References of "De Tullio, Pascal"
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See detailTriphenylphosphonium salts of 1,2,4-benzothiadiazine 1,1-dioxides related to diazoxide targeting mitochondrial ATP-sensitive potassium channels
Constant-Urban, C.; Charif, M.; Goffin, Eric ULg et al

in Bioorganic & Medicinal Chemistry Letters (2013), 23

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See detailEffects of diazoxide, benzothiadiazine and benzopyrane derivatives on mitochondrial proton and electron leaks of cardiomyocytes (H9C2 cell line).
Mouithys-Mickalad, Ange ULg; Ceusters, Justine ULg; Charef, M et al

Poster (2013)

Background: Mitochondria are double membrane- organelles that play a central role in cellular metabolism, calcium homeostasis and redox signaling. They have been also considered as main producers of ... [more ▼]

Background: Mitochondria are double membrane- organelles that play a central role in cellular metabolism, calcium homeostasis and redox signaling. They have been also considered as main producers of adenosine triphosphate (ATP) and reactive oxygen species (ROS). In many cancer cells those organelles become dysfunctional leading to a shift of energy metabolism from oxidative phosphorylation to active glycolysis and an increase of ROS generation. According to Warberg’ theory, cancer damage might occur at the mitochondrial level, affecting tiny structures within each cell implicated in the energy production through ATP. New insight is that mitochondria might be a good therapeutic target for metabolic syndromes, ischemia/reperfusion injury and organs transplantation. Therefore, search for novel molecules able to keep mitochondria functional are of relevant interest. Methodology: Cardiomyocytes (H9C2 cells) were from ATCC (USA) and grown till confluence. The basal cellular respiratory rate, proton and electron leaks as well as ATP production were measured with the High Resolution Oxygraphy (Oroboros, Austria). All compounds: diazoxide (DIAZ), diazoxide –related analogs (1: BPDZ-259, 2: BPDZ-444), and benzopyran derivatives (3: BPDZ-490, 4: BPDZ-711) were tested at final concentration of 10-5 M, except when specified and compared to control samples (cells with or without DMSO). Results and conclusion: The basal respiratory rate of H9C2 cells (5x106/mL) was changed depending on the chemical structure of the tested compounds: e.g. compound 3 strongly enhanced the routine respiration, while 4 displayed a marked lowering effect. In contrast, the addition of similar concentration of benzothiadiazin derivatives (1, 2) had no effect on routine respiration but also on the other respiratory parameters such as oligomycin-induced leak and ATP production. Similar profile was obtained with the reference molecule: diazoxide. Overall, our findings indicate that both diazoxide-like analogues (1 and 2) and diazoxide were without significant effect on basal respiration, ATP production, even on maximal respiration. Interestingly, two derivatives show opposite effects: compound 3 behaves as a uncoupling agent and the other one (4) exhibits a real lowering effect on respiration but that was reversible. The latter effect might be of interest if this kind of molecules could be used for further use as an agent for organ conservation during transplantation. Our results also demonstrate that diazoxide, a well-known Mito-KATP opener, did not exert its effect beside of clinical situation like ischemia/reperfusion injury. [less ▲]

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See detailLaser-induced choroidal neovascularization model to study age-related macular degeneration in mice.
LAMBERT, Vincent ULg; Lecomte, Julie ULg; Hansen, Sylvain ULg et al

in Nature Protocols (2013), 8(11), 2197-2211

The mouse model of laser-induced choroidal neovascularization (CNV) has been used extensively in studies of the exudative form of age-related macular degeneration (AMD). This experimental in vivo model ... [more ▼]

The mouse model of laser-induced choroidal neovascularization (CNV) has been used extensively in studies of the exudative form of age-related macular degeneration (AMD). This experimental in vivo model relies on laser injury to perforate Bruch's membrane, resulting in subretinal blood vessel recruitment from the choroid. By recapitulating the main features of the exudative form of human AMD, this assay has served as the backbone for testing antiangiogenic therapies. This standardized protocol can be applied to transgenic mice and can include treatments with drugs, recombinant proteins, antibodies, adenoviruses and pre-microRNAs to aid in the search for new molecular regulators and the identification of novel targets for innovative treatments. This robust assay requires 7-14 d to complete, depending on the treatment applied and whether immunostaining is performed. This protocol includes details of how to induce CNV, including laser induction, lesion excision, processing and different approaches to quantify neoformed vasculature. [less ▲]

