Co-reporter:Audrey Trommenschlager;Florian Chotard;Benoît Bertrand;Souheila Amor;Lucile Dondaine;Michel Picquet;Philippe Richard;Ali Bettaïeb;Pierre Le Gendre;Catherine Paul;Christine Goze
Dalton Transactions 2017 vol. 46(Issue 25) pp:8051-8056
Publication Date(Web):2017/06/27
DOI:10.1039/C7DT01377A
Two new gold(I)–BODIPY–imidazole based trackable therapeutic bimetallic complexes have been synthesized and fully characterized. They display strong antiproliferative properties on several types of cancers including colon, breast, and prostate and one of them presents a significant anti-inflammatory effect. Additionally, the two compounds could be visualised in vitro by confocal microscopy in the submicromolar range.
Co-reporter:Océane Florès;Audrey Trommenschlager;Souheila Amor;Fernanda Marques;Francisco Silva;Lurdes Gano;Franck Denat;Maria Paula Cabral Campello;Christine Goze;Pierre Le Gendre
Dalton Transactions 2017 vol. 46(Issue 42) pp:14548-14555
Publication Date(Web):2017/10/31
DOI:10.1039/C7DT01981E
A novel Ti/111In-heterometallic radiotheranostic along with non-radioactive Ti/In, Ti/Lu, and Ti/Y analogues has been reported, thanks to the design of a challenging synthesis of the first titanocene-DOTA ligand. The corresponding titanocene-BODIPY complex was developed for in vitro tracking by optical imaging. The different complexes were characterized and their antiproliferative properties were evaluated on three cancer cell lines (A2780, B16F1, and PC3). As a proof of concept, initial studies in healthy mice were performed with a Ti/111In derivative to obtain information about its uptake, its biodistribution, and its excretion. Confocal microscopy experiments were performed with fluorescent complexes to track it in vitro.
Co-reporter:Margot Wenzel, Andreia de Almeida, Emilia Bigaeva, Paul Kavanagh, Michel Picquet, Pierre Le Gendre, Ewen Bodio, and Angela Casini
Inorganic Chemistry 2016 Volume 55(Issue 5) pp:2544-2557
Publication Date(Web):February 11, 2016
DOI:10.1021/acs.inorgchem.5b02910
A series of new heterodinuclear luminescent complexes with two different organic ligands have been synthesized and characterized. A luminescent RuII(polypyridine) moiety and a metal-based anticancer fragment (AuCl, (p-cymene)RuCl2, (p-cymene)OsCl2, (Cp*)RhCl2, or Au-thioglucose) are the two general features of these complexes. All of the bimetallic compounds have been evaluated for their antiproliferative properties in vitro in human cancer cell lines. Only the complexes containing an Au(I) fragment exhibit antiproliferative activity in the range of cisplatin or higher. The photophysical and electrochemical properties of the bimetallic species have been investigated, and fluorescence microscopy experiments have been performed successfully. The most promising bimetallic cytotoxic complexes (i.e., with the Au-thioglucose scaffold) have shown to be easily taken up by cancer cells at 37 °C in the cytoplasm or in specific organelles. Interestingly, experiments repeated at 4 °C showed no uptake of the bimetallic species inside cells, which confirms involvement of active transport processes. To evaluate the role of glucose transporters in the cell uptake of the gold complexes, inhibition of the GluT-1 (glucose transporter isoform with high level of expression in cancer cells) was achieved, showing only scarce influence on the compounds’ uptake. Finally, the observed absence of interactions with nucleic acid model structures suggests that the gold compounds may have different intracellular targets with respect to cisplatin.
Co-reporter:Benoît Bertrand, Pierre-Emmanuel Doulain, Christine Goze and Ewen Bodio
Dalton Transactions 2016 vol. 45(Issue 33) pp:13005-13011
Publication Date(Web):18 Apr 2016
DOI:10.1039/C5DT04275E
In medicinal chemistry, the aim is not only to conceive ever more efficient molecules, but also to understand their mechanism of action. In very recent years, a new promising strategy was developed to tackle this issue: the conception of trackable therapeutic agents. Metal-based drugs are ideal to exploit this expanding area of research.
