18 results on '"Pascal Dao"'
Search Results
2. Straightforward synthetic route to gold(i)-thiolato glycoconjugate complexes bearing NHC ligands (NHC = N-heterocyclic carbene) and their promising anticancer activity
- Author
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Anthony Martin, Steven P. Nolan, Marina Saab, Pascal Dao, Nikolaos V. Tzouras, Thomas Scattolin, Rachid Benhida, Mauro Safir Filho, Kristof Van Hecke, Petra Lippmann, Ingo Ott, Institut de Chimie de Nice (ICN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Universiteit Gent = Ghent University [Belgium] (UGENT), Technische Universität Braunschweig = Technical University of Braunschweig [Braunschweig], Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
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chemistry.chemical_classification ,010405 organic chemistry ,Glycoconjugate ,General Chemistry ,[CHIM.THER]Chemical Sciences/Medicinal Chemistry ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,Catalysis ,0104 chemical sciences ,Thiosugars ,chemistry.chemical_compound ,chemistry ,Materials Chemistry ,Ic50 values ,Technical grade ,Acetone ,[CHIM.COOR]Chemical Sciences/Coordination chemistry ,Cancer cell lines ,Weak base ,Carbene - Abstract
International audience; A simple and eco-friendly route to gold-NHC complexes bearing different thiosugars is reported. The reaction between [Au(NHC)Cl] precursors, the thiosugars and a weak base proceeds under air using technical grade acetone under mild conditions (60 °C, 1h). The one-pot synthesis of the same complexes starting from the corresponding imidazolium salts was also investigated. The obtained complexes showed strong cytotoxic activities against selected cancer cell lines with IC50 values in the submicromolar to low micromolar concentration range.
- Published
- 2021
3. Nitroreductase sensitive styryl-benzothiazole profluorescent probes for the visualization of mitochondria under normoxic conditions
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Rachid Benhida, Pascal Dao, Mauro Safir Filho, Anthony Martin, Institut de Chimie de Nice (ICN), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)
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Fluorophore ,General Chemical Engineering ,General Physics and Astronomy ,Context (language use) ,02 engineering and technology ,Mitochondrion ,010402 general chemistry ,01 natural sciences ,Nitroreductase ,chemistry.chemical_compound ,fluorescence imaging ,Organelle ,[CHIM]Chemical Sciences ,mitochondria staining ,[CHIM.ORGA]Chemical Sciences/Organic chemistry ,General Chemistry ,021001 nanoscience & nanotechnology ,normoxic conditions ,Fluorescence ,0104 chemical sciences ,Staining ,Benzothiazole ,chemistry ,turn-ON fluorescence sensing ,Biophysics ,0210 nano-technology ,styryl-benzothiazole fluorophores - Abstract
International audience; Selective imaging of cellular organelles is a rapidly expanding field of research. Within this context we describe the development of two novel profluorescent probes, MitoP-2 and MitoP-3, for the precise staining of mitochondrial compartments. Herein, we demonstrate that caged, non-fluorescent styryl-benzothiazole probes harbouring a p-nitrobenzyl motif can be converted into their parent fluorophore under the action of the nitroreductase (NTR) enzyme. Two probes, MitoP-2 and MitoP-3, exhibited a turn-ON fluorescence signalling in NTR enzymatic assays. In addition, they also proved successful in the staining of the mitochondria in cellular experiments under normoxic conditions. Interestingly, while MitoP-2 and MitoP-3 structures only differ by the presence of a cationic mitochondrial-targeting unit, both were equally efficient in the staining of mitochondria. Hence, an activity-based approach (MitoP-2) is sufficient for the precise targeting of mitochondria and the use of cationic mitochondria-targeting units (phosphonium present on MitoP-3) can be considered superfluous in this case.