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See detailAMPA receptor positive allosteric modulators: a patent review
Pirotte, Bernard ULg; Francotte, Pierre ULg; Goffin, Eric ULg et al

in Expert Opinion on Therapeutic Patents (2013), 23

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See detailSéminaire des chercheurs Télévie 2013
Cimino, Jonathan ULg; Sounni, Nor Eddine ULg; Calligaris, David ULg et al

Poster (2012, December 10)

Séminaire des chercheurs Télévie 2013

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See detailMétabolomique et Chimie Médicinale, vers la découverte de nouvelles cibles thérapeutiques : application à la dégénérescence maculaire liée à l'âge (DMLA)
De Tullio, Pascal ULg

Conference (2012, May 25)

La métabolomique est une des sciences « omiques » les plus récemment développées. Elle consiste en l’étude de l’ensemble des composés de petit poids moléculaire (métabolites) présents dans une cellule, un ... [more ▼]

La métabolomique est une des sciences « omiques » les plus récemment développées. Elle consiste en l’étude de l’ensemble des composés de petit poids moléculaire (métabolites) présents dans une cellule, un organe, un organisme ou plus globalement un biofluide et qui constitue le métabolome. Elle s’inscrit dans la continuité de la génomique, de la transcriptomique et de la protéomique puisqu’elle étudie l’ensemble des composés de fonctionnement « terminaux » des organismes et permet de relier une modification du métabolisme à une ou plusieurs cascades biochimiques. Or, toute pathologie entraîne ou est liée inévitablement à un disfonctionnement plus ou moins important du métabolisme et donc doit modifier le profil du métabolome par des changements de concentration et l’apparition ou la disparition de certains métabolites particuliers. L’application de la métabolomique à l’étude d’une pathologie permettrait donc, en principe, de mettre en lumière des voies biologiques affectées ou modifiées par cette même pathologie. Et en ce sens, la métabolomique, tout comme la protéomique et dans une moindre mesure la génomique, identifie des cibles thérapeutiques potentielles, nouvelles ou non. En effet, en partant du principe que l’amélioration symptomatique de toute maladie est représentée par le retour à un état de fonctionnement « normal » de l’organisme affecté, c’est à dire à un profil de métabolisme « sain », il apparaît évident que moduler en ce sens les voies biochimiques identifiées par la métabolomique peut constituer une approche thérapeutique originale. Dans sa recherche de nouveaux médicaments, la Chimie Médicinale est bien entendu très « demandeuse » de nouvelles cibles ou d’approches pharmacologiques novatrices et donc la métabolomique représente un outil tout à fait intéressant pour les pharmacochimistes. Une étude métabolomique est caractérisée par différentes étapes. Elle débute par une sélection et une collecte contrôlée des échantillons à analyser (échantillons « pathologiques » et « sains »). Elle se poursuit par la préparation et l’analyse des échantillons de manière à obtenir le profil métabolique le plus complet, ce qui est en général réalisé via l’utilisation de la RMN ou de la spectrométrie de masse. Les données obtenues doivent ensuite être préparées (post-processing) pour l’analyse statistique discriminante finale (i.e. PCA ; ICA, PLS-DA…). Cette analyse doit permettre la discrimination des groupes « sain » et « malade » et l’identification des molécules entraînant cette discrimination, molécules souvent nommées « biomarqueurs ». Ces biomarqueurs peuvent ensuite être reliés à différentes voies biochimiques. La dégénérescence maculaire liée à l’âge (DMLA) est la principale cause de perte de vision dans le monde occidental. Elle est notamment caractérisée par une néovascularisation choroïdienne (NVC). Malgré le développement de nouvelles thérapies, les mécanismes moléculaires et les changements métaboliques sous-jacents à cette pathologie sont toujours mal compris. C’est pourquoi nous avons décidé d’étudier la DMLA par le biais d’une approche métabolomique basée à la fois sur l’étude de sera de patients atteints de DMLA et sur un modèle murin de NVC induite au laser. L’analyse des échantillons humains et murins a été menée par RMN du proton et a conduit à la distinction claire de deux groupes chez la souris (induites au laser ou non) et chez l’humain (patients atteints de DMLA ou sains). Chose remarquable, les « biomarqueurs » discriminants sont identiques dans l’étude clinique humaine et dans le modèle expérimental animal. Leur modulation permet une amélioration sensible des effets de l’impact laser chez la souris, laissant par la même entrevoir une possibilité de traitement efficace chez l’homme. Cette approche a donc permis non seulement d’identifier des voies biochimiques impliquées dans la pathologie et donc d’ouvrir de nouveaux axes de recherche pour une meilleure compréhension de l’étiologie de la pathologie mais également de proposer des solutions thérapeutiques potentielles novatrices. [less ▲]

