affinity to the TR active site motif and, as a result of that binding, causes pronounced TR inhibition. The pronounced enzyme inhibition caused by auranofin and the structural characterization of the Au–enzyme complex prompted us to consider more systematically TR inhibition by a group of structurally diverse Gold-containing Compounds. Indeed, during the last few years, we have been involved in the synthesis and characterization of several Gold complexes in view of their medicinal application. While the primary goal of our research was to obtain novel cytotoxic Compounds as candidate anticancer agents, other therapeutic applications were also considered. For instance, we found that some Gold Compounds possess pronounced antiplasmodial activities in vitro. As Gold Compounds are strongly thiophilic, we were prompted to test a panel of structurally diverse Compounds for inhibition of TR from Leishmania infantum. The panel of Gold Compounds (Figure 2) chosen for enzyme inhibition experiments included a variety of structurally different Gold(III) and Gold(I) Compounds that were previously prepared and characterized: More precisely, the panel contained six mononuclear Gold(III) Compounds: [(bipy)Au(OH)2][PF6] (bipy=2,2’-bipyridine), [Au(pbi)Cl2] (pbiH=2-(2’-pyridyl)benzimidazole; pbi=deprotonated analogue), pyridinyl-oxazoline complexes [Au(pyox)Cl2][PF6] (pyox = (S)-4-R-2-(pyridin-2-yl)-4,5-dihydro[a] Dr. G. Colotti, Dr. A. Ilari, Dr. A. Fiorillo, Dr. P. Baiocco Institute of Molecular Biology & Pathology; National Research Council (CNR) ; Institute Pasteur Fondazione Cenci Bolognetti ; Department of Biochemical Sciences, Sapienza University of Rome P.le A. Moro 5, 00185 Rome (Italy) E-mail : gianni.colotti@uniroma1.it [b] Prof. M. A. Cinellu, Dr. L. Maiore Department of Chemistry & Pharmacy, University of Sassari Via Vienna 2, 07100 Sassari (SS) (Italy) [c] F. Scaletti, Prof. L. Messori Department of Chemistry, University of Florence Via della Lastruccia 3, 50019 Sesto Fiorentino (FI) (Italy) E-mail : luigi.messori@unifi.it [d] Dr. C. Gabbiani Department of Chemistry & Industrial Chemistry, University of Pisa Via Risorgimento 35, 56126 Pisa (Italy)
Angela Casini - One of the best experts on this subject based on the ideXlab platform.
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Ex vivo toxicological evaluation of experimental anticancer Gold(i) complexes with lansoprazole-type ligands.
Toxicology Research, 2019Co-Authors: Natalia Estrada-ortiz, Elena Lopez-gonzales, Ben Woods, Stefan Stürup, Inge A. M. De Graaf, Geny M. M. Groothuis, Angela CasiniAbstract:Gold-based Compounds are of great interest in the field of medicinal chemistry as novel therapeutic (anticancer) agents due to their peculiar reactivity and mechanisms of action with respect to organic drugs. Despite their promising pharmacological properties, the possible toxic effects of Gold Compounds need to be carefully evaluated in order to optimize their design and applicability. This study reports on the potential toxicity of three experimental Gold-based anticancer Compounds featuring lansoprazole ligands (1–3) studied in an ex vivo model, using rat precision cut kidney and liver slices (PCKS and PCLS, respectively). The results showed a different toxicity profile for the tested Compounds, with the neutral complex 2 being the least toxic, even less toxic than cisplatin, followed by the cationic complex 1. The dinuclear cationic Gold complex 3 was the most toxic in both liver and kidney slices. This result correlated with the metal uptake of the different Compounds assessed by ICP-MS, where complex 3 showed the highest accumulation of Gold in liver and kidney slices. Interestingly compound 1 showed the highest selectivity towards cancer cells compared to the healthy tissues. Histomorphology evaluation showed a similar pattern for all three Au(I) complexes, where the distal tubular cells suffered the most extensive damage, in contrast to the damage in the proximal tubules induced by cisplatin. The binding of representative Gold Compounds with the model ubiquitin was also studied by ESI-MS, showing that after 24 h incubation only ‘naked’ Au ions were bound to the protein following ligands’ loss. The mRNA expression of stress response genes appeared to be similar for both evaluated organs, suggesting oxidative stress as the possible mechanism of toxicity. The obtained results open new perspectives towards the design and testing of bifunctional Gold complexes with chemotherapeutic applications.