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- 2020
4. Design and synthesis of new theranostic agents for near-infrared imaging of β-amyloid plaques and inhibition of β-amyloid aggregation in Alzheimer's disease
- Author
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Zhiyun Du, Bernard Meunier, Kun Zhang, Qian Chen, Chang-Zhi Dong, Pascal Dao, Feifei Ye, Huixiong Chen, School of Chemical Engineering and Light Industry, Guangdong University of Technology, Interfaces, Traitements, Organisation et Dynamique des Systèmes (ITODYS (UMR_7086)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Genetically modified mouse ,Cytotoxicity ,General Chemical Engineering ,Nanotechnology ,Neuropathology ,Beta-amyloid ,Fibril ,03 medical and health sciences ,0302 clinical medicine ,β amyloid ,medicine ,[CHIM.COOR]Chemical Sciences/Coordination chemistry ,Near infrared imaging ,Retina ,Inhibitors ,Chemistry ,Process Chemistry and Technology ,Alzheimer's disease ,Small molecule ,3. Good health ,Theranostic agents ,NIRF imaging ,030104 developmental biology ,medicine.anatomical_structure ,Biophysics ,030217 neurology & neurosurgery - Abstract
International audience; The presence of amyloid plaques predisposes clinical symptoms of cognitive impairment, which occurs much earlier than other clinical symptoms and plays a crucial role in the neuropathology of AD. Thus, developing probes for Aβ species imaging could be used for early diagnosis of AD, and blocking the initial steps of Aβ aggregation with small molecules has emerged as a valid disease-modifying therapy for Aβ. Herein, we report the design, synthesis and evaluation of a series of new theranostic agents, which can simultaneously perform near infra-red imaging of Aβ plaques, prevent self-aggregation of Aβ monomer, disaggregate preformed Aβ fibrils and play a protective effect on the toxicity of human neuroblastoma cells (SHSY5Y) induced by Aβ1–42. Most of these probes displayed maximum emission in PBS (>650 nm), which falls in the good range for NIRF probes. Importantly, these probes are found to have a high binding affinity toward Aβ aggregates, to exhibit a large fluorescence enhancement upon interaction with Aβ aggregates accompanied by a blueshift in the emission spectra of 20–40 nm and to show an excellent targeting ability for Aβ plaques in slices of brain and eye containing retina tissue from double transgenic mice. These molecules show a promising potential as theranostic agents for the diagnosis and therapy of AD.
- Published
- 2017
5. Synthesis of novel 1,2,4-triazine scaffold as FAK inhibitors with antitumor activity
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Mélanie Etheve-Quelquejeu, Daniel Lietha, Pascal Dao, Huixiong Chen, and Christiane Garbay
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0301 basic medicine ,Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,Biochemistry ,Focal adhesion ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Neoplasms ,Drug Discovery ,Humans ,Structure–activity relationship ,Protein Kinase Inhibitors ,Molecular Biology ,IC50 ,Cell Proliferation ,chemistry.chemical_classification ,biology ,Triazines ,Kinase ,Chemistry ,Cell growth ,Organic Chemistry ,Active site ,Molecular Docking Simulation ,030104 developmental biology ,Enzyme ,Docking (molecular) ,Drug Design ,Focal Adhesion Protein-Tyrosine Kinases ,030220 oncology & carcinogenesis ,biology.protein ,Molecular Medicine ,Drug Screening Assays, Antitumor - Abstract
A series of 1,3,5-triazinic inhibitors of focal adhesion kinase (FAK) has recently been shown to exert antiangiogenic activity against HUVEC cells and anticancer efficacy against several cancer cell lines. In this report, we designed and synthesized a series of new compounds containing a 1,2,4-triazine core as novel scaffold for FAK inhibitors. These compounds displayed 10-7M IC50 values, and the best one showed IC50 value of 0.23μM against FAK enzymatic activity. Among them, several inhibitors potently inhibited the proliferation of glioblastoma (U-87MG) and colon (HCT-116) cancer cell lines. Docking of compound 10 into the active site of the FAK kinase was performed to explore its potential binding mode.