Co-reporter:Moussa Ali; Lucile Dondaine; Anais Adolle; Carla Sampaio; Florian Chotard; Philippe Richard; Franck Denat; Ali Bettaieb; Pierre Le Gendre; Véronique Laurens; Christine Goze; Catherine Paul
Journal of Medicinal Chemistry 2015 Volume 58(Issue 11) pp:4521-4528
Publication Date(Web):May 14, 2015
DOI:10.1021/acs.jmedchem.5b00480
Gold phosphine complexes, such as auranofin, have been recognized for decades as antirheumatic agents. Clinical trials are now underway to validate their use in anticancer or anti-HIV treatments. However, their mechanisms of action remain unclear. A challenging question is whether the gold phosphine complex is a prodrug that is administered in an inactive precursor form or rather that the gold atom remains attached to the phosphine ligand during treatment. In this study, we present two novel gold complexes, which we compared to auranofin and to their phosphonium analogue. The chosen ligand is a phosphine-based smart probe, whose strong fluorescence depends on the presence of the gold atom. The in vitro biological action of the gold complexes and the phosphonium derivative were investigated, and a preliminary in vivo study in healthy zebrafish larvae allowed us to evaluate gold complex biodistribution and toxicity. The different analyses carried out showed that these gold complexes were stable and behaved differently from phosphonium and auranofin, both in vitro and in vivo. Two-photon microscopy experiments demonstrated that the cellular targets of these gold complexes are not the same as those of the phosphonium analogue. Moreover, despite similar IC50 values in some cancer cell lines, gold complexes displayed a low toxicity in vivo, in contrast to the phosphonium salt. They are therefore suitable for future in vivo investigations.
Co-reporter:Pierre-Emmanuel Doulain, Richard Decréau, Cindy Racoeur, Victor Goncalves, Laurence Dubrez, Ali Bettaieb, Pierre Le Gendre, Franck Denat, Catherine Paul, Christine Goze and Ewen Bodio
Dalton Transactions 2015 vol. 44(Issue 11) pp:4874-4883
Publication Date(Web):28 Nov 2014
DOI:10.1039/C4DT02977A
Four new red BODIPY–gold(I) theranostic compounds were synthesized. Some of them were vectorized by tethering a biovector (glucose or bombesin derivatives) to the metallic center. Their photophysical properties were studied. Additionally, their cytotoxicity was examined on different cancer cell lines and on a normal cell line, they were tracked in vitro by fluorescence detection, and their uptake was evaluated by ICP-MS measurements.
Co-reporter:Semra Tasan;Cynthia Licona
JBIC Journal of Biological Inorganic Chemistry 2015 Volume 20( Issue 1) pp:143-154
Publication Date(Web):2015/01/01
DOI:10.1007/s00775-014-1220-8
Two new gold-phosphine-porphyrin derivatives were synthesized and fully characterized, and their photophysical properties investigated along a water-soluble analog. The cytotoxicity of the compounds was tested on cancer cells (HCT116 and SW480), and their cell uptake was followed by fluorescence microscopy in vitro (on SW480). The proof that the water-soluble gold-phosphine-porphyrin is a biologically active compound that can be tracked in vitro was clearly established, especially concerning the water-soluble analog. Some preliminary photodynamic therapy (PDT) experiments were also performed. They highlight a dramatic increase of the cytotoxicity when the cells were illuminated for 30 min with white light.
Co-reporter:Benoît Bertrand;Anna Citta;Inge L. Franken
JBIC Journal of Biological Inorganic Chemistry 2015 Volume 20( Issue 6) pp:1005-1020
Publication Date(Web):2015 September
DOI:10.1007/s00775-015-1283-1
While N-heterocyclic carbenes (NHC) are ubiquitous ligands in catalysis for organic or industrial syntheses, their potential to form transition metal complexes for medicinal applications has still to be exploited. Within this frame, we synthesized new homo- and heterobimetallic complexes based on the Au(I)–NHC scaffold. The compounds were synthesized via a microwave-assisted method developed in our laboratories using Au(I)–NHC complexes carrying a pentafluorophenol ester moiety and another Au(I) phosphane complex or a bipyridine ligand bearing a pendant amine function. Thus, we developed two different methods to prepare homo- and heterobimetallic complexes (Au(I)/Au(I) or Au(I)/Cu(II), Au(I)/Ru(II), respectively). All the compounds were fully characterized by several spectroscopic techniques including far infrared, and were tested for their antiproliferative effects in a series of human cancer cells. They showed moderate anticancer properties. Their toxic effects were also studied ex vivo using the precision-cut tissue slices (PCTS) technique and initial results concerning their reactivity with the seleno-enzyme thioredoxin reductase were obtained.
Co-reporter:Pierre D. Harvey, Semra Tasan, Claude P. Gros, Charles H. Devillers, Philippe Richard, Pierre Le Gendre, and Ewen Bodio
Organometallics 2015 Volume 34(Issue 7) pp:1218-1227
Publication Date(Web):March 20, 2015
DOI:10.1021/om5011808
A series of (η6-p-cymene)ruthenium(II)- and osmium(II) complexes of porphyrin-phosphane derivatives have been synthesized as potential bimetallic theranostic candidates. The photophysical and electrochemical properties were investigated, and these species desirably exhibit no or almost no photoinduced intramolecular atom, energy, and electron transfer between the dye and the metallic fragment. These favorable features are mostly associated with the presence of their long chain (i.e., ∼ 1 nm) separating the two functional units. Interestingly, a decrease in emission intensity and lifetimes (up to 35-fold) has been observed, which was ascribed to a small heavy atom effect. This effect is possible as a chain folding driven by an intramolecular H-bond (N–H···Cl–M).