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Gold iii pyridine benzimidazole complexes as aquaglyceroporin inhibitors and antiproliferative agents
Inorganics, 2018Co-Authors: Brech Aikman, Graça Soveral, Margot N Wenzel, Andreia F Mosca, Andreia De Almeida, Wim T Klooster, Simon J Coles, Angela CasiniAbstract:Gold Compounds have been proven to be novel and versatile tools for biological applications, including as anticancer agents. Recently, we explored the potential of Au(III) complexes with bi-dentate N-donor ligands as inhibitors of the membrane water and glycerol channels aquaporins (AQPs), involved in different physiological and pathophysiological pathways. Here, eight new Au(III) complexes featuring a pyridine-benzimidazole scaffold have been synthesized and characterized via different methods. The stability of all the Compounds in aqueous solution and their reactivity with glutathione have been investigated by UV–visible spectroscopy. The Au(III) Compounds, tested for their AQPs inhibition properties in human Red Blood Cells (hRBC), are potent and selective inhibitors of AQP3. Furthermore, the Compounds’ antiproliferative effects have been studied in a small panel of human cancer cells expressing AQP3. The complexes show only very moderate anticancer effects in vitro and are mostly active against the melanoma A375 cells, with marked expression of AQP3 at the level of the nuclear membrane. In general, the AQP3 inhibition properties of these complexes hold promises to develop them as chemical probes to study the function of this protein isoform in biological systems.
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Mass Spectrometry Uncovers Molecular Reactivities of Coordination and Organometallic Gold(III) Drug Candidates in Competitive Experiments That Correlate with Their Biological Effects
2016Co-Authors: Samuel M. Meier, Maria Agostina Cinellu, Christopher Gerner, Bernhard K. Keppler, Angela CasiniAbstract:The reactivity of three cytotoxic organometallic Gold(III) complexes with cyclometalated C,N,N and C,N ligands (either six- or five-membered metallacycles), as well as that of two representative Gold(III) complexes with N-donor ligands, with biological nucleophiles has been studied by ESI-MS on ion trap and time-of-flight instruments. Specifically, the Gold Compounds were reacted with mixtures of nucleophiles containing l-histidine (imine), l-methionine (thioether), l-cysteine (thiol), l-glutamic acid (carboxylic acid), methylseleno-l-cysteine (selenoether), and in situ generated seleno-l-cysteine (selenol) to judge the preference of the Gold Compounds for binding to selenium-containing amino acid residues. Moreover, the Gold Compounds’ reactivity was studied with proteins and nucleic acid building blocks. These experiments revealed profound differences between the coordination and organometallic families and even within the family of organometallics, which allowed insights to be gained into the Compounds mechanisms of action. In particular, interactions with seleno-l-cysteine appear to reflect well the Compounds’ inhibition properties of the seleno-enzyme thioredoxin reductase and to a certain extent their antiproliferative effects in vitro. Therefore, mass spectrometry is successfully applied for linking the molecular reactivity and target preferences of metal-based drug candidates to their biological effects. Finally, this experimental setup is applicable to any other metallodrug that undergoes ligand substitution reactions and/or redox changes as part of its mechanism of action
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a Golden future in medicinal inorganic chemistry the promise of anticancer Gold organometallic Compounds
Dalton Transactions, 2014Co-Authors: Benoit Bertrand, Angela CasiniAbstract:From wedding rings on fingers to stained glass windows, by way of Olympic medals, Gold has been highly prized for millennia. Nowadays, organometallic Gold Compounds occupy an important place in the field of medicinal inorganic chemistry due to their unique chemical properties with respect to Gold coordination Compounds. In fact, several studies have proved that they can be used to develop highly efficient metal-based drugs with possible applications in the treatment of cancer. This Perspective summarizes the results obtained for different families of bioactive organometallic Gold Compounds including cyclometallated Gold(III) complexes with C,N-donor ligands, Gold(I) and Gold(I/III) N-heterocyclic (NHC) carbene complexes, as well as Gold(I) alkynyl complexes, with promising anticancer effects. Most importantly, we will focus on recent developments in the field and discuss the potential of this class of organometallic Compounds in relation to their versatile chemistry and innovative mechanisms of action.
