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Hedou D.,INSA Rouen | Dubouilh-Benard C.,INSA Rouen | Loaec N.,Protein Phosphorylation and Human Disease Group | Fruit C.,INSA Rouen | Besson T.,INSA Rouen
Molecules | Year: 2016

A library of thirty eight novel thiazolo[5,4-f ]quinazolin-9(8H)-one derivatives (series 8, 10, 14 and 17) was prepared via the Hügershoff reaction and a Cu catalyzed intramolecular C-S bond formation, helped by microwave-assisted technology when required. The efficient multistep synthesis of the key 6-amino-3-cyclopropylquinazolin-4(3H)-one (3) has been reinvestigated and performed on a multigram scale from the starting 5-nitroanthranilic acid. The inhibitory potency of the final products was evaluated against five kinases involved in Alzheimer's disease and showed that some molecules of the 17 series described in this paper are particularly promising for the development of novel multi-target inhibitors of kinases. © 2016 by the authors; licensee MDPI.


Loidreau Y.,University of Rouen | Marchand P.,University of Nantes | Dubouilh-Benard C.,University of Rouen | Nourrisson M.-R.,University of Nantes | And 3 more authors.
European Journal of Medicinal Chemistry | Year: 2013

Novel N-aryl-7-methoxybenzo[b]furo[3,2-d]pyrimidin-4-amines (1) and their N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amine analogues (2) were designed and prepared for the first time via microwave-accelerated multi-step synthesis. Various anilines were condensed with N′-(2-cyanaryl)-N,N- dimethylformimidamide intermediates obtained by reaction of 3-amino-6- methoxybenzofuran-2-carbonitrile (3) and 3-amino-6-methoxybenzothiophene-2- carbonitrile (4) precursors with dimethylformamide dimethylacetal. The inhibitory potency of the final products against five protein kinases (CDK5/p25, CK1δ/ε, GSK3α/β, DYRK1A and CLK1) was estimated. Compounds (2a-z) turned out to be particularly promising for the development of new pharmacological dual inhibitors of CLK1 and DYRK1A kinases.© 2012 Elsevier Masson SAS. All rights reserved.


Waiker D.K.,Rajiv Gandhi Technical University | Karthikeyan C.,Rajiv Gandhi Technical University | Poongavanam V.,University of Southern Denmark | Kongsted J.,University of Southern Denmark | And 3 more authors.
Bioorganic and Medicinal Chemistry | Year: 2014

A series of novel 4-anilinoquinazoline derivatives (3a-3j) has been synthesized and evaluated as potential inhibitors for protein kinases implicated in Alzheimer's disease. Among all the synthesized compounds, compound 3e (N-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazolin-4-amine) exhibited the most potent inhibitory activity against CLK1 and GSK-3α/β kinase with IC50 values of 1.5 μM and 3 μM, respectively. Docking studies were performed to elucidate the binding mode of the compounds to the active site of CLK1 and GSK-3β. The results of our study suggest that compound 3e may serve as a valuable template for the design and development of dual inhibitors of CLK1 and GSK-3α/β enzymes with potential therapeutic application in Alzheimer's disease. © 2014 Elsevier Ltd. All rights reserved.


Loidreau Y.,University of Rouen | Marchand P.,University of Nantes | Dubouilh-Benard C.,University of Rouen | Nourrisson M.-R.,University of Nantes | And 4 more authors.
European Journal of Medicinal Chemistry | Year: 2012

A useful and rapid access to libraries of N-arylbenzo[b]thieno[3,2-d] pyrimidin-4-amines and their pyrido and pyrazino analogues was designed and optimized for the first time via microwave-accelerated condensation and Dimroth rearrangement of the starting anilines with N′-(2-cyanoaryl)-N,N- dimethylformimidamides obtained by reaction of thiophene precursors with dimethylformamide dimethylacetal. The inhibitory potency of the final products against five protein kinases (CDK5/p25, CK1δ/ε, GSK3α/β, DYRK1A and CLK1) was estimated. N-arylpyrido[3′,2′:4,5]thieno[3,2-d] pyrimidin-4-amine series of compounds (4a-j) turned out to be particularly promising for the development of new pharmacological inhibitors of CK1 and CLK1 kinases. © 2012 Elsevier Masson SAS. All rights reserved.


