Advances in tetrahydropyrido[1,2-a]isoindolone (valmerins) series: Potent glycogen synthase kinase 3 and cyclin dependent kinase 5 inhibitors.
Identifieur interne : 000282 ( Main/Exploration ); précédent : 000281; suivant : 000283Advances in tetrahydropyrido[1,2-a]isoindolone (valmerins) series: Potent glycogen synthase kinase 3 and cyclin dependent kinase 5 inhibitors.
Auteurs : Rajâa Boulahjar [France] ; Aziz Ouach [France] ; Stéphane Bourg [France] ; Pascal Bonnet [France] ; Olivier Lozach [France] ; Laurent Meijer [France] ; Christiane Guguen-Guillouzo [France] ; Rémy Le Guevel [France] ; Saïd Lazar [Maroc] ; Mohamed Akssira [Maroc] ; Yves Troin [France] ; Gérald Guillaumet [France] ; Sylvain Routier [France]Source :
- European journal of medicinal chemistry [ 1768-3254 ] ; 2015.
Descripteurs français
- KwdFr :
- Glycogen Synthase Kinase 3 (antagonistes et inhibiteurs), Glycogen Synthase Kinase 3 (métabolisme), Humains (MeSH), Inhibiteurs de protéines kinases (composition chimique), Inhibiteurs de protéines kinases (pharmacologie), Inhibiteurs de protéines kinases (synthèse chimique), Isoindoles (composition chimique), Isoindoles (pharmacologie), Isoindoles (synthèse chimique), Kinase-5 cycline-dépendante (antagonistes et inhibiteurs), Kinase-5 cycline-dépendante (métabolisme), Lignée cellulaire tumorale (MeSH), Modèles moléculaires (MeSH), Pipéridines (composition chimique), Pipéridines (pharmacologie), Pipéridines (synthèse chimique), Prolifération cellulaire (effets des médicaments et des substances chimiques), Relation dose-effet des médicaments (MeSH), Relation structure-activité (MeSH), Structure moléculaire (MeSH).
- MESH :
- antagonistes et inhibiteurs : Glycogen Synthase Kinase 3, Kinase-5 cycline-dépendante.
- composition chimique : Inhibiteurs de protéines kinases, Isoindoles, Pipéridines.
- effets des médicaments et des substances chimiques : Prolifération cellulaire.
- métabolisme : Glycogen Synthase Kinase 3, Kinase-5 cycline-dépendante.
- pharmacologie : Inhibiteurs de protéines kinases, Isoindoles, Pipéridines.
- synthèse chimique : Inhibiteurs de protéines kinases, Isoindoles, Pipéridines.
- Humains, Lignée cellulaire tumorale, Modèles moléculaires, Relation dose-effet des médicaments, Relation structure-activité, Structure moléculaire.
English descriptors
- KwdEn :
- Cell Line, Tumor (MeSH), Cell Proliferation (drug effects), Cyclin-Dependent Kinase 5 (antagonists & inhibitors), Cyclin-Dependent Kinase 5 (metabolism), Dose-Response Relationship, Drug (MeSH), Glycogen Synthase Kinase 3 (antagonists & inhibitors), Glycogen Synthase Kinase 3 (metabolism), Humans (MeSH), Isoindoles (chemical synthesis), Isoindoles (chemistry), Isoindoles (pharmacology), Models, Molecular (MeSH), Molecular Structure (MeSH), Piperidines (chemical synthesis), Piperidines (chemistry), Piperidines (pharmacology), Protein Kinase Inhibitors (chemical synthesis), Protein Kinase Inhibitors (chemistry), Protein Kinase Inhibitors (pharmacology), Structure-Activity Relationship (MeSH).
- MESH :
- chemical , antagonists & inhibitors : Cyclin-Dependent Kinase 5, Glycogen Synthase Kinase 3.
- chemical , chemical synthesis : Isoindoles, Piperidines, Protein Kinase Inhibitors.
- chemical , chemistry : Isoindoles, Piperidines, Protein Kinase Inhibitors.
- drug effects : Cell Proliferation.
- chemical , metabolism : Cyclin-Dependent Kinase 5, Glycogen Synthase Kinase 3.
- chemical , pharmacology : Isoindoles, Piperidines, Protein Kinase Inhibitors.
- Cell Line, Tumor, Dose-Response Relationship, Drug, Humans, Models, Molecular, Molecular Structure, Structure-Activity Relationship.
