Advances in tetrahydropyrido[1,2-a]isoindolone (valmerins) series: Potent glycogen synthase kinase 3 and cyclin dependent kinase 5 inhibitors.

International audienceAn 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

Les sels d'onium à tâche spécifique (nouveaux supports (hydro-) solubles pour la synthèse organique)

Ce travail présente l'utilisation des liquides ioniques et de sels d'onium à tâche spécifique comme supports (hydro) solubles pour la synthèse organique supportée. après un préliminaire sur la synthèse organique supportée et un rappel sur la chimie des liquides ioniques, des sels d'onium à tâche spécifique ont été utilisés comme support soluble pour la réaction de baylis-hillman. Sont présentées ensuite la synthèse de sels d'onium à tâche spécifique et leur utilisation comme supports solubles en milieu aqueux, un acrylamide greffé sur un sel d'ammonium pour la réaction de michael et de heck et un aldéhyde supporté sur un chlorure d'ammonium pour la synthèse de tétrahydroquinoléines et de quinoléines ainsi que la réaction multi-composants de UGI. Au cours de ce travail, l accent est mis sur la possibilité de moduler les propriétés du sel d'onium à tâche spécifique en fonction des caractéristiques de stabilité et de solubilité souhaitées.RENNES1-BU Sciences Philo (352382102) / SudocSudocFranceF

Efficient Synthesis of the First N-Methyloxoarcyriaflavin Including an Original Central Seven-Membered Cycle

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Design of α\alpha7 nicotinic acetylcholine receptor ligands in quinuclidine, tropane and quinazoline series. Chemistry, molecular modeling, radiochemistry, in vitro and in rats evaluations of a [18^{18}F] quinuclidine derivative

International audienceIn this report, we describe the synthesis of a novel library of $\alpha$7 nAChR ligands based on the modulationof the quinuclidine, quinazoline and tropane moieties. Spirane derivatives were newly synthesized understereo specific 1,3 dipolar cylcoadditions. Only amide derivatives bonded efficiently to the receptor withKi measured between 14 and 133 nM. The best fluorinated candidate was selected and radiolabeled. Thepotent [$^{18}$F]4 PET tracer was evaluated in rats and its brain accumulation quantified

Novel optimization of valmerins (tetrahydropyrido[1,2-a]isoindolones) as potent dual CDK5/GSK3 inhibitors

International audienceAn 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 n

Novel Tetrahydropyrido[1,2-a]isoindolone Derivatives (Valmerins): Potent Cyclin-Dependent Kinase/Glycogen Synthase Kinase 3 Inhibitors with Antiproliferative Activities and Antitumor Effects in Human Tumor Xenografts

International audienceThe development of CDK and GSK3 inhibitors has been regarded as a potential therapeutic approach, and a substantial number of diverse structures have been reported to inhibit CDKs and GSK-3β in recent years. Only a few molecules have gone through or are currently undergoing clinical trials as CDK and GSK inhibitors. In this paper, we prepared valmerins, a new family containing the tetrahydropyrido[1,2-a]isoindone core. The fused heterocycle was prepared with a straightforward synthesis that was functionalized by a (het)arylurea. Twelve valmerins inhibited the CDK5 and GSK3 with an IC50 < 100 nM. A semiquantitative kinase scoring was realized, and a cellular screening was done. At the end of our study, we investigated the in vivo potency of one valmerin. Mice exhibited good tolerance to our lead, which proved its efficacy and clearly blocked tumor growth. Valmerins appear also as good candidates for further development as anticancer agents

Bis(het)aryl-1,2,3-triazole quinuclidines as α7 nicotinic acetylcholine receptor ligands: Synthesis, structure affinity relationships, agonism activity, [18F]-radiolabeling and PET study in rats

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