Norez C.,University of Poitiers | Vandebrouck C.,University of Poitiers | Bertrand J.,University of Poitiers | Noel S.,University of Poitiers | And 7 more authors.
British Journal of Pharmacology | Year: 2014

Background and Purpose The most common mutation in cystic fibrosis (CF), F508del, causes defects in trafficking, channel gating and endocytosis of the CF transmembrane conductance regulator (CFTR) protein. Because CF is an orphan disease, therapeutic strategies aimed at improving mutant CFTR functions are needed to target the root cause of CF.Experimental Approach Human CF airway epithelial cells were treated with roscovitine 100 ìM for 2 h before CFTR maturation, expression and activity were examined. The mechanism of action of roscovitine was explored by recording the effect of depleting endoplasmic reticulum (ER) Ca2+ on the F508del-CFTR/calnexin interaction and by measuring proteasome activity.Key Results Of the cyclin-dependent kinase (CDK) inhibitors investigated, roscovitine was found to restore the cell surface expression and defective channel function of F508del-CFTR in human CF airway epithelial cells. Neither olomoucine nor (S)-CR8, two very efficient CDK inhibitors, corrected F508del-CFTR trafficking demonstrating that the correcting effect of roscovitine was independent of CDK inhibition. Competition studies with inhibitors of the ER quality control (ERQC) indicated that roscovitine acts on the calnexin pathway and on the degradation machinery. Roscovitine was shown (i) to partially inhibit the interaction between F508del-CFTR and calnexin by depleting ER Ca2+ and (ii) to directly inhibit the proteasome activity in a Ca2+-independent manner.Conclusions and Implications Roscovitine is able to correct the defective function of F508del-CFTR by preventing the ability of the ERQC to interact with and degrade F508del-CFTR via two synergistic but CDK-independent mechanisms. Roscovitine has potential as a pharmacological therapy for CF. © 2014 The British Pharmacological Society.


Bettayeb K.,Protein Phosphorylation and Human Disease Group | Bettayeb K.,Rockefeller University | Baunbaek D.,Protein Phosphorylation and Human Disease Group | Delehouze C.,Protein Phosphorylation and Human Disease Group | And 10 more authors.
Genes and Cancer | Year: 2010

Neuroblastoma (NB), the most frequent extracranial solid tumor of children accounting for nearly 15% of all childhood cancer mortality, displays overexpression of antiapoptotic Bcl-2 and Mcl-1 in aggressive forms of the disease. The clinical phase 2 drug roscovitine (CYC202, seliciclib), a relatively selective inhibitor of cyclin-dependent kinases (CDKs), and CR8, a recently developed and more potent analog, induce concentration-dependent apoptotic cell death of NB cells (average IC50 values: 24.2 μM and 0.4 μM for roscovitine and CR8, respectively). Both roscovitine and CR8 trigger rapid downregulation of the short-lived survival factor Mcl-1 in the 9 investigated human NB cell lines. This effect was further analyzed in the human SH-SY5Y NB cell line. Down-regulation of Mcl-1 appears to depend on inhibition of CDKs rather than on interaction of roscovitine and CR8 with their secondary targets. CR8 is an adenosine triphosphate-competitive inhibitor of CDK9, and the structure of a CDK9/cyclin T/CR8 complex is described. Mcl-1 downregulation occurs both at the mRNA and protein levels. This effect can be accounted for by a reduction in Mcl-1 protein synthesis, under stable Mcl-1 degradation conditions. Mcl-1 down-regulation is accompanied by a transient increase in free Noxa, a proapoptotic factor. Mcl-1 down-regulation occurs independently of the presence or up-regulation of p53 and of the MYCN status. Taken together, these results suggest that the clinical drug roscovitine and its novel analog CR8 induce apoptotic tumor cell death by down-regulating Mcl-1, a key survival factor expressed in all NB cell lines. CDK inhibition may thus constitute a new approach to treat refractory high-risk NB. © The Author(s) 2010.