Co-reporter:Margot Wenzel, Emilia Bigaeva, Philippe Richard, Pierre Le Gendre, Michel Picquet, Angela Casini, Ewen Bodio
Journal of Inorganic Biochemistry 2014 Volume 141() pp:10-16
Publication Date(Web):December 2014
DOI:10.1016/j.jinorgbio.2014.07.011
A series of mono- and heterodinuclear gold(I) and platinum(II) complexes with a new bipyridylamine-phosphine ligand have been synthesized and characterized. The X-ray structures of the ligand precursor 4-iodo-N,N-di(pyridin-2-yl)benzamide, and of one gold derivative are reported. All the complexes display antiproliferative properties in vitro in human cancer cells in the range of cisplatin or higher, which appear to correlate with compounds' uptake. Interestingly, studies of the interactions of the compounds with models of DNA indicate different mechanisms of actions with respect to cisplatin. The biological activity study of these complexes provides useful information about the interest of designing multimetallic complexes for enhanced cytotoxic properties.Four mono/heterodinuclear gold(I) and platinum(II) complexes have been synthesized. The complexes display antiproliferative properties in cancer cells in the range of cisplatin or higher, which appear to correlate with compounds' uptake. Studies of the interactions of the compounds with DNA models indicate different mechanisms of action with respect to cisplatin.
Co-reporter:Benoît Bertr;Andreia de Almeida;Evelien P. M. van der Burgt;Michel Picquet;Anna Citta;Alessra Folda;Maria Pia Rigobello;Pierre Le Gendre;Angela Casini
European Journal of Inorganic Chemistry 2014 Volume 2014( Issue 27) pp:
Publication Date(Web):
DOI:10.1002/ejic.201490137
Co-reporter:Benoît Bertr;Andreia de Almeida;Evelien P. M. van der Burgt;Michel Picquet;Anna Citta;Alessra Folda;Maria Pia Rigobello;Pierre Le Gendre, ;Angela Casini
European Journal of Inorganic Chemistry 2014 Volume 2014( Issue 27) pp:
Publication Date(Web):
DOI:10.1002/ejic.201402795
Abstract
Invited for the cover of this issue is the group of Angela Casini at the Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute of Pharmacy, The Netherlands. The cover image shows the uptake of gold N-heterocyclic (NHC) complexes, bearing a fluorescent coumarin moiety, in cancer cells and the resulting anticancer effects.
Co-reporter:Benoît Bertr;Andreia de Almeida;Evelien P. M. van der Burgt;Michel Picquet;Anna Citta;Alessra Folda;Maria Pia Rigobello;Pierre Le Gendre;Angela Casini
European Journal of Inorganic Chemistry 2014 Volume 2014( Issue 27) pp:4532-4536
Publication Date(Web):
DOI:10.1002/ejic.201402248
Abstract
N-Heterocyclic carbene gold(I) complexes bearing a fluorescent coumarin ligand were synthesized and characterized by various techniques. The compounds were examined for their antiproliferative effects in normal and tumor cells in vitro; they demonstrated moderate activity and a certain degree of selectivity. The compounds were also shown to efficiently inhibit the selenoenzyme thioredoxin reductase (TrxR), whereas they were poorly effective towards the glutathione reductase (GR) and glutathione peroxidase enzymes. Notably, {3-[(7-methoxy-2-oxo-2H-chromen-4-yl)methyl]-1-methylimidazol-2-ylidene}(tetra-O-acetyl-1-thio-β-D-glucopyranosido)gold(I) (3) showed a pronounced inhibition of TrxR also in cell extracts, and it appeared to activate GR. Mechanistic information on the system derived from biotin-conjugated iodoacetamide assays showed selective metal binding to selenocysteine residues. Preliminary confocal fluorescence microscopy experiments proved that 3 enters tumor cells, where it reaches the nuclear compartment.