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A new target for Gold(I) Compounds: Glutathione-S-transferase inhibition by auranofin
Journal of Inorganic Biochemistry, 2012Co-Authors: Anastasia De Luca, Christian G. Hartinger, Paul J. Dyson, Mario Lo Bello, Angela CasiniAbstract:Nowadays, Gold Compounds occupy a relevant position constituting a promising class of experimental anticancer metallodrugs. Several research efforts have been devoted to the investigations of the pharmacological properties of Gold(I) complexes bearing phosphine ligands, such as the antiarthritic drug auranofin, that has also been shown to produce anticancer effects in vitro. In spite of the numerous studies that appeared in the literature the biological mechanisms of action of auranofin and analogues are still controversial. Here, we report on the inhibition effects of glutathione S-transferase P1-1 (GST P1-1) exerted by auranofin. The compound was able to inhibit GST P1-1 with a calculated IC50 of 32.9 +/- 0.5 mu M. Interestingly, the inhibition of GST P1-1 and its cysteine mutants by the Gold(I) compound is essentially the same, suggesting that probably the cysteine residues are not so essential for enzyme inactivation in contrast to other reported inhibitors. High-resolution electrospray ionisation Fourier transform ion cyclotron mass spectrometry (ESI FT-ICR MS) studies allowed characterising the binding of the compound with GST enzymes at a molecular level, confirming that similar Gold binding sites may be present in the wild-type protein and its Cys mutants. (C) 2012 Published by Elsevier Inc.
Stefania Nobili - One of the best experts on this subject based on the ideXlab platform.
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selection and characterization of a human ovarian cancer cell line resistant to auranofin
Oncotarget, 2017Co-Authors: Ida Landini, Enrico Mini, Luigi Messori, Andrea Lapucci, Alessandro Pratesi, Lara Massai, Cristina Napoli, Gabriele Perrone, Pamela Pinzani, Stefania NobiliAbstract:// Ida Landini 1 , Andrea Lapucci 1 , Alessandro Pratesi 2 , Lara Massai 2 , Cristina Napoli 3 , Gabriele Perrone 1 , Pamela Pinzani 4 , Luigi Messori 2, * , Enrico Mini 1, * and Stefania Nobili 3, * 1 Department of Experimental and Clinical Medicine, University of Florence, Firenze, Italy 2 Department of Chemistry “Ugo Schiff”, University of Florence, Firenze, Italy 3 Department of Health Sciences, University of Florence, Firenze, Italy 4 Department of Experimental and Clinical Biomedical Sciences, University of Florence, Firenze, Italy * These authors have contributed equally to this work Correspondence to: Enrico Mini, email: enrico.mini@unifi.it Stefania Nobili, email: stefania.nobili@unifi.it Luigi Messori, email: luigi.messori@unifi.it Keywords: auranofin; tumour drug resistance; human tumour cell lines; drug effects; gene expression Received: March 24, 2017 Accepted: August 08, 2017 Published: October 09, 2017 ABSTRACT The anti-arthritic drug auranofin exerts also potent antitumour activity in in vitro and in vivo models, whose mechanisms are not yet well defined. From an auranofin-sensitive human ovarian cancer cell line A2780, a highly resistant (>20-fold) subline (A2780/AF-R) was developed and characterized. Marked reduction of Gold accumulation occurred in auranofin-resistant A2780 cells. Also, moderately higher thioredoxin reductase activity in A2780/AF-R cells was observed while no changes in intracellular glutathione content occurred. Resistance to auranofin was associated with a low level of cross-resistance to some investigational Gold Compounds as well as to oxaliplatin and other anticancer drugs with different mode of action (i.e. melphalan, vinblastine, doxorubicin, etoposide, and paclitaxel). Reduced Gold accumulation was associated to substantial gene expression changes in various influx (e.g. SLC22A1, SLC47A1, SLCO1B1 ) and efflux (e.g. ABCB1, ABCC2, ABCC3 ) transporters. The expression levels of selected proteins (i.e. SLC22A1, SLC47A1, P-gp) were also changed accordingly. These data provide evidence that multiple drug transporters may act as mediators of transport of auranofin and other Gold Compounds in cancer cells. Further investigation into the molecular mechanisms mediating transport of auranofin and new Gold complexes in view of their potential clinical application in the treatment of cancer is warranted.
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synthesis structural characterization solution behavior and in vitro antiproliferative properties of a series of Gold complexes with 2 2 pyridyl benzimidazole as ligand comparisons of Gold iii versus Gold i and mononuclear versus binuclear derivatives
Inorganic Chemistry, 2012Co-Authors: M Serratrice, Ida Landini, Stefania Nobili, Maria Agostina Cinellu, Chiara Gabbiani, Annalisa Guerri, Laura Maiore, Maria Itria Pilo, Antonio Zucca, Enrico MiniAbstract:A variety of Gold(III) and Gold(I) derivatives of 2-(2′-pyridyl)benzimidazole (pbiH) were synthesized and fully characterized and their antiproliferative properties evaluated in a representative ovarian cancer cell line. The complexes include the mononuclear species [(pbi)AuX2] (X = Cl, 1; OAc, 2), [(pbiH)AuCl] (3), [(pbiH)Au(PPh3)][PF6] (4-PF6), and [(pbi)Au(L)] (L = PPh3, 5; TPA, 6), and the binuclear Gold(I)/Gold(I) and Gold(I)/Gold(III) derivatives [(PPh3)2Au2(μ2-pbi)][PF6] (10-PF6), [ClAu(μ3-pbi)AuCl2] (7),and [(PPh3)Au(μ3-pbi)AuX2][PF6] (X = Cl, 8-PF6; OAc, 9-PF6). The molecular structures of 6, 7, and 10-PF6 were determined by X-ray diffraction analysis. The chemical behavior of these Compounds in solution was analyzed both by cyclic voltammetry in DMF and absorption UV–vis spectroscopy in an aqueous buffer. Overall, the stability of these Gold Compounds was found to be acceptable for the cellular studies. For all complexes, relevant antiproliferative activities in vitro were documented against A27...