Hedou D.,CNRS Organic Chemistry, Bioorganic Chemistry: Reactivity and Analysis | Godeau J.,CNRS Organic Chemistry, Bioorganic Chemistry: Reactivity and Analysis | Loaec N.,Protein Phosphorylation and Human Disease Group | Fruit C.,CNRS Organic Chemistry, Bioorganic Chemistry: Reactivity and Analysis | Besson T.,CNRS Organic Chemistry, Bioorganic Chemistry: Reactivity and Analysis
Molecules | Year: 2016

A library of thirty novel thiazolo[5,4-f]quinazolin-9(8H)-one derivatives belonging to four series designated as 12, 13, 14 and 15 was efficiently prepared, helped by microwave-assisted technology when required. The efficient multistep synthesis of methyl 6-amino-2-cyano-benzo[d] thiazole-7-carboxylate (1) has been reinvestigated and performed on a multigram scale. The inhibitory potency of the final products against five kinases involved in Alzheimer's disease was evaluated. This study demonstrates that some molecules of the 12 and 13 series described in this paper are particularly promising for the development of new multi-target inhibitors of kinases. © 2016 by the authors; licensee MDPI.


Sliman F.,University Paris - Sud | Blairvacq M.,Protein Phosphorylation and Human Disease Group | Durieu E.,Protein Phosphorylation and Human Disease Group | Meijer L.,Protein Phosphorylation and Human Disease Group | And 2 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

Pim-1 kinase is a cytoplasmic serine/threonine kinase that controls programmed cell death by phosphorylating substrates that regulate both apotosis and cellular metabolism. A series of 2-styrylquinolines and quinoline-2-carboxamides has been identified as potent inhibitors of the Pim-1 kinase. The 8-hydroxy-quinoline 7-carboxylic acid moiety appeared to be a crucial pharmacophore for activity. Molecular modeling indicated that interaction of this scaffold with Asp186 and Lys67 residues within the ATP-binding pocket might be responsible for the kinase inhibitory potency. © 2010 Elsevier Ltd. All rights reserved.


Debray J.,CNRS Molecular Pharmacochemistry Department | Bonte S.,CNRS Molecular Pharmacochemistry Department | Lozach O.,Protein Phosphorylation and Human Disease Group | Meijer L.,Protein Phosphorylation and Human Disease Group | Demeunynck M.,CNRS Molecular Pharmacochemistry Department
Molecular Diversity | Year: 2012

A small library of heterocycle-fused quinazolin-4-ones was prepared and evaluated as kinase inhibitors. The key step of the two-step process involves the environmental friendly thermolysis of N-ethoxycarbonyl-N′-(hetero) arylguanidines at 130 C in water. The cyclization is fully regioselective. The most active molecules, 7-(2-hydroxyethylamino)- and 7-(3-hydroxypropylamino)- pyrazolo[4,3-f]quinazolin-9-ones, inhibit DYRK1A and CLK1 at submicromolar concentrations, indicating the potential interest of this new heterocycle in drug design. © 2012 Springer Science+Business Media B.V.


PubMed | Protein Phosphorylation and Human Disease Group, University of Southern Denmark and Rajiv Gandhi Technical University
Type: Journal Article | Journal: Bioorganic & medicinal chemistry | Year: 2014

A series of novel 4-anilinoquinazoline derivatives (3a-3j) has been synthesized and evaluated as potential inhibitors for protein kinases implicated in Alzheimers disease. Among all the synthesized compounds, compound 3e (N-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazolin-4-amine) exhibited the most potent inhibitory activity against CLK1 and GSK-3/ kinase with IC values of 1.5 M and 3 M, respectively. Docking studies were performed to elucidate the binding mode of the compounds to the active site of CLK1 and GSK-3. The results of our study suggest that compound 3e may serve as a valuable template for the design and development of dual inhibitors of CLK1 and GSK-3/ enzymes with potential therapeutic application in Alzheimers disease.

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