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- 2017
6. Development of Phenothiazine-Based Theranostic Compounds That Act Both as Inhibitors of β-Amyloid Aggregation and as Imaging Probes for Amyloid Plaques in Alzheimer’s Disease
- Author
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Kun Zhang, Chang-Zhi Dong, Yan Liu, Zhiyun Du, Bernard Meunier, Pascal Dao, Huixiong Chen, and Feifei Ye
- Subjects
Genetically modified mouse ,Pathology ,medicine.medical_specialty ,Physiology ,Cognitive Neuroscience ,Early detection ,Mice, Transgenic ,Neuroimaging ,Plaque, Amyloid ,Disease ,010402 general chemistry ,Fibril ,01 natural sciences ,Biochemistry ,Theranostic Nanomedicine ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Alzheimer Disease ,Phenothiazines ,β amyloid ,Phenothiazine ,medicine ,Animals ,Cytotoxicity ,Fluorescent Dyes ,Retina ,Spectroscopy, Near-Infrared ,Chemistry ,Optical Imaging ,Cell Biology ,General Medicine ,0104 chemical sciences ,Disease Models, Animal ,Early Diagnosis ,medicine.anatomical_structure ,Cancer research ,030217 neurology & neurosurgery - Abstract
Early detection of Alzheimer’s disease (AD) is imperative in enabling the understanding and clinical treatment of this disorder, as well as in preventing its progression. Imaging agents specifically targeting Aβ plaques in the brain and the retina may lead to the early diagnosis of AD. Among them, near-infrared fluorescent (NIRF) imaging has emerged as an attractive tool to noninvasively identify and monitor diseases during the preclinical and early stages. In the present study, we report the design, synthesis, and evaluation of a series of new near-infrared fluorescent probes. Most of these probes displayed maximum emission in PBS (>650 nm), which falls in the good range for NIRF probes. Among them, 4a1 showed the highest affinity toward Aβ aggregates (Kd = 7.5 nM) and an excellent targeting ability for Aβ plaques in slices of brain and retina tissue from double transgenic mice. These compounds are also found to effectively prevent Aβ fibril formation and disaggregate preformed Aβ fibrils, showing a prom...
- Published
- 2017
7. GAPDH Overexpression in the T Cell Lineage Promotes Angioimmunoblastic T Cell Lymphoma through an NF-κB-Dependent Mechanism
- Author
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Laura Mondragón, Philippe Gaulard, Jaap G Neels, Camila Rubio-Patiño, Frédéric Coutant, Laurent Boyer, François Lemonnier, Florian Muller, Elodie Villa, Rana Mhaidly, Vahid Asnafi, Thierry Passeron, Gian Marco De Donatis, Jean-François Peyron, Nicole Fabien, Els Verhoeyen, Sandrine Marchetti, Pascal Dao, Laura Sormani, Marie Jacquin, Marie Tosolini, Jean-Ehrland Ricci, Emma Proïcs, Anne Doye, Laurent Genestier, Jozef P. Bossowski, Anthony Martin, Véronique Imbert, Frederic Luciano, Jean-Jacques Fournié, Rachid Benhida, Caroline Pons, Johanna Chiche, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Nice (ICN), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Hospices Civils de Lyon (HCL), Centre méditérannéen de médecine moléculaire (C3M), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie de la survie et de la mort cellulaire et infection virale, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM), CCSD, Accord Elsevier, Université Nice Sophia Antipolis (... - 2019) (UNS), Université Nice Sophia Antipolis (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Service d'immunologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Immunogenomique et Inflammation, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (CRCL), Centre de Recherche en Cancérologie de Toulouse (CRCT), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (Equipe EVIR), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université Côte d'Azur (UCA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR50-Université Nice Sophia Antipolis (... - 2019) (UNS), and Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)