Abstract
An efficient synthetic strategy was developed to modulate the structure of the tetrahydropyridine isoindolone (Valmerin) skeleton. A library of more than 30 novel final structures was generated. Biological activities on CDK5 and GSK3 as well as cellular effects on cancer cell lines were measured for each novel compound. Additionally docking studies were performed to support medicinal chemistry efforts. A strong GSK3/CDK5 dual inhibitor (38, IC50 GSK3/CDK5 32/84 nM) was obtained. A set of highly selective GSK3 inhibitors was synthesized by fine-tuning structural modifications (29 IC50 GSK3/CDK5 32/320 nM). Antiproliferative effects on cells were correlated with the in vitro kinase activities and the best effects were obtained with lung and colon cell lines.
DOI: 10.1016/j.ejmech.2015.06.046
PubMed: 26142492
Affiliations:
- France, Maroc
- Auvergne (région administrative), Auvergne-Rhône-Alpes, Centre-Val de Loire, Région Bretagne, Région Centre
- Clermont-Ferrand, Orléans, Rennes, Roscoff
Links toward previous steps (curation, corpus...)
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- to stream PubMed, to step Curation: 000531
- to stream PubMed, to step Checkpoint: 000550
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- to stream Main, to step Curation: 000282
Le document en format XML
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Disease' Group, USR3151, Station Biologique, BP 74, 29682 Roscoff Cedex, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>C.N.R.S., 'Protein Phosphorylation & Human Disease' Group, USR3151, Station Biologique, BP 74, 29682 Roscoff Cedex</wicri:regionArea><placeName><region type="region" nuts="2">Région Bretagne</region><settlement type="city">Roscoff</settlement></placeName></affiliation></author><author><name sortKey="Guguen Guillouzo, Christiane" sort="Guguen Guillouzo, Christiane" uniqKey="Guguen Guillouzo C" first="Christiane" last="Guguen-Guillouzo">Christiane Guguen-Guillouzo</name><affiliation wicri:level="3"><nlm:affiliation>Plateforme ImPACcell-SFR BIOSIT UMS-CNRS3480 UMS-INSERM018, Université de Rennes1, 35043 Rennes Cedex, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Plateforme ImPACcell-SFR BIOSIT UMS-CNRS3480 UMS-INSERM018, Université de Rennes1, 35043 Rennes Cedex</wicri:regionArea><placeName><region 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Hassan II Mohammedia-Casablanca, BP 146, 28800 Mohammedia, Morocco.</nlm:affiliation><country xml:lang="fr">Maroc</country><wicri:regionArea>Laboratoire de Chimie, Bioorganique et Analytique, URAC 22 pôle Répam, Université Hassan II Mohammedia-Casablanca, BP 146, 28800 Mohammedia</wicri:regionArea><wicri:noRegion>28800 Mohammedia</wicri:noRegion></affiliation></author><author><name sortKey="Akssira, Mohamed" sort="Akssira, Mohamed" uniqKey="Akssira M" first="Mohamed" last="Akssira">Mohamed Akssira</name><affiliation wicri:level="1"><nlm:affiliation>Laboratoire de Chimie, Bioorganique et Analytique, URAC 22 pôle Répam, Université Hassan II Mohammedia-Casablanca, BP 146, 28800 Mohammedia, Morocco.</nlm:affiliation><country xml:lang="fr">Maroc</country><wicri:regionArea>Laboratoire de Chimie, Bioorganique et Analytique, URAC 22 pôle Répam, Université Hassan II Mohammedia-Casablanca, BP 146, 28800 Mohammedia</wicri:regionArea><wicri:noRegion>28800 Mohammedia</wicri:noRegion></affiliation></author><author><name sortKey="Troin, Yves" sort="Troin, Yves" uniqKey="Troin Y" first="Yves" last="Troin">Yves Troin</name><affiliation wicri:level="3"><nlm:affiliation>Clermont Université, ENSCCF, Laboratoire de Chimie des Hétérocycles et des Glucides, BP 10448, 63000 Clermont-Ferrand, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Clermont Université, ENSCCF, Laboratoire de Chimie des Hétérocycles et des Glucides, BP 10448, 63000 Clermont-Ferrand</wicri:regionArea><placeName><region type="region" nuts="2">Auvergne-Rhône-Alpes</region><region type="old region" nuts="2">Auvergne (région administrative)</region><settlement type="city">Clermont-Ferrand</settlement></placeName></affiliation></author><author><name sortKey="Guillaumet, Gerald" sort="Guillaumet, Gerald" uniqKey="Guillaumet G" first="Gérald" last="Guillaumet">Gérald Guillaumet</name><affiliation wicri:level="3"><nlm:affiliation>Univ Orleans, CNRS UMR 7311, Institut de Chimie Organique et Analytique, rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France. 