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Exploring the biochemical mechanisms of cytotoxic Gold Compounds: a proteomic study
JBIC Journal of Biological Inorganic Chemistry, 2010Co-Authors: Francesca Magherini, Alessandra Modesti, Michele Puglia, Ida Landini, Stefania Nobili, Enrico Mini, Maria Agostina Cinellu, Chiara Gabbiani, Luca Bini, Luigi MessoriAbstract:We have recently shown that a group of structurally diverse Gold Compounds are highly cytotoxic toward a panel of 36 human tumor cell lines through a variety of biochemical mechanisms. A classic proteomic approach is exploited here to gain deeper insight into those mechanisms. This investigation is focused on Auoxo6, a novel binuclear Gold(III) complex, and auranofin, a clinically established Gold(I) antiarthritic drug. First, the 72-h cytotoxicity profiles of Auoxo6 and auranofin were determined against A2780 human ovarian carcinoma cells. Subsequently, protein extraction from Gold-treated A2780 cells sensitive to cisplatin and 2D gel electrophoresis separation were carried out according to established procedures. Notably, both metallodrugs caused relatively modest changes in protein expression in comparison with controls as only 11 out of approximately 1,300 monitored spots showed appreciable quantitative changes. Very remarkably, six altered proteins were in common between the two treatments. Eight altered proteins were identified by mass spectrometry; among them was ezrin, a protein associated with the cytoskeleton and involved in apoptosis. Interestingly, two altered proteins, i.e., peroxiredoxins 1 and 6, are known to play crucial roles in the cell redox metabolism. Increased cleavage of heterogeneous ribonucleoprotein H was also evidenced, consistent with caspase 3 activation. Overall, the results of the present proteomic study point out that the mode of action of Auoxo6 is strictly related to that of auranofin, that the induced changes in protein expression are limited and selective, that both Gold Compounds trigger caspase 3 activation and apoptosis, and that a few affected proteins are primarily involved in cell redox homeostasis.
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Gold Compounds as anticancer agents: Chemistry, cellular pharmacology, and preclinical studies
Medicinal Research Reviews, 2010Co-Authors: Stefania Nobili, Ida Landini, Enrico Mini, Angela Casini, Chiara Gabbiani, Luigi MessoriAbstract:Gold Compounds are a class of metallodrugs with great potential for cancer treatment. During the last two decades, a large variety of Gold(I) and Gold(III) Compounds are reported to possess relevant antiproliferative properties in vitro against selected human tumor cell lines, qualifying themselves as excellent candidates for further pharmacological evaluation. The unique chemical properties of the Gold center confer very interesting and innovative pharmacological profiles to Gold-based metallodrugs. The primary goal of this review is to define the state of the art of preclinical studies on anticancer Gold Compounds, carried out either in vitro or in vivo. The available investigations of anticancer Gold Compounds are analyzed in detail, and particular attention is devoted to underlying molecular mechanisms. Notably, a few biophysical studies reveal that the interactions of cytotoxic Gold Compounds with DNA are generally far weaker than those of platinum drugs, implying the occurrence of a substantially different mode of action. A variety of alternative mechanisms were thus proposed, of which those involving either direct mitochondrial damage or proteasome inhibition or modulation of specific kinases are now highly credited. The overall perspectives on the development of Gold Compounds as effective anticancer drugs with an innovative mechanism of action are critically discussed on the basis of the available experimental evidence.
Chiara Gabbiani - One of the best experts on this subject based on the ideXlab platform.