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See detailN-Aryl-N'-(chroman-4-yl)ureas and thioureas display in vitro anticancer activity and selectivity on apoptosis-resistant glioblastoma cells: screening, synthesis of simplified derivatives, and structure-activity relationship analysis.
Goffin, Eric ULg; Lamoral-Theys, Delphine; Tajeddine, Nicolas et al

in European Journal of Medicinal Chemistry (2012), 54

A series of chroman derivatives previously reported as potassium channel openers, as well as some newly synthesized simplified structures, were examined for their in vitro effects on the growth of three ... [more ▼]

A series of chroman derivatives previously reported as potassium channel openers, as well as some newly synthesized simplified structures, were examined for their in vitro effects on the growth of three human high-grade glioma cell lines: U373, T98G, and Hs683. Significant in vitro growth inhibitory activity was observed with 2,2-dimethylchroman-type nitro-substituted phenylthioureas, such as compounds 4o and 4p. Interestingly, most tested phenylureas were found to be slightly less active, but more cell selective (normal versus tumor glial cells, such as 3d, 3e, and 3g), thus less toxic, than the corresponding phenylthioureas. No significant differences were observed in terms of chroman-derivative-induced growth inhibitory effects between glioma cells sensitive to pro-apoptotic stimuli (Hs683 glioma cells) and glioma cells associated with various levels of resistance to pro-apoptotic stimuli (U373 and T98G glioma cells), a feature that suggests non-apoptotic-mediated growth inhibition. Flow cytometry analyses confirmed the absence of pro-apoptotic effects for phenylthioureas and phenylureas when analyzed in U373 glioma cells and demonstrated U373 cell cycle arrest in the G0/G1 phase. Computer-assisted phase-contrast videomicroscopy revealed that 3d and 3g displayed cytostatic effects, while 3e displayed cytotoxic ones. As a result, this work identified phenylurea-type 2,2-dimethylchromans as a new class of antitumor agents to be further explored for an innovative therapeutic approach for high-grade glioma and/or for a possible new mechanism of action. [less ▲]

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See detailNew substituted aryl esters and aryl amides of 3,4-dihydro-2H-1,2,4- benzothiadiazine 1,1-dioxides as positive allosteric modulators of AMPA receptors
Dintilhac, Gaëlle ULg; Arslan, Deniz ULg; Dilly, Sébastien ULg et al

in MedChemComm (2011), 2

AMPA receptor potentiators belonging to 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides have been found to be of great interest as cognitive enhancers. Previous structure–activity relationships have ... [more ▼]

