- Structure-Activity Relationship in the Leucettine Family of Kinase Inhibitors
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The protein kinase DYRK1A is involved in Alzheimer's disease, Down syndrome, diabetes, viral infections, and leukemia. Leucettines, a family of 2-aminoimidazolin-4-ones derived from the marine sponge alkaloid Leucettamine B, have been developed as pharmacological inhibitors of DYRKs (dual specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases). We report here on the synthesis and structure-activity relationship (SAR) of 68 Leucettines. Leucettines were tested on 11 purified kinases and in 5 cellular assays: (1) CLK1 pre-mRNA splicing, (2) Threonine-212-Tau phosphorylation, (3) glutamate-induced cell death, (4) autophagy and (5) antagonism of ligand-activated cannabinoid receptor CB1. The Leucettine SAR observed for DYRK1A is essentially identical for CLK1, CLK4, DYRK1B, and DYRK2. DYRK3 and CLK3 are less sensitive to Leucettines. In contrast, the cellular SAR highlights correlations between inhibition of specific kinase targets and some but not all cellular effects. Leucettines deserve further development as potential therapeutics against various diseases on the basis of their molecular targets and cellular effects.
- Ahn, Kwang H.,Bazureau, Jean-Pierre,Burgy, Guillaume,Deau, Emmanuel,Durieu, Emilie,Fant, Xavier,Herault, Yann,Kendall, Debra A.,Khurana, Leepakshi,L'Helgoual'Ch, Jean-Martial,Limanton, Emmanuelle,Lindberg, Mattias F.,Meijer, Laurent,Nguyen, Thu Lan,Roche, Didier,Tahtouh, Tania,Bruyère, Céline,Carreaux, Fran?ois,Guiheneuf, Solène,Miege, Frédéric,Sévère, Elodie,Villiers, Beno?t
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supporting information
(2022/01/03)
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- Sulfenyl Ynamides in Gold Catalysis: Synthesis of Oxo-functionalised 4-aminoimidazolyl Fused Compounds by Intermolecular Annulation Reactions
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Functionalised N-heterocyclic pyridinium N-aminides have been designed and synthesised to evaluate a nitrenoid-based annulation strategy into imidazole-fused oxo-substituted frameworks of importance to medicinal and agrochemical discovery programmes. Sulfenyl substituted ynamides were identified as privileged reactants affording productive gold-catalysed annulation reactions with these and other nitrenoids. This annulation method provides selective and efficient access into geminally amino-sulfenyl substituted nitrogen heterocycles under mild reaction conditions. (Figure presented.).
- Arce, Elsa M.,Lamont, Scott G.,Davies, Paul W.
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supporting information
p. 2503 - 2509
(2020/04/30)
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- Sulfated and Oxygenated Imidazoline Derivatives: Synthesis, Antioxidant Activity and Light-Mediated Antibacterial Activity
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Imidazoline derivatives with different exocyclic substituents were simply prepared from common starting materials. The procedures were carried out in an eco-friendly manner. The antioxidant activity of these derivatives was explored by different experimental assays, such as ABTS.+ and DPPH. scavenging assay, as well as reducing power assay. The structural differences are discussed in terms of the results. Sulfur analogs showed higher antioxidant activity than their oxygenated counterparts. The same tendency was observed in microbiological studies, in which the same imidazoline compounds were assayed for light-mediated activity against of Staphylococcus aureus and Escherichia coli strains. A light-enhanced activity was observed for almost all the sulfated imidazolines after exposure to UV-A (400-320 nm) light.
- Alves Borges Leal, Antonio L.,Barreto, Humberto M.,Faillace, Martín S.,Muratori da Costa, Luciana,Peláez, Walter J.,Silva, Ana P.