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Electronic address: sylvain.routier@univ-orleans.fr.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Univ Orleans, CNRS UMR 7311, Institut de Chimie Organique et Analytique, rue de Chartres, BP 6759, 45067 Orléans Cedex 2</wicri:regionArea><placeName><region type="region" nuts="2">Centre-Val de Loire</region><region type="old region" nuts="2">Région Centre</region><settlement type="city">Orléans</settlement></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2015">2015</date><idno type="RBID">pubmed:26142492</idno><idno type="pmid">26142492</idno><idno type="doi">10.1016/j.ejmech.2015.06.046</idno><idno type="wicri:Area/PubMed/Corpus">000533</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000533</idno><idno type="wicri:Area/PubMed/Curation">000531</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000531</idno><idno 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6759, 45067 Orléans Cedex 2</wicri:regionArea><placeName><region type="region" nuts="2">Centre-Val de Loire</region><region type="old region" nuts="2">Région Centre</region><settlement type="city">Orléans</settlement></placeName></affiliation></author><author><name sortKey="Ouach, Aziz" sort="Ouach, Aziz" uniqKey="Ouach A" first="Aziz" last="Ouach">Aziz Ouach</name><affiliation wicri:level="3"><nlm:affiliation>Univ Orleans, CNRS UMR 7311, Institut de Chimie Organique et Analytique, rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Univ Orleans, CNRS UMR 7311, Institut de Chimie Organique et Analytique, rue de Chartres, BP 6759, 45067 Orléans Cedex 2</wicri:regionArea><placeName><region type="region" nuts="2">Centre-Val de Loire</region><region type="old region" nuts="2">Région Centre</region><settlement type="city">Orléans</settlement></placeName></affiliation></author><author><name sortKey="Bourg, Stephane" sort="Bourg, Stephane" uniqKey="Bourg S" first="Stéphane" last="Bourg">Stéphane Bourg</name><affiliation wicri:level="3"><nlm:affiliation>Univ Orleans, CNRS UMR 7311, Institut de Chimie Organique et Analytique, rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Univ Orleans, CNRS UMR 7311, Institut de Chimie Organique et Analytique, rue de Chartres, BP 6759, 45067 Orléans Cedex 2</wicri:regionArea><placeName><region type="region" nuts="2">Centre-Val de Loire</region><region type="old region" nuts="2">Région Centre</region><settlement type="city">Orléans</settlement></placeName></affiliation></author><author><name sortKey="Bonnet, Pascal" sort="Bonnet, Pascal" uniqKey="Bonnet P" first="Pascal" last="Bonnet">Pascal Bonnet</name><affiliation wicri:level="3"><nlm:affiliation>Univ Orleans, CNRS UMR 7311, Institut de Chimie Organique et Analytique, rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Univ Orleans, CNRS UMR 7311, Institut de Chimie Organique et Analytique, rue de Chartres, BP 6759, 45067 Orléans Cedex 2</wicri:regionArea><placeName><region type="region" nuts="2">Centre-Val de Loire</region><region type="old region" nuts="2">Région Centre</region><settlement type="city">Orléans</settlement></placeName></affiliation></author><author><name sortKey="Lozach, Olivier" sort="Lozach, Olivier" uniqKey="Lozach O" first="Olivier" last="Lozach">Olivier Lozach</name><affiliation wicri:level="3"><nlm:affiliation>C.N.R.S., 'Protein Phosphorylation & Human Disease' Group, USR3151, Station Biologique, BP 74, 29682 Roscoff Cedex, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>C.N.R.S., 'Protein Phosphorylation & Human Disease' Group, USR3151, Station Biologique, BP 74, 29682 Roscoff Cedex</wicri:regionArea><placeName><region type="region" nuts="2">Région Bretagne</region><settlement type="city">Roscoff</settlement></placeName></affiliation></author><author><name sortKey="Meijer, Laurent" sort="Meijer, Laurent" uniqKey="Meijer