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metal based Compounds as prospective antileishmanial agents inhibition of trypanothione reductase by selected Gold complexes
ChemMedChem, 2013Co-Authors: Gianni Colotti, Maria Agostina Cinellu, Chiara Gabbiani, Federica Scaletti, Laura Maiore, Andrea Ilari, Annarita Fiorillo, Paola Baiocco, Luigi MessoriAbstract:Leishmaniasis is a set of severe parasitic diseases for which only a limited number of effective drugs are available, including two antimony-based agents (sodium stibogluconate and meglumine antimoniate). Furthermore, resistance toward clinically established drugs is rapidly emerging and spreading. Thus, there is an urgent need for the discovery of new antileishmanial agents. Trypanothione reductase (TR) is a crucial redox enzyme in Leishmania, trypanosomatid protozoa that are the causative agents of Leishmaniasis ; TR plays a pivotal role in maintaining an intracellular reducing environment in trypanosomatids. More precisely, TR is a 54.68 kDa NADPH-dependent flavoprotein oxidoreductase; it is enzymatically active as a homodimer in which there are two active sites, each formed by residues from both subunits. TR requires NADPH as a co-substrate and FAD as a flavin cofactor. 3] Studies have validated TR as a reliable and druggable target for the development of antileishmanial agents. Like most enzymes involved in polyamine metabolism in Leishmania, TR contains a number of functional cysteine residues in its active site and can be potently inhibited by a variety of thiophilic metal-containing species. Accordingly, many of the drugs currently used to treat trypanosomatid infections are metal-based Compounds, containing either arsenic or antimony. Nonetheless, Compounds containing other metals, such as silver, palladium, and platinum, have also been shown to inhibit TR and prevent parasite growth. In recent years, the development of several new Gold complexes for a variety of medicinal applications and the identification of novel uses for existing Gold-based drugs have attracted the attention of researchers toward this family of metal Compounds as potential antiparasitic agents. A study by Baiocco et al. provided valuable insight into the molecular basis for the antileishmanial action of antimonial drugs. The crystal structure of reduced TR in complex with NADPH and Sb was solved, showing an Sb ion sitting in the active site. The Sb ion was reported to be tightly bound to the two redox-active catalytic cysteine residues (Cys52 and Cys57), to a threonine residue (Thr335), and to His461’ of the twofold-symmetry-related subunit in the dimer; these are the main residues of the trypanothione binding site. These findings indicate that thiophilic metal-based Compounds in general can potentially serve as inhibitors of TR, and in turn, these Compounds could constitute prospective antileishmanial agents. Recently, the interaction of the clinically established antirheumatic agent auranofin with TR was investigated, and a low-resolution crystal structure was obtained for an auranofin–TR complex. Again, the Gold center was found to be tightly bound to two cysteine residues in the active site of the enzyme, thereby hampering hydride transfer from the protein to trypanothione. The thiosugar of auranofin also contributes to TR inhibition by occupying the trypanothione binding site within TR (Figure 1). This structure proves that Au binds with high affinity to the TR active site motif and, as a result of that binding, causes pronounced TR inhibition. The pronounced enzyme inhibition caused by auranofin and the structural characterization of the Au–enzyme complex prompted us to consider more systematically TR inhibition by a group of structurally diverse Gold-containing Compounds. Indeed, during the last few years, we have been involved in the synthesis and characterization of several Gold complexes in view of their medicinal application. While the primary goal of our research was to obtain novel cytotoxic Compounds as candidate anticancer agents, other therapeutic applications were also considered. For instance, we found that some Gold Compounds possess pronounced antiplasmodial activities in vitro. As Gold Compounds are strongly thiophilic, we were prompted to test a panel of structurally diverse Compounds for inhibition of TR from Leishmania infantum. The panel of Gold Compounds (Figure 2) chosen for enzyme inhibition experiments included a variety of structurally different Gold(III) and Gold(I) Compounds that were previously prepared and characterized: More precisely, the panel contained six mononuclear Gold(III) Compounds: [(bipy)Au(OH)2][PF6] (bipy=2,2’-bipyridine), [Au(pbi)Cl2] (pbiH=2-(2’-pyridyl)benzimidazole; pbi=deprotonated analogue), pyridinyl-oxazoline complexes [Au(pyox)Cl2][PF6] (pyox = (S)-4-R-2-(pyridin-2-yl)-4,5-dihydro[a] Dr. G. Colotti, Dr. A. Ilari, Dr. A. Fiorillo, Dr. P. Baiocco Institute of Molecular Biology & Pathology; National Research Council (CNR) ; Institute Pasteur Fondazione Cenci Bolognetti ; Department of Biochemical Sciences, Sapienza University of Rome P.le A. Moro 5, 00185 Rome (Italy) E-mail : gianni.colotti@uniroma1.it [b] Prof. M. A. Cinellu, Dr. L. Maiore Department of Chemistry & Pharmacy, University of Sassari Via Vienna 2, 07100 Sassari (SS) (Italy) [c] F. Scaletti, Prof. L. Messori Department of Chemistry, University of Florence Via della Lastruccia 3, 50019 Sesto Fiorentino (FI) (Italy) E-mail : luigi.messori@unifi.it [d] Dr. C. Gabbiani Department of Chemistry & Industrial Chemistry, University of Pisa Via Risorgimento 35, 56126 Pisa (Italy)
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medicinal Gold Compounds form tight adducts with the copper chaperone atox 1 biological and pharmacological implications
Chemical Communications, 2012Co-Authors: Chiara Gabbiani, Maria Agostina Cinellu, Lara Massai, Federica Scaletti, Elena Michelucci, Luigi MessoriAbstract:Based on ESI-MS measurements, we show here that some representative cytotoxic Gold(III) Compounds produce stable adducts upon reaction with the copper chaperone Atox-1; notably, such adducts contain Gold in the oxidation state +1. These findings are of interest to understand the intracellular metabolism of medicinal Gold species and to develop new potent inhibitors of the copper trafficking system.
