Monomeric Ti(IV)-based complexes incorporating luminescent nitrogen ligands: synthesis, structural characterization, emission spectroscopy and cytotoxic activities

This manuscript describes the synthesis of a series of neutral titanium(IV) monomeric complexes constructed around a TiO4N2 core. The two nitrogen atoms that compose the coordination sphere of the metallic center belong to 2,2′-bipyrimidine ligands homo-disubstituted in the 4 and 4′ positions by methyl (2a), phenylvinyl (2b), naphthylvinyl (2c) or anthrylvinyl (2d) groups. The crystal structures of these complexes named [Ti(1)2(2a)], [Ti(1)2(2b)], [Ti(1)2(2c)] and [Ti(1)2(2d)] (where 1 is a 2,2′-biphenolato ligand substituted in the 6 and 6′ positions by phenyl groups) are reported. The hydrolytic stability of the four complexes is evaluated by monitoring the evolution of the free 2a–d signals by 1H NMR spectroscopy. For the conditions tested (6 mM, DMSO-d6/D2O: 8/1), a rather good stability with t1/2 ranging from 180 to 300 min is determined for the complexes. In the presence of an acid (DCl), the hydrolysis of [Ti(1)2(2a)] is faster than without an acid. The cytotoxic activity against gastric cancer cells of the titanium-based compounds and the free disubstituted 2,2′-bipyrimidine ligands is tested, showing IC50 ranging from 6.2 ± 1.2 μM to 274 ± 56 μM. The fluorescence studies of the ligands 2a–d, and the complexes [Ti(1)2(2a–d)] reveal an important fluorescence loss of the ligands 2c and 2d upon coordination with the Ti(1)2 fragment. Frontier orbitals obtained by DFT calculations permit us to explain this fluorescence quenching.Other supports : Centre National pour la Recherche Scientifique (CNRS, France), ARC, Ligue contre le Cancer, European action COST CM1105 (C. G.

Expression and functional studies of the GDNF family receptor alpha 3 in the pancreas

International audienceThe generation of therapeutic β-cells from human pluripotent stem cells relies on the identification of growth factors that faithfully mimic pancreatic β-cell development in vitro . In this context, the aim of the study was to determine the expression and function of the glial cell line derived neurotrophic factor receptor alpha 3 (GFRα3) and its ligand artemin (Artn) in islet cell development and function. GFRα3 and Artn expression were characterized by in situ hybridization, immunochemistry, and qRT-PCR. We used GFRα3-deficient mice to study GFRα3 function and generated transgenic mice overexpressing Artn in the embryonic pancreas to study Artn function. We found that GFRα3 is expressed at the surface of a subset of Ngn3-positive endocrine progenitors as well as of embryonic α- and β-cells, while Artn is found in the pancreatic mesenchyme. Adult β-cells lack GFRα3 but α-cells express the receptor. GFRα3 was also found in parasympathetic and sympathetic intra-islet neurons as well as in glial cells in the embryonic and adult pancreas. The loss of GFRα3 or overexpression of Artn has no impact on Ngn3 and islet cell formation and maintenance in the embryo. Islet organization and innervation as well as glucose homeostasis is normal in GFRα3-deficient mice suggesting functional redundancy

Trans-C versus Cis-C thermally induced isomerisation of a terpyridine adduct of cytotoxic cycloruthenated compound

International audienceTwo novel cycloruthenated compounds, 2 and 3, derived from cycloruthenated 2-phenyl pyridine(Ru(PhPy)) have been synthesized by adding one equivalent of 2,20;60,200-terpyridine (terpy) to [Ru(2-C6H4-20-C5H4N-kC,N)(MeCN)4]PF6 in MeOH/MeCN (16:1) at reflux temperature as a mixture of 1:1 isomers. The structures of both compounds that were formed under kinetic and thermodynamic control respectively, differ by the position of the central pyridine unit of terpy that was found trans or cis to the C-Ru bond of the Ru(PhPy) unit for 2 and 3 respectively. Whereas 2 did not afford substitution reactions when treated with any ligand, the substitution by MeOH or H2O of the MeCN trans to C in 3 could be followed by UV-vis spectroscopy. Moreover, the reaction in MeOH between 3 and imidazoles afforded new cycloruthenated compounds, 6a and 6b whose cytotoxicities, together with that of 2 and 3, against HCT116 and AGS cancer cells were determined