L" first="Laurent" last="Meijer">Laurent Meijer</name><affiliation wicri:level="3"><nlm:affiliation>C.N.R.S., 'Protein Phosphorylation & Human Disease' Group, USR3151, Station Biologique, BP 74, 29682 Roscoff Cedex, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>C.N.R.S., 'Protein Phosphorylation & Human Disease' Group, USR3151, Station Biologique, BP 74, 29682 Roscoff Cedex</wicri:regionArea><placeName><region type="region" nuts="2">Région Bretagne</region><settlement type="city">Roscoff</settlement></placeName></affiliation></author><author><name sortKey="Guguen Guillouzo, Christiane" sort="Guguen Guillouzo, Christiane" uniqKey="Guguen Guillouzo C" first="Christiane" last="Guguen-Guillouzo">Christiane Guguen-Guillouzo</name><affiliation wicri:level="3"><nlm:affiliation>Plateforme ImPACcell-SFR BIOSIT UMS-CNRS3480 UMS-INSERM018, Université de Rennes1, 35043 Rennes Cedex, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Plateforme ImPACcell-SFR BIOSIT UMS-CNRS3480 UMS-INSERM018, Université de Rennes1, 35043 Rennes Cedex</wicri:regionArea><placeName><region type="region" nuts="2">Région Bretagne</region><settlement type="city">Rennes</settlement></placeName></affiliation></author><author><name sortKey="Le Guevel, Remy" sort="Le Guevel, Remy" uniqKey="Le Guevel R" first="Rémy" last="Le Guevel">Rémy Le Guevel</name><affiliation wicri:level="3"><nlm:affiliation>Plateforme ImPACcell-SFR BIOSIT UMS-CNRS3480 UMS-INSERM018, Université de Rennes1, 35043 Rennes Cedex, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Plateforme ImPACcell-SFR BIOSIT UMS-CNRS3480 UMS-INSERM018, Université de Rennes1, 35043 Rennes Cedex</wicri:regionArea><placeName><region type="region" nuts="2">Région Bretagne</region><settlement type="city">Rennes</settlement></placeName></affiliation></author><author><name sortKey="Lazar, Said" sort="Lazar, Said" uniqKey="Lazar S" first="Saïd" last="Lazar">Saïd Lazar</name><affiliation wicri:level="1"><nlm:affiliation>Laboratoire de Chimie, Bioorganique et Analytique, URAC 22 pôle Répam, Université Hassan II Mohammedia-Casablanca, BP 146, 28800 Mohammedia, Morocco.</nlm:affiliation><country xml:lang="fr">Maroc</country><wicri:regionArea>Laboratoire de Chimie, Bioorganique et Analytique, URAC 22 pôle Répam, Université Hassan II Mohammedia-Casablanca, BP 146, 28800 Mohammedia</wicri:regionArea><wicri:noRegion>28800 Mohammedia</wicri:noRegion></affiliation></author><author><name sortKey="Akssira, Mohamed" sort="Akssira, Mohamed" uniqKey="Akssira M" first="Mohamed" last="Akssira">Mohamed Akssira</name><affiliation wicri:level="1"><nlm:affiliation>Laboratoire de Chimie, Bioorganique et Analytique, URAC 22 pôle Répam, Université Hassan II Mohammedia-Casablanca, BP 146, 28800 Mohammedia, Morocco.</nlm:affiliation><country xml:lang="fr">Maroc</country><wicri:regionArea>Laboratoire de Chimie, Bioorganique et Analytique, URAC 22 pôle Répam, Université Hassan II Mohammedia-Casablanca, BP 146, 28800 Mohammedia</wicri:regionArea><wicri:noRegion>28800 Mohammedia</wicri:noRegion></affiliation></author><author><name sortKey="Troin, Yves" sort="Troin, Yves" uniqKey="Troin Y" first="Yves" last="Troin">Yves Troin</name><affiliation wicri:level="3"><nlm:affiliation>Clermont Université, ENSCCF, Laboratoire de Chimie des Hétérocycles et des Glucides, BP 10448, 63000 Clermont-Ferrand, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Clermont Université, ENSCCF, Laboratoire de Chimie des Hétérocycles et des Glucides, BP 10448, 63000 Clermont-Ferrand</wicri:regionArea><placeName><region type="region" nuts="2">Auvergne-Rhône-Alpes</region><region type="old region" nuts="2">Auvergne (région administrative)</region><settlement type="city">Clermont-Ferrand</settlement></placeName></affiliation></author><author><name sortKey="Guillaumet, Gerald" sort="Guillaumet, Gerald" uniqKey="Guillaumet G" first="Gérald" last="Guillaumet">Gérald Guillaumet</name><affiliation wicri:level="3"><nlm:affiliation>Univ Orleans, CNRS UMR 7311, Institut de Chimie Organique et Analytique, rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France. Electronic address: gerald.guillaumet@univ-orleans.fr.