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synthesis structural characterization solution behavior and in vitro antiproliferative properties of a series of Gold complexes with 2 2 pyridyl benzimidazole as ligand comparisons of Gold iii versus Gold i and mononuclear versus binuclear derivatives
Inorganic Chemistry, 2012Co-Authors: M Serratrice, Ida Landini, Stefania Nobili, Maria Agostina Cinellu, Chiara Gabbiani, Annalisa Guerri, Laura Maiore, Maria Itria Pilo, Antonio Zucca, Enrico MiniAbstract:A variety of Gold(III) and Gold(I) derivatives of 2-(2′-pyridyl)benzimidazole (pbiH) were synthesized and fully characterized and their antiproliferative properties evaluated in a representative ovarian cancer cell line. The complexes include the mononuclear species [(pbi)AuX2] (X = Cl, 1; OAc, 2), [(pbiH)AuCl] (3), [(pbiH)Au(PPh3)][PF6] (4-PF6), and [(pbi)Au(L)] (L = PPh3, 5; TPA, 6), and the binuclear Gold(I)/Gold(I) and Gold(I)/Gold(III) derivatives [(PPh3)2Au2(μ2-pbi)][PF6] (10-PF6), [ClAu(μ3-pbi)AuCl2] (7),and [(PPh3)Au(μ3-pbi)AuX2][PF6] (X = Cl, 8-PF6; OAc, 9-PF6). The molecular structures of 6, 7, and 10-PF6 were determined by X-ray diffraction analysis. The chemical behavior of these Compounds in solution was analyzed both by cyclic voltammetry in DMF and absorption UV–vis spectroscopy in an aqueous buffer. Overall, the stability of these Gold Compounds was found to be acceptable for the cellular studies. For all complexes, relevant antiproliferative activities in vitro were documented against A27...
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Exploring the biochemical mechanisms of cytotoxic Gold Compounds: a proteomic study
JBIC Journal of Biological Inorganic Chemistry, 2010Co-Authors: Francesca Magherini, Alessandra Modesti, Michele Puglia, Ida Landini, Stefania Nobili, Enrico Mini, Maria Agostina Cinellu, Chiara Gabbiani, Luca Bini, Luigi MessoriAbstract:We have recently shown that a group of structurally diverse Gold Compounds are highly cytotoxic toward a panel of 36 human tumor cell lines through a variety of biochemical mechanisms. A classic proteomic approach is exploited here to gain deeper insight into those mechanisms. This investigation is focused on Auoxo6, a novel binuclear Gold(III) complex, and auranofin, a clinically established Gold(I) antiarthritic drug. First, the 72-h cytotoxicity profiles of Auoxo6 and auranofin were determined against A2780 human ovarian carcinoma cells. Subsequently, protein extraction from Gold-treated A2780 cells sensitive to cisplatin and 2D gel electrophoresis separation were carried out according to established procedures. Notably, both metallodrugs caused relatively modest changes in protein expression in comparison with controls as only 11 out of approximately 1,300 monitored spots showed appreciable quantitative changes. Very remarkably, six altered proteins were in common between the two treatments. Eight altered proteins were identified by mass spectrometry; among them was ezrin, a protein associated with the cytoskeleton and involved in apoptosis. Interestingly, two altered proteins, i.e., peroxiredoxins 1 and 6, are known to play crucial roles in the cell redox metabolism. Increased cleavage of heterogeneous ribonucleoprotein H was also evidenced, consistent with caspase 3 activation. Overall, the results of the present proteomic study point out that the mode of action of Auoxo6 is strictly related to that of auranofin, that the induced changes in protein expression are limited and selective, that both Gold Compounds trigger caspase 3 activation and apoptosis, and that a few affected proteins are primarily involved in cell redox homeostasis.