Gold(III) to Ruthenium(III) Metal Exchange in Dithiocarbamato Complexes Tunes Their Biological Mode of Action for Cytotoxicity in Cancer Cells

Malignant tumors have affected the human being since the pharaoh period, but in the last century the incidence of this disease has increased due to a large number of risk factors, including deleterious lifestyle habits (i.e., smoking) and the higher longevity. Many efforts have been spent in the last decades on achieving an early stage diagnosis of cancer, and more effective cures, leading to a decline in age-standardized cancer mortality rates. In the last years, our research groups have developed new metal-based complexes, with the aim to obtain a better selectivity for cancer cells and less side effects than the clinically established reference drug cisplatin. This work is focused on four novel Au(III) and Ru(III) complexes that share the piperidine dithiocarbamato (pipe-DTC) as the ligand, in a different molar ratio. The compounds [AuCl2(pipeDTC)], [Au(pipeDTC)2]Cl, [Ru(pipeDTC)3] and β-[Ru2(pipeDTC)5] have been synthesized and fully characterized by several chemical analyses. We have then investigated their biological properties in two different cell lines, namely, AGS (gastric adenocarcinoma) and HCT116 (colon carcinomas), showing significant differences among the four compounds. First, the two gold-based compounds and β-[Ru2(pipeDTC)5] display IC50 in the µM range, significantly lower than cisplatin. Second, we showed that [AuCl2(pipeDTC)] and β-[Ru2(pipeDTC)5]Cl drive different molecular mechanisms. The first was able to induce the protein level of the DNA damage response factor p53 and the autophagy protein p62, in contrast to the second that induced the ATF4 protein level, but repressed p62 expression. This study highlights that the biological activity of different complexes bringing the same organic ligand depends on the electronic and structural properties of the metal, which are able to fine tune the biological properties, giving us precious information that can help to design more selective anticancer drugs

Gold(III) to Ruthenium(III) Metal Exchange in Dithiocarbamato Complexes Tunes Their Biological Mode of Action for Cytotoxicity in Cancer Cells

International audienceMalignant tumors have affected the human being since the pharaoh period, but in the last century the incidence of this disease has increased due to a large number of risk factors, including deleterious lifestyle habits (i.e., smoking) and the higher longevity. Many efforts have been spent in the last decades on achieving an early stage diagnosis of cancer, and more effective cures, leading to a decline in age-standardized cancer mortality rates. In the last years, our research groups have developed new metal-based complexes, with the aim to obtain a better selectivity for cancer cells and less side effects than the clinically established reference drug cisplatin. This work is focused on four novel Au(III) and Ru(III) complexes that share the piperidine dithiocarbamato (pipe-DTC) as the ligand, in a different molar ratio. The compounds [AuCl2(pipeDTC)], [Au(pipeDTC)2]Cl, [Ru(pipeDTC)3] and β-[Ru2(pipeDTC)5] have been synthesized and fully characterized by several chemical analyses. We have then investigated their biological properties in two different cell lines, namely, AGS (gastric adenocarcinoma) and HCT116 (colon carcinomas), showing significant differences among the four compounds. First, the two gold-based compounds and β-[Ru2(pipeDTC)5] display IC50 in the µM range, significantly lower than cisplatin. Second, we showed that [AuCl2(pipeDTC)] and β-[Ru2(pipeDTC)5]Cl drive different molecular mechanisms. The first was able to induce the protein level of the DNA damage response factor p53 and the autophagy protein p62, in contrast to the second that induced the ATF4 protein level, but repressed p62 expression. This study highlights that the biological activity of different complexes bringing the same organic ligand depends on the electronic and structural properties of the metal, which are able to fine tune the biological properties, giving us precious information that can help to design more selective anticancer drugs

Qui veut laver ma blouse ? La légitimation collective d’activités teintes. Le cas des équipes de gestion de pôles