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Univ Orleans, CNRS UMR 7311, Institut de Chimie Organique et Analytique, rue de Chartres, BP 6759, 45067 Orléans Cedex 2</wicri:regionArea><placeName><region type="region" nuts="2">Centre-Val de Loire</region><region type="old region" nuts="2">Région Centre</region><settlement type="city">Orléans</settlement></placeName></affiliation></author><author><name sortKey="Routier, Sylvain" sort="Routier, Sylvain" uniqKey="Routier S" first="Sylvain" last="Routier">Sylvain Routier</name><affiliation wicri:level="3"><nlm:affiliation>Univ Orleans, CNRS UMR 7311, Institut de Chimie Organique et Analytique, rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France. Electronic address: sylvain.routier@univ-orleans.fr.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Univ Orleans, CNRS UMR 7311, Institut de Chimie Organique et Analytique, rue de Chartres, BP 6759, 45067 Orléans Cedex 2</wicri:regionArea><placeName><region type="region" nuts="2">Centre-Val de Loire</region><region type="old region" nuts="2">Région Centre</region><settlement type="city">Orléans</settlement></placeName></affiliation></author></analytic><series><title level="j">European journal of medicinal chemistry</title><idno type="eISSN">1768-3254</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Cell Line, Tumor (MeSH)</term><term>Cell Proliferation (drug effects)</term><term>Cyclin-Dependent Kinase 5 (antagonists & inhibitors)</term><term>Cyclin-Dependent Kinase 5 (metabolism)</term><term>Dose-Response Relationship, Drug (MeSH)</term><term>Glycogen Synthase Kinase 3 (antagonists & inhibitors)</term><term>Glycogen Synthase Kinase 3 (metabolism)</term><term>Humans (MeSH)</term><term>Isoindoles (chemical synthesis)</term><term>Isoindoles (chemistry)</term><term>Isoindoles (pharmacology)</term><term>Models, Molecular (MeSH)</term><term>Molecular Structure (MeSH)</term><term>Piperidines (chemical synthesis)</term><term>Piperidines (chemistry)</term><term>Piperidines (pharmacology)</term><term>Protein Kinase Inhibitors (chemical synthesis)</term><term>Protein Kinase Inhibitors (chemistry)</term><term>Protein Kinase Inhibitors (pharmacology)</term><term>Structure-Activity Relationship (MeSH)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Glycogen Synthase Kinase 3 (antagonistes et inhibiteurs)</term><term>Glycogen Synthase Kinase 3 (métabolisme)</term><term>Humains (MeSH)</term><term>Inhibiteurs de protéines kinases (composition chimique)</term><term>Inhibiteurs de protéines kinases (pharmacologie)</term><term>Inhibiteurs de protéines kinases (synthèse chimique)</term><term>Isoindoles (composition chimique)</term><term>Isoindoles (pharmacologie)</term><term>Isoindoles (synthèse chimique)</term><term>Kinase-5 cycline-dépendante (antagonistes et inhibiteurs)</term><term>Kinase-5 cycline-dépendante (métabolisme)</term><term>Lignée cellulaire tumorale (MeSH)</term><term>Modèles moléculaires (MeSH)</term><term>Pipéridines (composition chimique)</term><term>Pipéridines (pharmacologie)</term><term>Pipéridines (synthèse chimique)</term><term>Prolifération cellulaire (effets des médicaments et des substances chimiques)</term><term>Relation dose-effet des médicaments (MeSH)</term><term>Relation structure-activité (MeSH)</term><term>Structure moléculaire (MeSH)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Cyclin-Dependent Kinase 5</term><term>Glycogen Synthase Kinase 3</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Isoindoles</term><term>Piperidines</term><term>Protein Kinase Inhibitors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Isoindoles</term><term>Piperidines</term><term>Protein Kinase Inhibitors</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Glycogen Synthase Kinase 3</term><term>Kinase-5 cycline-dépendante</term></keywords><keywords scheme="MESH" qualifier="composition chimique" xml:lang="fr"><term>Inhibiteurs de protéines kinases</term><term>Isoindoles</term><term>Pipéridines</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Cell Proliferation</term></keywords><keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Prolifération