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0301 basic medicine ,Male ,Cancer Research ,[SDV]Life Sciences [q-bio] ,T-Lymphocytes ,Datasets as Topic ,chemistry.chemical_compound ,0302 clinical medicine ,Glyceraldehyde 3-phosphate dehydrogenase ,ComputingMilieux_MISCELLANEOUS ,biology ,NF-kappa B ,Middle Aged ,3. Good health ,[SDV] Life Sciences [q-bio] ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Gene Knockdown Techniques ,Female ,Signal Transduction ,Genetically modified mouse ,Angioimmunoblastic T-cell lymphoma ,Lineage (genetic) ,T cell ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Mice, Transgenic ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Protein Serine-Threonine Kinases ,Lymphoma, T-Cell ,03 medical and health sciences ,stomatognathic system ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Cell Lineage ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,Protein Kinase Inhibitors ,Aged ,NF-κB ,medicine.disease ,Lymphoma ,Disease Models, Animal ,030104 developmental biology ,HEK293 Cells ,chemistry ,Immunoblastic Lymphadenopathy ,biology.protein ,Cancer research ,Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) ,Function (biology) - Abstract
GAPDH is emerging as a key player in T cell development and function. To investigate the role of GAPDH in T cells, we generated a transgenic mouse model overexpressing GAPDH in the T cell lineage. Aged mice developed a peripheral Tfh-like lymphoma that recapitulated key molecular, pathological, and immunophenotypic features of human angioimmunoblastic T cell lymphoma (AITL). GAPDH induced non-canonical NF-κB pathway activation in mouse T cells, which was strongly activated in human AITL. We developed a NIK inhibitor to reveal that targeting the NF-κB pathway prolonged AITL-bearing mouse survival alone and in combination with anti-PD-1. These findings suggest the therapeutic potential of targeting NF-κB signaling in AITL and provide a model for future AITL therapeutic investigations.
- Published
- 2018
8. Development of highly sensitive fluorescent probes for the detection of β-galactosidase activity – application to the real-time monitoring of senescence in live cells
- Author
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Pascal Dao, Anthony Martin, Mauro Safir Filho, Maeva Gesson, Rachid Benhida, Institut de Chimie de Nice (ICN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Fundação) = CAPES Foundation [Brasilia] (CAPES), Centre méditerranéen de médecine moléculaire (C3M), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)
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Confocal ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Analytical Chemistry ,Flow cytometry ,Cell Line, Tumor ,Electrochemistry ,medicine ,Fluorescence microscope ,Environmental Chemistry ,Humans ,[CHIM]Chemical Sciences ,Spectroscopy ,Cellular Senescence ,Fluorescent Dyes ,medicine.diagnostic_test ,Chemistry ,Galactosidase activity ,021001 nanoscience & nanotechnology ,Flow Cytometry ,beta-Galactosidase ,Fluorescence ,In vitro ,0104 chemical sciences ,Microscopy, Fluorescence ,Cell culture ,Biophysics ,0210 nano-technology ,Linker ,Biomarkers - Abstract
International audience; We report the development of four novel fluorescent probes to monitor the activity of the β-galactosidase enzyme (β-gal), in vitro and in living cells. The fluorophores are based on a 6-amino-styryl-benzothiazole push-pull core and display a strong ICT emission. The probes encompass the fluorescent motif that is connected to a β-D-galactopyranoside moiety through a self-immolative benzyl carbamate linker (βGal-1-4). The screening of four different fluorophores enabled us to access new light-up and two-band ratiometric reporters. The four probes, βGal-1-4, exhibited an extremely fast response and over 200-fold fluorescence enhancement (βGal-1) following the enzymatic cleavage of the β-D-galactopyranoside unit. This rapid and extremely sensitive response allowed the detection of senescence-associated β-galactosidase (SA-β-gal) activity; a widely used biomarker of senescence. More importantly, βGal-1 also enabled us to monitor, in real-time, the emergence of senescence in live cells, i.e. the phenotypic transformation from normal to senescent cell. These findings underpin the fact that βGal-1 may find useful applications in biomedical research. Importantly, βGal-1 is suitable for epifluorescence and confocal microscopies, and flow cytometry techniques; which are among the most common analytical tools in biology.
