Novel optimization of valmerins (tetrahydropyrido[1,2-a]isoindolones) as potent dual CDK5/GSK3 inhibitors.
Identifieur interne : 000320 ( Main/Exploration ); précédent : 000319; suivant : 000321Novel optimization of valmerins (tetrahydropyrido[1,2-a]isoindolones) as potent dual CDK5/GSK3 inhibitors.
Auteurs : Aziz Ouach [France] ; Rajâa Boulahjar [France] ; Christine Vala [France] ; Stéphane Bourg [France] ; Pascal Bonnet [France] ; Christiane Guguen-Guillouzo [France] ; Myriam Ravache [France] ; Rémy Le Guevel [France] ; Olivier Lozach [France] ; Saïd Lazar [Maroc] ; Yves Troin [France] ; Laurent Meijer [France] ; Sandrine Ruchaud [France] ; Mohamed Akssira [Maroc] ; Gérald Guillaumet [France] ; Sylvain Routier [France]Source :
- European journal of medicinal chemistry [ 1768-3254 ] ; 2016.
Descripteurs français
- KwdFr :
- MESH :
- antagonistes et inhibiteurs : Glycogen synthase kinase 3 beta, Kinase-5 cycline-dépendante.
- composition chimique : Antienzymes.
- pharmacologie : Antienzymes, Indoles.
- Humains, Lignée cellulaire tumorale, Relation structure-activité.
English descriptors
- KwdEn :
- MESH :
- chemical , antagonists & inhibitors : Cyclin-Dependent Kinase 5, Glycogen Synthase Kinase 3 beta.
- chemical , chemistry : Enzyme Inhibitors.
- chemical , pharmacology : Enzyme Inhibitors, Indoles.
- Cell Line, Tumor, Humans, Structure-Activity Relationship.
Abstract
An efficient synthetic strategy able to modulate the structure of the tetrahydropyridine isoindolone (Valmerin) skeleton was developed. 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 to support the SAR, a docking study was performed. A potent GSK3/CDK5 dual inhibitor (37, IC50 CDK5/GSK3 35/7 nM) was obtained. Best antiproliferative effects were obtained on lung and prostate cell lines with IC50 = 20 nM.
DOI: 10.1016/j.ejmech.2016.02.072
PubMed: 27019296
Affiliations:
- France, Maroc
- Auvergne (région administrative), Auvergne-Rhône-Alpes, Centre-Val de Loire, Région Bretagne, Région Centre
- Clermont-Ferrand, Orléans, Rennes, Roscoff
- Université d'Orléans
Links toward previous steps (curation, corpus...)
- to stream PubMed, to step Corpus: 000496
- to stream PubMed, to step Curation: 000494
- to stream PubMed, to step Checkpoint: 000472
- to stream Main, to step Merge: 000320
- to stream Main, to step Curation: 000320
Le document en format XML
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Ravache</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 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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="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, B.P. 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, B.P. 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="Ruchaud, Sandrine" sort="Ruchaud, Sandrine" uniqKey="Ruchaud S" first="Sandrine" last="Ruchaud">Sandrine Ruchaud</name><affiliation wicri:level="3"><nlm:affiliation>C.N.R.S., 'Protein Phosphorylation & Human Disease' Group, USR3151, Station Biologique, B.P. 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, B.P. 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="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>Mohammedia</wicri:noRegion></affiliation></author><author><name sortKey="Guillaumet, Gerald" sort="Guillaumet, Gerald" uniqKey="Guillaumet G" first="Gérald" last="Guillaumet">Gérald Guillaumet</name><affiliation wicri:level="4"><nlm:affiliation>Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, 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>Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, 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><orgName type="university">Université d'Orléans</orgName></affiliation></author><author><name sortKey="Routier, Sylvain" sort="Routier, Sylvain" uniqKey="Routier S" first="Sylvain" last="Routier">Sylvain Routier</name><affiliation wicri:level="4"><nlm:affiliation>Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, 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>Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, 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><orgName type="university">Université d'Orléans</orgName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2016">2016</date><idno type="RBID">pubmed:27019296</idno><idno type="pmid">27019296</idno><idno type="doi">10.1016/j.ejmech.2016.02.072</idno><idno type="wicri:Area/PubMed/Corpus">000496</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000496</idno><idno type="wicri:Area/PubMed/Curation">000494</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000494</idno><idno type="wicri:Area/PubMed/Checkpoint">000472</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000472</idno><idno type="wicri:Area/Main/Merge">000320</idno><idno type="wicri:Area/Main/Curation">000320</idno><idno type="wicri:Area/Main/Exploration">000320</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Novel optimization of valmerins (tetrahydropyrido[1,2-a]isoindolones) as potent dual CDK5/GSK3 inhibitors.