cellulaire</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Cyclin-Dependent Kinase 5</term><term>Glycogen Synthase Kinase 3</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Glycogen Synthase Kinase 3</term><term>Kinase-5 cycline-dépendante</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Inhibiteurs de protéines kinases</term><term>Isoindoles</term><term>Pipéridines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Isoindoles</term><term>Piperidines</term><term>Protein Kinase Inhibitors</term></keywords><keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Inhibiteurs de protéines kinases</term><term>Isoindoles</term><term>Pipéridines</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Line, Tumor</term><term>Dose-Response Relationship, Drug</term><term>Humans</term><term>Models, Molecular</term><term>Molecular Structure</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Modèles moléculaires</term><term>Relation dose-effet des médicaments</term><term>Relation structure-activité</term><term>Structure moléculaire</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">An efficient synthetic strategy was developed to modulate the structure of the tetrahydropyridine isoindolone (Valmerin) skeleton. A library of more than 30 novel final structures was generated. Biological activities on CDK5 and GSK3 as well as cellular effects on cancer cell lines were measured for each novel compound. Additionally docking studies were performed to support medicinal chemistry efforts. A strong GSK3/CDK5 dual inhibitor (38, IC50 GSK3/CDK5 32/84 nM) was obtained. A set of highly selective GSK3 inhibitors was synthesized by fine-tuning structural modifications (29 IC50 GSK3/CDK5 32/320 nM). Antiproliferative effects on cells were correlated with the in vitro kinase activities and the best effects were obtained with lung and colon cell lines. </div></front></TEI><affiliations><list><country><li>France</li><li>Maroc</li></country><region><li>Auvergne (région administrative)</li><li>Auvergne-Rhône-Alpes</li><li>Centre-Val de Loire</li><li>Région Bretagne</li><li>Région Centre</li></region><settlement><li>Clermont-Ferrand</li><li>Orléans</li><li>Rennes</li><li>Roscoff</li></settlement></list><tree><country name="France"><region name="Centre-Val de Loire"><name sortKey="Boulahjar, Rajaa" sort="Boulahjar, Rajaa" uniqKey="Boulahjar R" first="Rajâa" last="Boulahjar">Rajâa Boulahjar</name></region><name sortKey="Bonnet, Pascal" sort="Bonnet, Pascal" uniqKey="Bonnet P" first="Pascal" last="Bonnet">Pascal Bonnet</name><name sortKey="Bourg, Stephane" sort="Bourg, Stephane" uniqKey="Bourg S" first="Stéphane" last="Bourg">Stéphane Bourg</name><name sortKey="Guguen Guillouzo, Christiane" sort="Guguen Guillouzo, Christiane" uniqKey="Guguen Guillouzo C" first="Christiane" last="Guguen-Guillouzo">Christiane Guguen-Guillouzo</name><name sortKey="Guillaumet, Gerald" sort="Guillaumet, Gerald" uniqKey="Guillaumet G" first="Gérald" last="Guillaumet">Gérald Guillaumet</name><name sortKey="Le Guevel, Remy" sort="Le Guevel, Remy" uniqKey="Le Guevel R" first="Rémy" last="Le Guevel">Rémy Le Guevel</name><name sortKey="Lozach, Olivier" sort="Lozach, Olivier" uniqKey="Lozach O" first="Olivier" last="Lozach">Olivier Lozach</name><name sortKey="Meijer, Laurent" sort="Meijer, Laurent" uniqKey="Meijer L" first="Laurent" last="Meijer">Laurent Meijer</name><name sortKey="Ouach, Aziz" sort="Ouach, Aziz" uniqKey="Ouach A" first="Aziz" last="Ouach">Aziz Ouach</name><name sortKey="Routier, Sylvain" sort="Routier, Sylvain" uniqKey="Routier S" first="Sylvain" last="Routier">Sylvain Routier</name><name sortKey="Troin, Yves" sort="Troin, Yves" uniqKey="Troin Y" first="Yves" last="Troin">Yves Troin</name></country><country name="Maroc"><noRegion><name sortKey="Lazar, Said" sort="Lazar, Said" uniqKey="Lazar S" first="Saïd" last="Lazar">Saïd Lazar</name></noRegion><name sortKey="Akssira, Mohamed" sort="Akssira, Mohamed" uniqKey="Akssira M" first="Mohamed" last="Akssira">Mohamed Akssira</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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