AMPA receptor potentiators belonging to 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides have been found to be of great interest as cognitive enhancers. Previous structure–activity relationships have demonstrated the importance for activity of the nature of the substituent at the 7-position of the heterocycle. This work aims to explore the impact on AMPA potentiation of the introduction of different aryl and aralkyl ester or aryl amide groups at the 7-position. The new synthesized compounds were evaluated as AMPA receptor potentiators by examining their effect on rat brain primary cell cultures on AMPA-evoked membrane depolarisation using fluorescent membrane potential dyes and on imaging-based plate reader. The most potent compound of this series was 2-methylphenyl 4-methyl- 3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide 16c which provoked a strong potentiation of AMPA current with a potency close to that reported for the best reference compounds of the benzothiadiazine class (i.e cyclothiazide). This work also revealed that only the ortho-substitution of the phenyl group of 1,2,4-benzothiadiazine-7-carboxylate esters provided potent AMPA receptor potentiators opening the way to further chemical exploration. [less ▲]

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See detailQuality Assessment of Polygonum cuspidatum and Polygonum multiflorum by 1H NMR Metabolite Fingerprinting and Profiling Analysis.
Frederich, Michel ULg; Wauters, Jean-Noël ULg; Tits, Monique ULg et al

in Planta Medica (2011), 77

The quality assessment and control of traditional Chinese medicines (TCM) nowadays receives a great deal of attention worldwide and particularly in Europe with its increasing local use. POLYGONUM ... [more ▼]

The quality assessment and control of traditional Chinese medicines (TCM) nowadays receives a great deal of attention worldwide and particularly in Europe with its increasing local use. POLYGONUM CUSPIDATUM Siebold & Zucc. and POLYGONUM MULTIFLORUM Thunb. are two members of the Polygonaceae family, which are widely used as Chinese medicinal plants. The aim of this study was to achieve an overview of the quality of P. CUSPIDATUM and P. MULTIFLORUM samples available on the Chinese market and to identify important metabolites for their discrimination, using (1)H NMR-based metabolomics. (1)H NMR and multivariate analysis techniques were applied to almost 60 plant samples collected in different places in China. Using (1)H NMR metabolomics, it was possible, without previous evaporation or separation steps, to obtain metabolic fingerprints to distinguish between the species. The important metabolites for discrimination were stilbene derivatives. Finally, a clear distinction between the two species was possible and the discriminant metabolites were identified. [less ▲]

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See detailModulation of the 6-position of benzopyran derivatives and inhibitory effects on the insulin releasing process
Florence, Xavier; Dilly, Sébastien ULg; De Tullio, Pascal ULg et al

in Bioorganic & Medicinal Chemistry (2011)

The synthesis of different series of 4- and 6-substituted R/S-3,4-dihydro-2,2-dimethyl-2H-1- benzopyrans is described. All of these new benzopyran derivatives were bearing, at the 4- position, a ... [more ▼]

The synthesis of different series of 4- and 6-substituted R/S-3,4-dihydro-2,2-dimethyl-2H-1- benzopyrans is described. All of these new benzopyran derivatives were bearing, at the 4- position, a phenylthiourea moiety substituted on the phenyl ring by a meta or a para-electronwithdrawing group such as Cl or CN. The study aimed at exploring the influence of the nature of the substituent at the 6-position in order to develop new benzopyran-type KATP channel activators exhibiting an improved selectivity towards the insulin secreting cells. The original compounds were examined in vitro on rat pancreatic islets (inhibition of insulin release) as well as on rat aorta rings (vasorelaxant effect) and their activity was compared to that of the reference KATP channel activators (±)-cromakalim, (±)-pinacidil, diazoxide and to previously synthesized cromakalim analogues. Structure–activity relationships indicated that the inhibitory effect on the insulin secreting cells was related to the lipophilicity of the molecules and to the size of the substituent located at the 6-position. A marked inhibitory activity on the insulin secretory process was obtained with molecules bearing a bulky tertbutyloxycarbonylamino group at the 6-position (20-23). The latter compounds were found to have the same efficacy on the pancreatic endocrine tissue than some previously described molecules. Lastly, radioisotopic experiments further identified R/S-N-4-chlorophenyl-N’-(6- tert-butyloxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)thiourea (23) as a KATP channel opener. [less ▲]

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