A5062604061- Cancer-related Molecular Pathways
- Synthesis and Biological Evaluation
- Synthesis and Reactivity of Heterocycles
- Cancer therapeutics and mechanisms
- Quinazolinone synthesis and applications
- Microtubule and mitosis dynamics
- Bioactive Compounds and Antitumor Agents
- Synthesis and Characterization of Heterocyclic Compounds
- Synthesis and biological activity
- Chemical Synthesis and Analysis
- Synthesis and bioactivity of alkaloids
- 14-3-3 protein interactions
- RNA Interference and Gene Delivery
- Marine Sponges and Natural Products
- Microbial Natural Products and Biosynthesis
- Advanced biosensing and bioanalysis techniques
- Cancer Mechanisms and Therapy
- Synthesis of Organic Compounds
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Synthetic Organic Chemistry Methods
- Synthesis and pharmacology of benzodiazepine derivatives
- Synthesis of heterocyclic compounds
- Synthesis and Reactions of Organic Compounds
- Carbohydrate Chemistry and Synthesis
Station Biologique de Roscoff
2009-2021
Centre National de la Recherche Scientifique
2009-2019
Université de Bretagne Occidentale
2016-2019
Laboratoire Chimie Electrochimie Moléculaires et Chimie Analytique
2016-2019
Université de Rennes
2009-2016
Laboratoire de Mathématiques d'Orsay
2016
Sorbonne Université
2015
Centre Oscar Lambret
2012
Bioénergétique et Ingénierie des Protéines
2011
Technische Universität Braunschweig
2008
(R)-Roscovitine (CYC202) is often referred to as a "selective inhibitor of cyclin-dependent kinases." Besides its use biological tool in cell cycle, neuronal functions, and apoptosis studies, it currently evaluated potential drug treat cancers, neurodegenerative diseases, viral infections, glomerulonephritis. We have investigated the selectivity (R)-roscovitine using three different methods: 1) testing on wide panel purified kinases that, along with previously published data, now reaches 151...
We report the synthesis and biological characterization of 3-(pyrimidin-4-yl)-7-azaindoles (meriolins), a chemical hybrid between natural products meridianins variolins, derived from marine organisms. Meriolins display potent inhibitory activities toward cyclin-dependent kinases (CDKs) and, to lesser extent, other (GSK-3, DYRK1A). The crystal structures 1e (meriolin 5) variolin B (Bettayeb, K.; Tirado, O. M.; Marionneau-Lambert, S.; Ferandin, Y.; Lozach, O.; Morris, J.; Mateo-Lozano,...
Lamellarins, a family of hexacyclic pyrrole alkaloids originally isolated from marine invertebrates, display promising anti-tumor activity. They induce apoptotic cell death through multi-target mechanisms, including inhibition topoisomerase I, interaction with DNA and direct effects on mitochondria. We here report that lamellarins inhibit several protein kinases relevant to cancer such as cyclin-dependent kinases, dualspecificity tyrosine phosphorylation activated kinase 1A, casein 1,...
We here report on the synthesis, optimization, and biological characterization of leucettines, a family kinase inhibitors derived from marine sponge leucettamine B. Stepwise synthesis analogues starting natural structure, guided by activity testing eight purified kinases, led to highly potent CLKs DYRKs, two families kinases involved in alternative pre-mRNA splicing Alzheimer's disease/Down syndrome. Leucettine L41 was cocrystallized with CLK3. It interacts key residues located within...
The protein kinase DYRK1A has been suggested to act as one of the intracellular regulators contributing neurological alterations found in individuals with Down syndrome. For an assessment role DYRK1A, selective synthetic inhibitors are valuable pharmacological tools. However, described literature so far either not sufficiently or have tested against closely related kinases from DYRK and CLK families. aim this study was identification exhibiting selectivity versus structurally functionally...
Glycogen synthase kinase -3 (GSK-3) is a key enzyme involved in numerous physiological events and major diseases, such as Alzheimer's disease, diabetes, cardiac hypertrophy. Indirubins are bis-indoles that can be generated from various natural sources or chemically synthesized. While rather potent selective GSK-3 inhibitors, most indirubins exhibit low water solubility. To address the issue of solubility, we have designed novel analogues 6-bromo-indirubin-3′-oxime with increased...