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- Evaluation of michael-type acceptor reactivity of 5-benzylidenebarbiturates, 5-benzylidenerhodanines, and related heterocycles using NMR
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Despite existing experimental and computational tools to assess the risk, the non-specific chemical modification of protein thiol groups remains a significant source of false-positive hits, particularly in academic drug discovery. Herein, we describe the
- Arsovska, Emilija,Trontelj, Jurij,Zidar, Nace,Tomai, Tihomir,Mai, Lucija Peterlin,Kikelj, Danijel,Plavec, Janez,Zega, Anamarija
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p. 637 - 644
(2014/12/11)
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- Bicyclic imidazole-4-one derivatives: A new class of antagonists for the orphan G protein-coupled receptors GPR18 and GPR55
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GPR18 and GPR55 are orphan G protein-coupled receptors (GPCRs) that interact with certain cannabinoid (CB) receptor ligands. In the present study bicyclic imidazole-4-one derivatives were discovered as new scaffolds for the development of antagonists for
- Rempel,Atzler,Behrenswerth,Karcz,Schoeder,Hinz,Kaleta,Thimm,Kiec-Kononowicz,Müller
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p. 632 - 649
(2014/05/06)
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- Chemical synthesis and biological validation of immobilized protein kinase inhibitory Leucettines
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Leucettines, a family of marine sponge-derived 2-aminoimidazolone alkaloids, are potent inhibitors of DYRKs (dual-specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases). They constitute promising pharmacological leads for the treatment of several diseases, including Alzheimer's disease and Down syndrome. In order to investigate the scope of potential targets of Leucettine L41, a representative member of the chemical class, we designed an affinity chromatography strategy based on agarose-immobilized leucettines. A synthesis protocol for the attachment of a polyethylene (3 or 4 units) linker to L41 was first established. The linker attachment site on L41 was selected on the basis of the co-crystal structure of L41 with several kinases. L41 was then covalently bound to agarose beads through the primary amine located at the end of the linker. Control, kinase inactive Leucettine was also immobilized, as well as free linker devoid of ligand. Extracts of several mouse tissues revealed a complex pattern of interacting proteins, some of which probably resulting from non-specific, hydrophobic binding, while others representing bona fide Leucettine-interacting proteins. DYRK1A and GSK-3 (glycogen synthase kinase-3) were confirmed as interacting targets by Western blotting in various mouse tissues. The Leucettine affinity chromatography resin constitutes a powerful tool to purify and identify the targets of this new promising therapeutic class of molecules.
- Burgy, Guillaume,Tahtouh, Tania,Durieu, Emilie,Foll-Josselin, Béatrice,Limanton, Emmanuelle,Meijer, Laurent,Carreaux, Fran?ois,Bazureau, Jean-Pierre
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p. 728 - 737
(2013/06/04)
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- Privileged scaffolds or promiscuous binders: A comparative study on rhodanines and related heterocycles in medicinal chemistry
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Rhodanines and related five-membered heterocycles with multiple heteroatoms have recently gained a reputation of being unselective compounds that appear as "frequent hitters" in screening campaigns and therefore have little value in drug discovery. However, this judgment appears to be based mostly on anecdotal evidence. Having identified various rhodanines and related compounds in screening campaigns, we decided to perform a systematic study on their promiscuity. An amount of 163 rhodanines, hydantoins, thiohydantoins, and thiazolidinediones were synthesized and tested against several targets. The compounds were also characterized with respect to aggregation and electrophilic reactivity, and the binding modes of rhodanines and related compounds in published X-ray cocrystal structures were analyzed. The results indicate that the exocyclic, double bonded sulfur atom in rhodanines and thiohydantoins, in addition to other structural features, offers a particularly high density of interaction sites for polar interactions and hydrogen bonds. This causes a promiscuous behavior at concentrations in the "screening range" but should not be regarded as a general knockout criterion that excludes such screening hits from further development. It is suggested that special criteria for target affinity and selectivity are applied to these classes of compounds and that their exceptional and potentially valuable biomolecular binding properties are consequently exploited in a useful way.
- Mendgen, Thomas,Steuer, Christian,Klein, Christian D.
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supporting information; experimental part
p. 743 - 753
(2012/03/11)
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- Synthesis and anti-inflammatory activity of some new N and S-alkylated arylidene-thioxo-imidazolidinones
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New arylidene-thioxo-imidazolidinones and S-alkylated arylidene- imidazolidinone derivatives were prepared from substituted 2-thioxo- imidazolidin-4-one by nucleophilic addition of cyanoacrylates. N and S-alkylation was achieved treating 5-arylidene-2-thi
- Santos,Mourao,Uchoa,Silva,Malta,Moura,Lima,Galdino,Pitta,Barbe
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p. 433 - 440
(2007/10/03)
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- Synthesis, conformational analysis and antitumor testing of 5-(Z)-arylidene-4-imidazolidinone derivatives
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A series of 5-(Z)-arylidene-2-amino-4-imidazolidinones 16-34, 5-(Z)-arylidene-2-(2-carboxyphenylamino)-4-imidazolidinones 35-41, 5-(Z)-arylidene-3-aminomethyl-2-thioxo-4-imidazolidinones 42-55 and 5-(Z)-arylidene-3-aminomethyl-2-methylmercapto-4-imidazoli
- Khodair,El-Subbagh,Al-Obaid
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p. 159 - 181
(2007/10/03)
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- CONDENSATION ON ALUMINA: III - SYNTHESIS OF 5-ALKYLIDENE, 2-THIOHYDANTOIN FROM 3-ACETYL, 2-THIOHYDANTOIN
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A convenient procedure for the synthesis of 5-alkylidene, 2-thiohydantoin is described.
- Villemin, D.,Ricard, M.
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p. 283 - 290
(2007/10/02)
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