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Gold Compounds as anticancer agents: Chemistry, cellular pharmacology, and preclinical studies
Medicinal Research Reviews, 2010Co-Authors: Stefania Nobili, Ida Landini, Enrico Mini, Angela Casini, Chiara Gabbiani, Luigi MessoriAbstract:Gold Compounds are a class of metallodrugs with great potential for cancer treatment. During the last two decades, a large variety of Gold(I) and Gold(III) Compounds are reported to possess relevant antiproliferative properties in vitro against selected human tumor cell lines, qualifying themselves as excellent candidates for further pharmacological evaluation. The unique chemical properties of the Gold center confer very interesting and innovative pharmacological profiles to Gold-based metallodrugs. The primary goal of this review is to define the state of the art of preclinical studies on anticancer Gold Compounds, carried out either in vitro or in vivo. The available investigations of anticancer Gold Compounds are analyzed in detail, and particular attention is devoted to underlying molecular mechanisms. Notably, a few biophysical studies reveal that the interactions of cytotoxic Gold Compounds with DNA are generally far weaker than those of platinum drugs, implying the occurrence of a substantially different mode of action. A variety of alternative mechanisms were thus proposed, of which those involving either direct mitochondrial damage or proteasome inhibition or modulation of specific kinases are now highly credited. The overall perspectives on the development of Gold Compounds as effective anticancer drugs with an innovative mechanism of action are critically discussed on the basis of the available experimental evidence.
Enrico Mini - One of the best experts on this subject based on the ideXlab platform.
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selection and characterization of a human ovarian cancer cell line resistant to auranofin
Oncotarget, 2017Co-Authors: Ida Landini, Enrico Mini, Luigi Messori, Andrea Lapucci, Alessandro Pratesi, Lara Massai, Cristina Napoli, Gabriele Perrone, Pamela Pinzani, Stefania NobiliAbstract:// Ida Landini 1 , Andrea Lapucci 1 , Alessandro Pratesi 2 , Lara Massai 2 , Cristina Napoli 3 , Gabriele Perrone 1 , Pamela Pinzani 4 , Luigi Messori 2, * , Enrico Mini 1, * and Stefania Nobili 3, * 1 Department of Experimental and Clinical Medicine, University of Florence, Firenze, Italy 2 Department of Chemistry “Ugo Schiff”, University of Florence, Firenze, Italy 3 Department of Health Sciences, University of Florence, Firenze, Italy 4 Department of Experimental and Clinical Biomedical Sciences, University of Florence, Firenze, Italy * These authors have contributed equally to this work Correspondence to: Enrico Mini, email: enrico.mini@unifi.it Stefania Nobili, email: stefania.nobili@unifi.it Luigi Messori, email: luigi.messori@unifi.it Keywords: auranofin; tumour drug resistance; human tumour cell lines; drug effects; gene expression Received: March 24, 2017 Accepted: August 08, 2017 Published: October 09, 2017 ABSTRACT The anti-arthritic drug auranofin exerts also potent antitumour activity in in vitro and in vivo models, whose mechanisms are not yet well defined. From an auranofin-sensitive human ovarian cancer cell line A2780, a highly resistant (>20-fold) subline (A2780/AF-R) was developed and characterized. Marked reduction of Gold accumulation occurred in auranofin-resistant A2780 cells. Also, moderately higher thioredoxin reductase activity in A2780/AF-R cells was observed while no changes in intracellular glutathione content occurred. Resistance to auranofin was associated with a low level of cross-resistance to some investigational Gold Compounds as well as to oxaliplatin and other anticancer drugs with different mode of action (i.e. melphalan, vinblastine, doxorubicin, etoposide, and paclitaxel). Reduced Gold accumulation was associated to substantial gene expression changes in various influx (e.g. SLC22A1, SLC47A1, SLCO1B1 ) and efflux (e.g. ABCB1, ABCC2, ABCC3 ) transporters. The expression levels of selected proteins (i.e. SLC22A1, SLC47A1, P-gp) were also changed accordingly. These data provide evidence that multiple drug transporters may act as mediators of transport of auranofin and other Gold Compounds in cancer cells. Further investigation into the molecular mechanisms mediating transport of auranofin and new Gold complexes in view of their potential clinical application in the treatment of cancer is warranted.