- Published
- 2018
9. Design, Synthesis, and Evaluation of Novel Imidazo[1,2-a][1,3,5]triazines and Their Derivatives as Focal Adhesion Kinase Inhibitors with Antitumor Activity
- Author
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Xavier Coumoul, Jean-Phillipe Herbeuval, Céline Tomkiewicz-Raulet, Christiane Garbay, Nikaïa Smith, Marta Camacho-Artacho, Huixiong Chen, Pascal Dao, Daniel Lietha, and Expédite Yen-Pon
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Models, Molecular ,Cell Survival ,Antineoplastic Agents ,Apoptosis ,Focal adhesion ,Cell Movement ,Cell Line, Tumor ,Drug Discovery ,Cell Adhesion ,Humans ,Phosphorylation ,Protein Kinase Inhibitors ,IC50 ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,Molecular Structure ,Triazines ,Chemistry ,Cell growth ,Imidazoles ,Adhesion ,Cell cycle ,HCT116 Cells ,Protein Structure, Tertiary ,G2 Phase Cell Cycle Checkpoints ,Enzyme ,Models, Chemical ,Biochemistry ,Cell culture ,Drug Design ,Focal Adhesion Protein-Tyrosine Kinases ,Molecular Medicine ,Protein Binding - Abstract
A series of triazinic inhibitors of focal adhesion kinase (FAK) have been recently shown to exert antiangiogenic activity against HUVEC cells and anticancer efficacy against several cancer cell lines. We report herein that we further explored the heterocyclic core of these inhibitors by a fused imidazole ring with the triazine to provide imidazo[1,2-a][1,3,5]triazines. Importantly, these new compounds displayed 10(-7)-10(-8) M IC50 values, and the best inhibitor showed IC50 value of 50 nM against FAK enzymatic activity. Several inhibitors potently inhibited the proliferation of a panel of cancer cell lines expressing high levels of FAK. Apoptosis analysis in U87-MG and HCT-116 cell lines suggested that these compounds delayed cell cycle progression by arresting cells in the G2/M phase of the cell cycle, retarding cell growth. Further investigation demonstrated that these compounds strongly inhibited cell-matrix adhesion, migration, and invasion of U87-MG cells.
- Published
- 2014
10. Synthesis of novel diarylamino-1,3,5-triazine derivatives as FAK inhibitors with anti-angiogenic activity
- Author
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Ali Loukaci, Yves Lepelletier, Françoise Raynaud, Rafika Jarray, Huixiong Chen, Pascal Dao, Johanne Le Coq, Réda Hadj-Slimane, Daniel Lietha, and Christiane Garbay
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Cell Survival ,Morpholines ,Clinical Biochemistry ,Pharmaceutical Science ,Angiogenesis Inhibitors ,Crystallography, X-Ray ,Inhibitory postsynaptic potential ,Biochemistry ,Focal adhesion ,chemistry.chemical_compound ,Enzyme activator ,1,3,5-Triazine ,Drug Discovery ,Human Umbilical Vein Endothelial Cells ,Humans ,Transferase ,Enzyme Inhibitors ,Molecular Biology ,Molecular Structure ,Triazines ,Kinase ,Organic Chemistry ,Anti angiogenic ,Endothelial Cells ,Enzyme Activation ,chemistry ,Protein kinase domain ,Focal Adhesion Protein-Tyrosine Kinases ,Molecular Medicine - Abstract
We report herein the synthesis of novel diarylamino-1,3,5-triazine derivatives as FAK (focal adhesion kinase) inhibitors and the evaluation of their anti-angiogenic activity on HUVEC cells. Generally, the effects of these compounds on endothelial cells could be correlated with their kinase inhibitory activity. The most efficient compounds displayed inhibition of viability against HUVEC cells in the micromolar range, as observed with TAE-226, which was designed by Novartis Pharma AG. X-ray crystallographic analysis of the co-crystal structure for compound 34 revealed that the mode of interaction with the FAK kinase domain is highly similar to that observed in the complex of TAE-226.