</title><author><name sortKey="Ouach, Aziz" sort="Ouach, Aziz" uniqKey="Ouach A" first="Aziz" last="Ouach">Aziz Ouach</name><affiliation wicri:level="4"><nlm:affiliation>Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, Rue de Chartres, BP 6759, 45067, Orléans Cedex 2, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, 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><orgName type="university">Université d'Orléans</orgName></affiliation></author><author><name sortKey="Boulahjar, Rajaa" sort="Boulahjar, Rajaa" uniqKey="Boulahjar R" first="Rajâa" last="Boulahjar">Rajâa Boulahjar</name><affiliation wicri:level="4"><nlm:affiliation>Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, Rue de Chartres, BP 6759, 45067, Orléans Cedex 2, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, 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><orgName type="university">Université d'Orléans</orgName></affiliation></author><author><name sortKey="Vala, Christine" sort="Vala, Christine" uniqKey="Vala C" first="Christine" last="Vala">Christine Vala</name><affiliation wicri:level="4"><nlm:affiliation>Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, Rue de Chartres, BP 6759, 45067, Orléans Cedex 2, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, 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><orgName type="university">Université d'Orléans</orgName></affiliation></author><author><name sortKey="Bourg, Stephane" sort="Bourg, Stephane" uniqKey="Bourg S" first="Stéphane" last="Bourg">Stéphane Bourg</name><affiliation wicri:level="4"><nlm:affiliation>Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, Rue de Chartres, BP 6759, 45067, Orléans Cedex 2, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, 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><orgName type="university">Université d'Orléans</orgName></affiliation></author><author><name sortKey="Bonnet, Pascal" sort="Bonnet, Pascal" uniqKey="Bonnet P" first="Pascal" last="Bonnet">Pascal Bonnet</name><affiliation wicri:level="4"><nlm:affiliation>Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, Rue de Chartres, BP 6759, 45067, Orléans Cedex 2, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, 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><orgName type="university">Université d'Orléans</orgName></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="Ravache, Myriam" sort="Ravache, Myriam" uniqKey="Ravache M" first="Myriam" last="Ravache">Myriam Ravache</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="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, B.P. 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, B.P. 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="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>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>Université Clermont Auvergne, Sigma-Clermont, Institut de Chimie de Clermont-Ferrand, UMR CNRS 6296, BP 10448, F-63000, Clermont-Ferrand, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Université Clermont Auvergne, Sigma-Clermont, Institut de Chimie de Clermont-Ferrand, UMR CNRS 6296, BP 10448, F-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="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, B.P. 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, B.P. 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="Ruchaud, Sandrine" sort="Ruchaud, Sandrine" uniqKey="Ruchaud S" first="Sandrine" last="Ruchaud">Sandrine Ruchaud</name><affiliation wicri:level="3"><nlm:affiliation>C.N.R.S., 'Protein Phosphorylation & Human Disease' Group, USR3151, Station Biologique, B.P. 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, B.P. 