Co-reporter:Dr. Louis Adriaenssens;Dr. Qiang Liu;Dr. Fanny Chaux-Picquet;Dr. Semra Tasan;Dr. Michel Picquet; Franck Denat; Pierre LeGendre;Dr. Ferna Marques;Dr. Célia Fernes;Dr. Filipa Mendes;Dr. Lurdes Gano;Dr. Maria Paula Cabral Campello;Dr. Ewen Bodio
ChemMedChem 2014 Volume 9( Issue 7) pp:1567-1573
Publication Date(Web):
DOI:10.1002/cmdc.201300494
Abstract
A novel RuII(arene) theranostic complex is presented. It is based on a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid macrocycle bearing a triarylphosphine and can be tracked in vivo by using the γ emission of 153Sm atoms. Notably, the heteroditopic ligand can be selectively metalated with ruthenium at the phosphorus atom despite the presence of other functionalities that are prone to metal coordination. Subsequent labeling with radionuclides such as 153Sm can then be performed easily. The resulting heterobimetallic complex exhibits favorable solubility and stability properties in biologically relevant media. It also shows in vitro cytotoxicity in line with that expected for this type of metallodrug, and is nontoxic to the organism as a whole. As a proof of concept, initial studies in healthy mice were performed to obtain information about the uptake, biodistribution, and excretion of the radiolabeled complex.
Co-reporter:Semra Tasan, Olivier Zava, Benoît Bertrand, Claire Bernhard, Christine Goze, Michel Picquet, Pierre Le Gendre, Pierre Harvey, Franck Denat, Angela Casini and Ewen Bodio
Dalton Transactions 2013 vol. 42(Issue 17) pp:6102-6109
Publication Date(Web):21 Nov 2012
DOI:10.1039/C2DT32055J
A new BODIPY–phosphane was synthesized and proved to be a versatile tool for imaging organometallic complexes. It also led to easy access to a new family of theranostics, featuring gold, ruthenium and osmium complexes. The compounds’ cytotoxicity was tested on cancer cells, and their cell uptake was followed by fluorescence microscopy in vitro.
Co-reporter:Benoît Bertrand, Pierre-Emmanuel Doulain, Christine Goze and Ewen Bodio
Dalton Transactions 2016 - vol. 45(Issue 33) pp:NaN13011-13011
Publication Date(Web):2016/04/18
DOI:10.1039/C5DT04275E
In medicinal chemistry, the aim is not only to conceive ever more efficient molecules, but also to understand their mechanism of action. In very recent years, a new promising strategy was developed to tackle this issue: the conception of trackable therapeutic agents. Metal-based drugs are ideal to exploit this expanding area of research.
Co-reporter:Semra Tasan, Olivier Zava, Benoît Bertrand, Claire Bernhard, Christine Goze, Michel Picquet, Pierre Le Gendre, Pierre Harvey, Franck Denat, Angela Casini and Ewen Bodio
Dalton Transactions 2013 - vol. 42(Issue 17) pp:NaN6109-6109
Publication Date(Web):2012/11/21
DOI:10.1039/C2DT32055J
A new BODIPY–phosphane was synthesized and proved to be a versatile tool for imaging organometallic complexes. It also led to easy access to a new family of theranostics, featuring gold, ruthenium and osmium complexes. The compounds’ cytotoxicity was tested on cancer cells, and their cell uptake was followed by fluorescence microscopy in vitro.
Co-reporter:Audrey Trommenschlager, Florian Chotard, Benoît Bertrand, Souheila Amor, Lucile Dondaine, Michel Picquet, Philippe Richard, Ali Bettaïeb, Pierre Le Gendre, Catherine Paul, Christine Goze and Ewen Bodio
Dalton Transactions 2017 - vol. 46(Issue 25) pp:NaN8056-8056
Publication Date(Web):2017/05/22
DOI:10.1039/C7DT01377A
Two new gold(I)–BODIPY–imidazole based trackable therapeutic bimetallic complexes have been synthesized and fully characterized. They display strong antiproliferative properties on several types of cancers including colon, breast, and prostate and one of them presents a significant anti-inflammatory effect. Additionally, the two compounds could be visualised in vitro by confocal microscopy in the submicromolar range.
Co-reporter:Pierre-Emmanuel Doulain, Richard Decréau, Cindy Racoeur, Victor Goncalves, Laurence Dubrez, Ali Bettaieb, Pierre Le Gendre, Franck Denat, Catherine Paul, Christine Goze and Ewen Bodio
Dalton Transactions 2015 - vol. 44(Issue 11) pp:NaN4883-4883
Publication Date(Web):2014/11/28
DOI:10.1039/C4DT02977A
Four new red BODIPY–gold(I) theranostic compounds were synthesized. Some of them were vectorized by tethering a biovector (glucose or bombesin derivatives) to the metallic center. Their photophysical properties were studied. Additionally, their cytotoxicity was examined on different cancer cell lines and on a normal cell line, they were tracked in vitro by fluorescence detection, and their uptake was evaluated by ICP-MS measurements.