- Published
- 2013
11. High yielding microwave-assisted synthesis of tri-substituted 1,3,5-triazines using Pd-catalyzed aryl and heteroarylamination
- Author
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Pascal Dao, Christiane Garbay, and Huixiong Chen
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Chemistry ,Aryl ,Organic Chemistry ,Supramolecular chemistry ,Biochemistry ,High yielding ,Coupling reaction ,Catalysis ,chemistry.chemical_compound ,Microwave chemistry ,Yield (chemistry) ,Drug Discovery ,Organic chemistry ,Conformational isomerism - Abstract
A rapid and efficient Pd-catalyzed aryl and heteroarylamination under microwave irradiation has been developed for various tri-substituted triazines that can serve as versatile building blocks for both supramolecular and medicinal chemistry research. Particularly valuable features of this method included the short reaction time, good yield, and convenient operation.
- Published
- 2012
12. Restoration of TRAIL-induced apoptosis in resistant human pancreatic cancer cells by a novel FAK inhibitor, PH11
- Author
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Pascal Dao, Nikaïa Smith, Daniel Scott-Algara, Christiane Garbay, Huixiong Chen, Jean-Philippe Herbeuval, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Régulation des Infections Rétrovirales, Institut Pasteur [Paris], and Institut Pasteur [Paris] (IP)
- Subjects
MESH: Signal Transduction ,Cancer Research ,MESH: CASP8 and FADD-Like Apoptosis Regulating Protein ,Time Factors ,MESH: Triazines ,CASP8 and FADD-Like Apoptosis Regulating Protein ,Apoptosis ,TRAIL ,FAK inhibitor ,[SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity ,MESH: Dose-Response Relationship, Drug ,TNF-Related Apoptosis-Inducing Ligand ,0302 clinical medicine ,MESH: Molecular Targeted Therapy ,Medicine ,MESH: Protein Kinase Inhibitors ,Molecular Targeted Therapy ,0303 health sciences ,Kinase ,Triazines ,Imidazoles ,MESH: Drug Resistance, Neoplasm ,3. Good health ,Cell biology ,Oncology ,030220 oncology & carcinogenesis ,Caspases ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Tumor necrosis factor alpha ,RNA Interference ,MESH: Pancreatic Neoplasms ,MESH: TNF-Related Apoptosis-Inducing Ligand ,MESH: Imidazoles ,Signal Transduction ,MESH: Focal Adhesion Kinase 1 ,MESH: Enzyme Activation ,c-FLIP ,MESH: Cell Line, Tumor ,MESH: RNA Interference ,Antineoplastic Agents ,Transfection ,Focal adhesion ,03 medical and health sciences ,Pancreatic cancer ,Cell Line, Tumor ,Humans ,Protein kinase B ,Protein Kinase Inhibitors ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,Pancreatic cancer cell lines ,MESH: Caspases ,MESH: Humans ,Dose-Response Relationship, Drug ,business.industry ,MESH: Proto-Oncogene Proteins c-akt ,MESH: Apoptosis ,MESH: Transfection ,MESH: Time Factors ,Cancer ,medicine.disease ,Enzyme Activation ,Pancreatic Neoplasms ,PI3K/AKT pathway ,Drug Resistance, Neoplasm ,Focal Adhesion Kinase 1 ,Cancer research ,MESH: Antineoplastic Agents ,MESH: Phosphatidylinositol 3-Kinase ,Phosphatidylinositol 3-Kinase ,business ,Proto-Oncogene Proteins c-akt - Abstract
International audience; Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) emerges as one of the most-promising experimental cancer therapeutic drugs and is currently being tested in clinical trials. However, both intrinsic and acquired resistance of human cancer cells to TRAIL-induced apoptosis poses a huge problem in establishing clinically efficient TRAIL therapies. To assess the regulation of TRAIL-resistance in human pancreatic cancer cells, we studied the TRAIL resistant pancreatic cell line PANC-1. We show that treatment with PH11, a novel Focal Adhesion Kinase (FAK) inhibitor in association with TRAIL rapidly induces apoptosis in TRAIL-resistant PANC-1 cells, but not in normal human fibroblast cells. To explain sensitization, we showed that PH11 restores TRAIL apoptotic pathway in PANC-1 cells through down-regulation of c-FLIP via inhibition of FAK and the phosphatidylinositol-3 kinase (PI3K)/AKT pathways. These findings suggest that this combined treatment may offer an attractive therapeutic strategy for safely and efficiently treating pancreatic cancer.
