A large diversity of 2-aminoimidazolone alkaloids is produced by various marine invertebrates, especially by the marine Calcareous sponges Leucetta and Clathrina. The phylogeny of these sponges and the wide scope of 2-aminoimidazolone alkaloids they produce are reviewed in this article. The origin (invertebrate cells, associated microorganisms, or filtered plankton), physiological functions, and natural molecular targets of these alkaloids are largely unknown. Following the identification of leucettamine B as an inhibitor of selected protein kinases, we synthesized a family of analogues, collectively named leucettines, as potent inhibitors of DYRKs (dual-specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) and potential pharmacological leads for the treatment of several diseases, including Alzheimer’s disease and Down syndrome. We assembled a small library of marine sponge- and ascidian-derived 2-aminoimidazolone alkaloids, along with several synthetic analogues, and tested them on a panel of mammalian and protozoan kinases. Polyandrocarpamines A and B were found to be potent and selective inhibitors of DYRKs and CLKs. They inhibited cyclin D1 phosphorylation on a DYRK1A phosphosite in cultured cells. 2-Aminoimidazolones thus represent a promising chemical scaffold for the design of potential therapeutic drug candidates acting as specific inhibitors of disease-relevant kinases, and possibly other disease-relevant targets.

deltif Amrane, et al.. Assessment of VOC absorption in hydrophobic ionic liquids: Measurement of partition and diffusion coefficients and simulation of a packed column. Chemical Engineering Journal, Elsevier, 2019, 360, pp. AbstractPartition coefficients of toluene and dichloromethane (DCM) in 23 hydrophobic ionic liquids (ILs), which can be used potentially for the physical absorption of volatile organic compounds (VOCs), were measured at 298 K. The partition coefficients, expressed as Henry's law constants, were 400 to 1300 times for toluene and 10 to 47 times for DCM lower in the selected ILs than in water. Thus, the toluene and DCM diffusion coefficients were measured in three high potential hydrophobic ILs and in [Bmim][NTf 2 ] using a thermogravimetric microbalance. Diffusivity measurements were performed at 298K for toluene and between 278 and 308K for DCM. Diffusion coefficients in ILs, ranging between 1 and 4×10 -11 m 2 s -1 , were from 18 to 90 times lower than in water at 298 K. The diffusion coefficients were correlated to the temperature, the solute molar volume, the IL viscosity and molar volume with an average error of 4.2%. Finally, a 3 m industrial packed column was simulated for the removal of DCM and toluene in [AllylEt 2 S][NTf 2 ] and [bmim][NTf 2 ], which both present moderate viscosities of nearly 50 mPa s at 293K. The overall mass-transfer coefficient, the removal efficiency and the pressure drop were calculated and compared to those obtained using other heavy solvents (a silicon * Corresponding author : pierre-francois.biard@ensc-rennes.fr, Tel: + 33 2 23 23 81 49 2 oil and di-(2-ethylhexyl) adipate). This prospective simulation has demonstrated a good potential of ionic liquids for the toluene removal. Nonetheless, the DCM removal efficiencies simulated were lower than 44%. It suggests that even more efficient ionic liquids can be tuned and synthesized in the future for this specific application. Highlights Toluene partition coefficients in 23 ILs were in the range 0.5-3.5 Pa m 3 mol -1  Dichloromethane partition coefficients in 23 ILs were in the range 5-17 Pa m 3 mol -1  VOC diffusion coefficients in the range 1-4×10 -11 m 2 s -1 were measured in 4 ILs  The computed toluene removal efficiency in a packed column was from 52 to 99.6%  The computed dichloromethane removal efficiency in a packed column was lower than 44% Graphical abstractVicious air containing VOC: Treated air Ionic liquid Loaded ionic liquid Metal Pall rings 3.0 m 1.0 m •Toluene •Dichloromethane Operating conditions Hydrodynamics Mass-transfer rate (K l a°) Pressure drop Removal efficiency Solvent assessment for VOC removal in a packed column Partition coefficient Diffusion coefficient Ionic liquid properties (m, r, s) Static headspace method Static thermogravimetric method Measurements Simulation •[bmim][NTf 2 ] •[AllylEt 2 S][NTf 2 ] Finally, the hydrodynamics and mass-transfer in a packed column fed with [Bmim][NTf 2 ] and [AllylEt 2 S][NTf 2 ] were simulated for DCM and toluene absorption. * AR is the affinity r...

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.