Abstract Protein kinases represent promising anticancer drug targets. We describe here the meriolins, a new family of inhibitors cyclin-dependent (CDK). Meriolins chemical structural hybrid between meridianins and variolins, two families kinase extracted from various marine invertebrates. Variolin B is currently in preclinical evaluation as an antitumor agent. A selectivity study done on 32 showed that, compared with variolin B, meriolins display enhanced specificity toward CDKs, marked...
The synthesis of new meridianin derivatives is described. indolic ring system was substituted at the C-4 to C-7 positions either by a bromine atom or nitro amino groups. Additionally, an iodine various aryl groups were introduced C-5 position 2-aminopyrimidine ring. These compounds as well some their synthetic intermediates tested for kinase inhibitory potencies and in vitro antiproliferative activities. We found that this series particularly interesting development inhibitors DYRK1A CLK1...
Novel 2-benzylidene-benzofuran-3-ones were designed and synthesized to mimic flavopiridol, a well-established inhibitor of cyclin-dependent kinases (CDKs) which is currently undergoing clinical evaluation. The underlying design concepts as well the synthesis structure−activity relationships (CDKs 1, 2, 4 enzyme assays) these mimics are described. Inhibitors CDKs 1 2 that more potent selective than flavopiridol obtained.
We here report the synthesis and biological evaluation of new phenylcarbazole derivatives designed as potential anticancer agents. Indole hydroxyindole were used to generate three scaffolds that successively exploited introduce various substituents on maleimide moiety. The includes a final intramolecular key Heck-type reaction, which was carried out with triflate derivative or bromophenyl derivative. Each step optimized complete chemical strategy is detailed. Several compounds showed marked...
Recently, the serine/threonine kinase glycogen synthase kinase-3 (GSK-3) emerged as a regulator of pancreatic β cell growth and survival. On basis previous observation that GSK-3 inhibitors like 1-azakenpaullone promote protection replication, paullone derivatives were synthesized including 1-aza-, 2-aza-, 12-oxapaullone scaffolds. In enzymatic assays distinct 1-azapaullones found to exhibit selective inhibitory activity. Within series 1-azapaullones, three stimulated INS-1E replication...
DYRK kinases are involved in alternative pre-mRNA splicing as well neuropathological states such Alzheimer's disease and Down syndrome. In this study, we present the design, synthesis, biological evaluation of indirubins inhibitors with enhanced selectivity. Modifications bis-indole included polar or acidic functionalities at positions 5' 6' a bromine trifluoromethyl group position 7, affording analogues that possess high activity pronounced specificity. Compound 6i carrying 5'-carboxylate...
The total synthesis of the optically active (aR)- and (aS)-16-methyllamellarins N (3a 3b) was achieved via resolution on HPLC chiral stationary phase. kinase inhibitory activities both enantiomers were evaluated eight protein kinases relevant to cancer neurodegenerative diseases (CDK1/cyclin B, CDK2/cyclin A, CDK5/p25, GSK-3α/β, PIM1, DYRK1A, CLK3, CK1). Isomer (aR)-3b exhibited potent but nonselective inhibition all except CK1, while (aS)-3a selectively inhibited only DYRK1A. different...
Two new acridone alkaloids, chlorospermines A and B (1 2), were isolated from the stem bark of Glycosmis chlorosperma, together with known atalaphyllidine (3) acrifoline (4), by means bioguided isolation using an in vitro enzyme assay against DYRK1A. Acrifoline (4) to a lesser extent chlorospermine (2) showed significant inhibiting activity on DYRK1A IC50's 0.075, 5.7, 2.2 μM, respectively. Their selectivity profile was evaluated panel various kinases, molecular docking calculations provided...
Indirubins are kinase inhibitory bis-indoles that can be generated from various plant, mollusk, mammalian, and bacterial sources or chemically synthesized. We here report on the synthesis biological evaluation of 3'-substituted 7-halogenoindirubins. Molecular modeling assays suggest steric hindrance prevents 7-halogenoindirubins interacting with classical targets other indirubins such as cyclin-dependent kinases glycogen synthase kinase-3. Surprisingly induce cell death in a diversity human...