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="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>Mohammedia</wicri:noRegion></affiliation></author><author><name sortKey="Guillaumet, Gerald" sort="Guillaumet, Gerald" uniqKey="Guillaumet G" first="Gérald" last="Guillaumet">Gérald Guillaumet</name><affiliation wicri:level="4"><nlm:affiliation>Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, 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>Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, 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><orgName type="university">Université d'Orléans</orgName></affiliation></author><author><name sortKey="Routier, Sylvain" sort="Routier, Sylvain" uniqKey="Routier S" first="Sylvain" last="Routier">Sylvain Routier</name><affiliation wicri:level="4"><nlm:affiliation>Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, 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>Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, 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><orgName type="university">Université d'Orléans</orgName></affiliation></author></analytic><series><title level="j">European journal of medicinal chemistry</title><idno type="eISSN">1768-3254</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Cell Line, Tumor (MeSH)</term><term>Cyclin-Dependent Kinase 5 (antagonists & inhibitors)</term><term>Enzyme Inhibitors (chemistry)</term><term>Enzyme Inhibitors (pharmacology)</term><term>Glycogen Synthase Kinase 3 beta (antagonists & inhibitors)</term><term>Humans (MeSH)</term><term>Indoles (pharmacology)</term><term>Structure-Activity Relationship (MeSH)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Antienzymes (composition chimique)</term><term>Antienzymes (pharmacologie)</term><term>Glycogen synthase kinase 3 beta (antagonistes et inhibiteurs)</term><term>Humains (MeSH)</term><term>Indoles (pharmacologie)</term><term>Kinase-5 cycline-dépendante (antagonistes et inhibiteurs)</term><term>Lignée cellulaire tumorale (MeSH)</term><term>Relation structure-activité (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 beta</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Enzyme Inhibitors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Enzyme Inhibitors</term><term>Indoles</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Glycogen synthase kinase 3 beta</term><term>Kinase-5 cycline-dépendante</term></keywords><keywords scheme="MESH" qualifier="composition chimique" xml:lang="fr"><term>Antienzymes</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antienzymes</term><term>Indoles</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Line, Tumor</term><term>Humans</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Relation structure-activité</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">An efficient synthetic strategy able to modulate the structure of the tetrahydropyridine isoindolone (Valmerin) skeleton was developed. 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 to support the SAR, a docking study was performed. A potent GSK3/CDK5 dual inhibitor (37, IC50 CDK5/GSK3 35/7 nM) was obtained. Best antiproliferative effects were obtained on lung and prostate cell lines with IC50 = 20 nM.</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><orgName><li>Université d'Orléans</li></orgName></list><tree><country name="France"><region name="Centre-Val de Loire"><name sortKey="Ouach, Aziz" sort="Ouach, Aziz" uniqKey="Ouach A" first="Aziz" last="Ouach">Aziz Ouach</name></region><name sortKey="Bonnet, Pascal" sort="Bonnet, Pascal" uniqKey="Bonnet P" first="Pascal" last="Bonnet">Pascal Bonnet</name><name sortKey="Boulahjar, Rajaa" sort="Boulahjar, Rajaa" uniqKey="Boulahjar R" first="Rajâa" last="Boulahjar">Rajâa Boulahjar</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="Ravache, Myriam" sort="Ravache, Myriam" uniqKey="Ravache M" first="Myriam" last="Ravache">Myriam Ravache</name><name sortKey="Routier, Sylvain" sort="Routier, Sylvain" uniqKey="Routier S" first="Sylvain" last="Routier">Sylvain Routier</name><name sortKey="Ruchaud, Sandrine" sort="Ruchaud, Sandrine" uniqKey="Ruchaud S" first="Sandrine" last="Ruchaud">Sandrine Ruchaud</name><name sortKey="Troin, Yves" sort="Troin, Yves" uniqKey="Troin Y" first="Yves" last="Troin">Yves Troin</name><name sortKey="Vala, Christine" sort="Vala, Christine" uniqKey="Vala C" first="Christine" last="Vala">Christine Vala</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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