National audienceFrench hospitals’ governance reform has, directly or not, created new roles: clinical directors, senior nurse assistants, business managers and executive managers. These roles are still recent and not yet legitimate within hospitals. Furthermore, they are associated with a strong social stigma in those organizations: care management. Our work aims at better understanding the way clinical directions’ teams consider their management activities as dirty work; and the strategies through which they try to legitimate these activities in front of their colleagues. We carried out a case study of 7 “Mother-Child” clinical directions’ teams in France, through a qualitative methodology (56 interviews, including 25 interviews with targeted actors; 20 observations of directorate meetings). Our results show that activity legitimization strategies vary depending on actors and teams. They are both organizationally based (delegation) and discursively based (reframing, recalibrating, audience diversifying). We specifically suggest that these strategies depend on clinical directions’ team organization. We discuss two layouts of strategies: strategies of clinical director’s delegation and those of collective commitment. Tinted roles’ legitimization thus depends on both individuals’ discursive resources (and places for discussions) and individual’s power within the organization (and hierarchical and functional relationships).Directement ou non, la nouvelle gouvernance hospitalière a créé de nouveaux rôles : chef de pôle d’activité, cadre coordonnateur de pôle, cadre administratif de pôle, directeur délégué de pôle. Ces rôles, encore récents et peu légitimes au sein des hôpitaux, sont en plus associés à une teinte sociale encore prégnante dans ces organisations : la gestion des soins. Notre travail vise à mieux comprendre la manière dont les équipes de pôle conçoivent leurs activités de gestion en tant que sale boulot ; ainsi que les stratégies par lesquelles ils tentent de les légitimer auprès de leurs collègues. Pour cela, nous avons mené une étude de 7 cas d’équipes de gestion de pôles « Mère-Enfant » en France, à partir d’une démarche qualitative (56 entretiens, dont 25 avec les acteurs ciblés ; 20 observations de réunions de pôle). Nos résultats montrent que les stratégies de légitimation des activités diffèrent selon les acteurs et les équipes de pôle. Elles sont à la fois d’ordre organisationnel (délégation) et discursif (recadrage, recalibrage, diversification de l’audience). En particulier, nous avançons que ces stratégies découlent des modes d’organisation dans chaque équipe de pôle. Notre discussion nous amène à distinguer deux configurations de stratégies : les stratégies par délégation du chef de pôle et celles par endossement de l’ensemble de l’équipe. La légitimation de rôles teintés dépend donc à la fois des ressources discursives des individus (et donc des instances de dialogue) mais aussi du pouvoir de chacun dans l’organisation (et donc des liens hiérarchiques et fonctionnels qui les unissent)

Efficacy and tolerability of Janus kinase inhibitors in myelofibrosis: a systematic review and network meta-analysis

International audienceMyelofibrosis is a myeloproliferative neoplasm associated with constitutional symptoms, increasing splenomegaly, and worsening cytopenias. Janus kinase (JAK) inhibitors have been used for the treatment of myelofibrosis for several years, but there is a lack of comparative information between those treatments. A systematic review and network meta-analysis was performed on randomized controlled trials in patients with myelofibrosis receiving JAK inhibitor or placebo or control. Primary outcomes were efficacy on spleen volume reduction and total symptom score reduction. Additional analyses were conducted on anemia and thrombopenia events. Seven studies were included in the network meta-analysis including 1953 patients randomly assigned to four JAK inhibitors-ruxolitinib, fedratinib, pacritinib, momelotinib-or control. In first-line therapy, momelotinib and fedratinib were associated with comparable efficacy to ruxolitinib, and with less toxicity on erythrocytes and platelets, respectively. Pacritinib was less effective on splenomegaly than ruxolitinib as a first-line treatment but seemed effective in second line, after ruxolitinib exposure. Fedratinib and ruxolitinib that are FDA approved in myelofibrosis have both confirmed being valuable option to treat splenomegaly and constitutional symptoms, and their slightly different tolerance-profiles can guide therapeutic choice for first-line treatment, according to patient profile. Momelotinib could be another option especially due to its positive effect on anemia