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synthesis structural characterization solution behavior and in vitro antiproliferative properties of a series of Gold complexes with 2 2 pyridyl benzimidazole as ligand comparisons of Gold iii versus Gold i and mononuclear versus binuclear derivatives
Inorganic Chemistry, 2012Co-Authors: M Serratrice, Ida Landini, Stefania Nobili, Maria Agostina Cinellu, Chiara Gabbiani, Annalisa Guerri, Laura Maiore, Maria Itria Pilo, Antonio Zucca, Enrico MiniAbstract:A variety of Gold(III) and Gold(I) derivatives of 2-(2′-pyridyl)benzimidazole (pbiH) were synthesized and fully characterized and their antiproliferative properties evaluated in a representative ovarian cancer cell line. The complexes include the mononuclear species [(pbi)AuX2] (X = Cl, 1; OAc, 2), [(pbiH)AuCl] (3), [(pbiH)Au(PPh3)][PF6] (4-PF6), and [(pbi)Au(L)] (L = PPh3, 5; TPA, 6), and the binuclear Gold(I)/Gold(I) and Gold(I)/Gold(III) derivatives [(PPh3)2Au2(μ2-pbi)][PF6] (10-PF6), [ClAu(μ3-pbi)AuCl2] (7),and [(PPh3)Au(μ3-pbi)AuX2][PF6] (X = Cl, 8-PF6; OAc, 9-PF6). The molecular structures of 6, 7, and 10-PF6 were determined by X-ray diffraction analysis. The chemical behavior of these Compounds in solution was analyzed both by cyclic voltammetry in DMF and absorption UV–vis spectroscopy in an aqueous buffer. Overall, the stability of these Gold Compounds was found to be acceptable for the cellular studies. For all complexes, relevant antiproliferative activities in vitro were documented against A27...
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Exploring the biochemical mechanisms of cytotoxic Gold Compounds: a proteomic study
JBIC Journal of Biological Inorganic Chemistry, 2010Co-Authors: Francesca Magherini, Alessandra Modesti, Michele Puglia, Ida Landini, Stefania Nobili, Enrico Mini, Maria Agostina Cinellu, Chiara Gabbiani, Luca Bini, Luigi MessoriAbstract:We have recently shown that a group of structurally diverse Gold Compounds are highly cytotoxic toward a panel of 36 human tumor cell lines through a variety of biochemical mechanisms. A classic proteomic approach is exploited here to gain deeper insight into those mechanisms. This investigation is focused on Auoxo6, a novel binuclear Gold(III) complex, and auranofin, a clinically established Gold(I) antiarthritic drug. First, the 72-h cytotoxicity profiles of Auoxo6 and auranofin were determined against A2780 human ovarian carcinoma cells. Subsequently, protein extraction from Gold-treated A2780 cells sensitive to cisplatin and 2D gel electrophoresis separation were carried out according to established procedures. Notably, both metallodrugs caused relatively modest changes in protein expression in comparison with controls as only 11 out of approximately 1,300 monitored spots showed appreciable quantitative changes. Very remarkably, six altered proteins were in common between the two treatments. Eight altered proteins were identified by mass spectrometry; among them was ezrin, a protein associated with the cytoskeleton and involved in apoptosis. Interestingly, two altered proteins, i.e., peroxiredoxins 1 and 6, are known to play crucial roles in the cell redox metabolism. Increased cleavage of heterogeneous ribonucleoprotein H was also evidenced, consistent with caspase 3 activation. Overall, the results of the present proteomic study point out that the mode of action of Auoxo6 is strictly related to that of auranofin, that the induced changes in protein expression are limited and selective, that both Gold Compounds trigger caspase 3 activation and apoptosis, and that a few affected proteins are primarily involved in cell redox homeostasis.
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Gold Compounds as anticancer agents: Chemistry, cellular pharmacology, and preclinical studies
Medicinal Research Reviews, 2010Co-Authors: Stefania Nobili, Ida Landini, Enrico Mini, Angela Casini, Chiara Gabbiani, Luigi MessoriAbstract:Gold Compounds are a class of metallodrugs with great potential for cancer treatment. During the last two decades, a large variety of Gold(I) and Gold(III) Compounds are reported to possess relevant antiproliferative properties in vitro against selected human tumor cell lines, qualifying themselves as excellent candidates for further pharmacological evaluation. The unique chemical properties of the Gold center confer very interesting and innovative pharmacological profiles to Gold-based metallodrugs. The primary goal of this review is to define the state of the art of preclinical studies on anticancer Gold Compounds, carried out either in vitro or in vivo. The available investigations of anticancer Gold Compounds are analyzed in detail, and particular attention is devoted to underlying molecular mechanisms. Notably, a few biophysical studies reveal that the interactions of cytotoxic Gold Compounds with DNA are generally far weaker than those of platinum drugs, implying the occurrence of a substantially different mode of action. A variety of alternative mechanisms were thus proposed, of which those involving either direct mitochondrial damage or proteasome inhibition or modulation of specific kinases are now highly credited. The overall perspectives on the development of Gold Compounds as effective anticancer drugs with an innovative mechanism of action are critically discussed on the basis of the available experimental evidence.