- Published
- 2015
13. High yielding microwave-assisted synthesis of 2-(arylmethyl)amino-4-arylamino-6-alkyl-1,3,5-triazines
- Author
-
Christiane Garbay, Pascal Dao, Huixiong Chen, and Alice Laporte
- Subjects
chemistry.chemical_classification ,Scope (project management) ,chemistry ,Feature (computer vision) ,Organic Chemistry ,Drug Discovery ,Microwave irradiation ,Organic chemistry ,Biochemistry ,High yielding ,Microwave assisted ,Alkyl - Abstract
An efficient and practical procedure was developed to prepare novel 2-(arylmethyl)amino-4-arylamino-6-alkyl-1,3,5-triazines, starting from dicyandiamide and the corresponding arylamines under microwave irradiation and its scope is demonstrated with a number of examples. The valuable feature of this procedure included the short reaction times, high yields, and easy operation.
- Published
- 2010
14. ChemInform Abstract: Synthesis of Novel Diarylamino-1,3,5-triazine Derivatives as FAK Inhibitors with anti-Angiogenic Activity
- Author
-
Johanne Le Coq, Yves Lepelletier, Françoise Raynaud, Pascal Dao, Huixiong Chen, Réda Hadj-Slimane, Ali Loukaci, Rafika Jarray, Christiane Garbay, and Daniel Lietha
- Subjects
chemistry.chemical_compound ,Biochemistry ,1,3,5-Triazine ,Chemistry ,education ,embryonic structures ,Anti angiogenic ,Autophosphorylation ,cardiovascular system ,General Medicine ,biological phenomena, cell phenomena, and immunity ,HUVEC Cells ,humanities - Abstract
Compound (Ia) is found to show significant decrease of autophosphorylation of FAK in HUVEC cells.
- Published
- 2013
15. Inhibition of both focal adhesion kinase and fibroblast growth factor receptor 2 pathways induces anti-tumor and anti-angiogenic activities
- Author
-
Yves Lepelletier, Réda Hadj-Slimane, Huixiong Chen, Rafika Jarray, Nikaïa Smith, Françoise Raynaud, Pascal Dao, Jean-Philippe Herbeuval, Daniel Lietha, Christiane Garbay, and Johanne Le Coq
- Subjects
Models, Molecular ,Cancer Research ,Angiogenesis ,Cell Survival ,Neovascularization, Physiologic ,Angiogenesis Inhibitors ,Apoptosis ,Fibroblast growth factor ,Focal adhesion ,Neoplasms ,Cell Adhesion ,Human Umbilical Vein Endothelial Cells ,Humans ,Phosphorylation ,Receptor, Fibroblast Growth Factor, Type 2 ,Receptor ,Protein Kinase Inhibitors ,Cell Proliferation ,Tube formation ,Binding Sites ,Dose-Response Relationship, Drug ,Fibroblast growth factor receptor 2 ,Chemistry ,Cell Cycle ,HCT116 Cells ,Cell biology ,Endothelial stem cell ,Enzyme Activation ,Oncology ,Focal Adhesion Kinase 1 ,Cancer research ,Signal transduction ,Signal Transduction - Abstract
FAK and FGFR2 signaling pathways play important roles in cancer development, progression and tumor angiogenesis. PHM16 is a novel ATP competitive inhibitor of FAK and FGFR2. To evaluate the therapeutic efficacy of this agent, we examined its anti-angiogenic effect in HUVEC and its anti-tumor effect in different cancer cell lines. We showed PHM16 inhibited endothelial cell viability, adherence and tube formation along with the added ability to induce endothelial cell apoptosis. This compound significantly delayed tumor cell growth. Together, these data showed that inhibition of both FAK and FGFR2 signaling pathways can enhance anti-tumor and anti-angiogenic activities.