Certifié « Cadre administratif de pôle ». L’encastrement identitaire pour légitimer un nouveau rôle

International audienceThe hospital new governance reform has created a brand new role of administrative man- ager of clinical directorates. This administrative manager should assist a clinical director, along with a senior nurse, however he has no clear instruction about his/her activities, while his/her environment is highly institutionalized. This article aims at investigating the legitimization process of this new role within clinical directorates’ teams: how adminis- trative managers try to legitimize their role as perceived by their colleagues? To address the issue, we resort to the literature relating to both new organizational practices legit- imization, and identity work; our empirics consists in case studies of 4 “Mother-Child” clinical directorate teams in France, each of one involving an administrative manager. We proceed through qualitative methods including 30 interviews and 8 meeting observations. Our results show how administrative managers struggle to integrate their identity into their colleagues’ work systems, while justifying to them the usefulness of their role. We finally discuss the concept of identity embeddedness in relation to neo-institutional and identity work theories, as well as implications for clinical directory teams.La nouvelle gouvernance hospitalière a créé un nouveau rôle de cadre administratif de pôle d’activité, rôle totalement inédit dans les hôpitaux. Censé assister le chef de pôle, en collaboration avec un cadre coordonnateur, ce cadre administratif n’a cependant pas une ligne de fonctionnement claire, d’autant plus dans un environnement qui, lui, est fortement institutionnalisé. Nous posons dans ce travail la question de la légitimation de ce nouveau rôle au sein des équipes de pôle : comment les cadres administratifs procèdent-ils pour légitimer leur rôle aux yeux de leurs collègues ? Pour y répondre, nous mobilisons la litté- rature concernant la légitimation de nouvelles pratiques ainsi que celle relative au travail identitaire ; puis nous utilisons une étude de 4 cas d’équipes de pôle « Mère-Enfant » en France, comprenant chacune un cadre administratif, à partir d’une démarche qualitative (30 entretiens, 8 observations de réunions). Nos résultats montrent comment les cadres administratifs de pôle s’attèlent à insérer leur identité dans le fonctionnement des équipes de pôle, tout en justifiant l’utilité de leur rôle auprès de ces acteurs. Nous discutons finalement le concept d’encastrement identitaire en lien avec la théorie néo-institutionnelle et celle du travail identitaire, ainsi que les implications pour la gestion des équipes de pôle

Impact of cyclometalated ruthenium(II) complexes on lactate dehydrogenase activity and cytotoxicity in gastric and colon cancer cells

International audienceLactate dehydrogenase (LDH) is a redox enzyme often overexpressed in cancer cells allowing their survival in stressful metabolic tumor environment. Ruthenium(II) complexes have been shown to impact on the activity of purified horseradish peroxidase and glucose oxidase but the physiological relevance remains unclear. In this study we investigated how ruthenium complexes impact on the activity of LDH in vitro and in cancer cells and performed a comparative study using polypyridine ruthenium(II) complex [Ru(bpy)3]2+ (1) and its structurally related cyclometalated 2-phenylpyridinato counterpart [Ru(phpy)(bpy)2]+ (2) (bpy=2,2'-bipyridine, phpyH=2-phenylpyridine). We show that the cytotoxicity in gastric and colon cancer cells induced by 2 is significantly higher compared to 1. The kinetic inhibition mechanisms on purified LDH and the corresponding inhibition constants Ki or i0.5 values were calculated. Though complexes 1 and 2 are structurally very similar (one Ru-C bond in 2 replaces one Ru-N bond in 1), their inhibition modes are different. Cyclometalated complex 2 behaves exclusively as a non-competitive inhibitor of LDH from rabbit muscle (LDHrm), strongly suggesting that 2 does not interact with LDH in the vicinities of either lactate/pyruvate or NAD+/NADH binding sites. Sites of interaction of 1 and 2 with LDHrm were revealed theoretically through computational molecular docking. Inhibition of LDH activity by 2 was confirmed in cancer cells. Altogether, these results revealed an inhibition of LDH activity by ruthenium complex through a direct interaction structurally tuned by a Ru-C bond