No abstract

The performance of a redox compound in redox flow batteries (RFB) highly depends on the electrolytic medium and operating conditions. It is exemplified in this work with the commercially available and relatively low-cost dye 3,4-dihydroxy-9,10-anthraquinone-2-sulfonic acid (ARS), which was used as negolyte in basic medium. At high pH, the ARS behavior revealed interesting features for RFB applications, such as a low halfwave potential of À 0.99 V (vs Ag/AgCl), negatively shifted by phenolate groups, and an improved solubility compared with acidic medium depending on the nature of the cations. For the highly soluble ARS potassium salt (ARSK), a maximum power density of 117 mW cm À 2 and a demonstrated energy density of 20 Wh L À 1 were obtained with K 4 [Fe(CN) 6 ] as posolyte. The capacity slightly decreased during cycling, reaching 90 % after 325 cycles. A long cycling of ARS sodium salt (ARSNa) over 11 operating months was demonstrated in this work. A slow chemical degradation was highlighted giving rise to the formation of 3-hydroxy-9,10-anthraquinone-2-sulfonic acid (HAQS) as the main degradation product due to hydrodeoxygenation reaction. Interestingly, this compound exhibited high performance in RFB and a good stability with a loss of capacity of 0.29 % per day.

Synthesis of several hydrophobic ionic liquids (ILs), which might be selected as good candidates for degradation of hydrophobic volatile organic compounds in a two-phase partitioning bioreactor (TPPB), were carried out. Several bioassays were also realized, such as toxicity evaluation on activated sludge and zebrafish, cytotoxicity, fluoride release in aqueous phase and biodegradability in order to verify their possible effects in case of discharge in the aquatic environment and/or human contact during industrial manipulation. The synthesized compounds consist of alkylimidazoliums, functionalized imidazoliums, isoqinoliniums, triazoliums, sulfoniums, pyrrolidiniums and morpholiniums and various counter-ions such as: PF6(-), NTf2(-) and NfO(-). Toxicity evaluation on activated sludge of each compound (5% v/v of IL) was assessed by using a glucose uptake inhibition test. Toxicity against zebrafish and cytotoxicity were evaluated by the ImPACCell platform of Rennes (France). Fluoride release in water was estimated by regular measurements using ion chromatography equipment. IL biodegradability was determined by measuring BOD28 of aqueous samples (compound concentration,1mM). All ILs tested were not biodegradable; while some of them were toxic toward activated sludge. Isoquinolinium ILs were toxic to human cancerous cell lines. Nevertheless no toxicity was found against zebrafish Danio rerio. Only one IL released fluoride after long-time agitation.

Iron chelation in tumoral cells has been reported as potentially useful during antitumoral treatment. Our aim was to develop new polyaminoquinoline iron chelators targeting tumoral cells. For this purpose, we designed, synthesized, and evaluated the biological activity of a new generation of iron chelators, which we named Quilamines, based on an 8-hydroxyquinoline (8-HQ) scaffold linked to linear polyamine vectors. These were designed to target tumor cells expressing an overactive polyamine transport system (PTS). A set of Quilamines bearing variable polyamine chains was designed and assessed for their ability to interact with iron. Quilamines were also screened for their cytostatic/cytotoxic effects and their selective uptake by the PTS in the CHO cell line. Our results show that both the 8-HQ moiety and the polyamine part participate in the iron coordination. HQ1-44, the most promising Quilamine identified, presents a homospermidine moiety and was shown to be highly taken up by the PTS and to display an efficient antiproliferative activity that occurred in the micromolar range. In addition, cytotoxicity was only observed at concentrations higher than 100 μM. We also demonstrated the high complexation capacity of HQ1-44 with iron while much weaker complexes were formed with other cations, indicative of a high selectivity. We applied the density functional theory to study the binding energy and the electronic structure of prototypical iron(III)-Quilamine complexes. On the basis of these calculations, Quilamine HQ1-44 is a strong tridentate ligand for iron(III) especially in the form of a 1:2 complex.

Dispacamide A and new analogs of this marine alkaloid were prepared in seven steps with an overall yield ranging from 12 to 33%. The key step of the strategy was a stereocontrolled Knoevenagel condensation under microwave dielectric heating in the last step. In this condensation, the 2-aminoimidazolin-4-one hydrochloride partners 10a-c were synthesized in three steps with good overall yields (33-79%) via the ring closure of N-guanidino acetic acids 9a-c and the aldehydes 5a,b as the two others building-blocks, in 3 steps with 60-66% overall yields. The six synthetic products have been obtained with a Z geometry about their exocyclic bond on the basis of (13)C/(1)H long-range coupling constants using a gHSQMBC experiment.