- Published
- 2013
16. ChemInform Abstract: High Yielding Microwave-Assisted Synthesis of Tri-Substituted 1,3,5-Triazines Using Pd-Catalyzed Aryl and Heteroarylamination
- Author
-
Pascal Dao, Christiane Garbay, and Huixiong Chen
- Subjects
chemistry.chemical_compound ,Chemistry ,Aryl ,Yield (chemistry) ,Microwave irradiation ,Supramolecular chemistry ,General Medicine ,High yielding ,Microwave assisted ,Combinatorial chemistry ,Catalysis - Abstract
A rapid and efficient Pd-catalyzed aryl and heteroarylamination under microwave irradiation has been developed for various tri-substituted triazines that can serve as versatile building blocks for both supramolecular and medicinal chemistry research. Particularly valuable features of this method included the short reaction time, good yield, and convenient operation.
- Published
- 2012
17. ChemInform Abstract: High-Yielding Microwave-Assisted Synthesis of 2-(Arylmethyl)amino-4-arylamino-6-alkyl-1,3,5-triazines
- Author
-
Christiane Garbay, Huixiong Chen, Alice Laporte, and Pascal Dao
- Subjects
chemistry.chemical_classification ,chemistry ,General Medicine ,Microwave assisted ,High yielding ,Combinatorial chemistry ,Alkyl ,Sequence (medicine) - Abstract
A three-step sequence is developed for the conversion of dicyandiamide and arylamines into the title compounds (VII).
- Published
- 2010
18. Disruption of the glucocorticoid receptor assembly with heat shock protein 90 by a peptidic antiglucocorticoid
- Author
-
Pierre Formstecher, Hai-Pascal Dao-Phan, and Philippe Lefebvre
- Subjects
Molecular Sequence Data ,Peptide ,Biology ,Transfection ,Dexamethasone ,chemistry.chemical_compound ,Mice ,Endocrinology ,Glucocorticoid receptor ,Receptors, Glucocorticoid ,Heat shock protein ,Animals ,Humans ,Amino Acid Sequence ,HSP90 Heat-Shock Proteins ,Receptor ,Fluorescent Antibody Technique, Indirect ,Molecular Biology ,Glucocorticoids ,chemistry.chemical_classification ,Antiglucocorticoid ,Osmolar Concentration ,Antibodies, Monoclonal ,General Medicine ,DNA ,Ligand (biochemistry) ,Hsp90 ,Rats ,Nuclear receptor ,chemistry ,Biochemistry ,COS Cells ,biology.protein ,Peptides ,Receptors, Progesterone ,Sequence Alignment - Abstract
Association of glucocorticoid (GR) and progesterone (PR) receptors with a set of molecular chaperones, including the 90-kDa heat shock protein (hsp90), is a dynamic process required for proper folding and maintaining these nuclear receptors under a transcriptionally inactive, ligand-responsive state. Mutational studies of the chicken hsp90 complementary DNA suggested that three regions of this protein (A, B, and Z) interact with the hormone-binding domain of GR, whereas region A is dispensable for hsp90 binding to PR. We found that this 69-amino acid region can be narrowed down to a 35-mer α-helical, acidic peptide, which is by itself able to inhibit hsp90 association to GR translated in vitro. The hsp90-free GR did not bind ligand, but was devoid of any specific DNA-binding activity, and higher peptide concentrations specifically inhibited the binding of activated GR to DNA. When overexpressed in cultured cells, this peptide acted as an antiglucocorticoid and inhibited the antiactivating protein-1 activity and the ligand-dependent nuclear transfer of GR. None of these effects, either in vivo and in vitro, was observed for PR. The region from residue 232 to residue 265 of hsp90 is, therefore, a domain critical for its association to GR, an association that is a prerequisite for receptor transcriptional activity. More importantly, these results demonstrate that targeting specific protein/protein interaction interfaces is a powerful means to specifically modulate nuclear receptor signaling pathways in a ligand-independent manner.
- Published
- 1997
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