12 research outputs found

    Stereospecific Synthesis of α-Amino Allylsilane Derivatives through a [3,3]-Allyl Cyanate Rearrangement. Mild Formation of Functionalized Disiloxanes

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    International audienceAn efficient asymmetric synthesis of α-amino allylsilane derivatives is reported. The strategy is based on a [3,3]-allyl cyanate sigmatropic rearrangement from enantioenriched γ-hydroxy alkenylsilyl compounds. The isocyanate intermediate can be trapped by several nucleophiles, opening the way for the preparation of unknown chiral functionalized compounds such as the α-ureido allylsilanes as well as carbamate derivatives. A computational study was conducted to rationalize the complete 1,3-chirality transfer of this kind of rearrangement. Moreover, starting from products bearing a phenyldimethyl silyl substituent, the α-amino silane derivatives or the corresponding disiloxanes can be obtained under hydrogenation conditions in an exclusive way according to the used catalyst. © 2016 American Chemical Society

    Asymmetric synthesis of trans-4,5-disubstituted γ-butyrolactones involving a key allylboration step. First access to (-)-nicotlactone B and (-)-galbacin

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    International audienceAn efficient asymmetric synthesis of trans-4,5-disubstituted γ-butyrolactones from aldehydes and enantioenriched γ-carbamate alkenylboronates is reported. The cornerstone of this strategy is the implementation of sequential [3,3]-allyl cyanate rearrangement/allylboration/nucleophilic addition/cyclisation reactions. Diverse γ-butyrolactones such as the flavouring compounds, (+)-trans-whiskey lactone and (+)-trans-cognac lactone, as well as an advanced intermediate towards the first synthesis of natural products, (-)-nicotlactone B and (-)-galbacin, have thus been obtained

    Leucettines, a family of pharmacological inhibitors of DYRKs and CLKs kinases derived from the marine sponge Leucettamine B

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    International audienceWe here report on leucettines, a family of kinase inhibitors derived from the marine sponge leucettamine B. Stepwise synthesis of analogues, followed by activity testing on 8 purified kinases led to highly potent inhibitors of CLKs & DYRKs, two families of kinases involved in pre-mRNA splicing and Alzheimer's disease. Leucettine L41 was co-crystallized with DYRK1A, -2, CLK3 and PIM1. Leucettine L41 inhibits phosphorylation of pre-RNA splicing regulating Ser/Arg-rich proteins. Leucettine L41 modulates alternative pre-mRNA splicing in a cellular systems. The selectivity of Leucettine L41 was extensively characterized. Leucettine L41 provides protection against glutamate-induced cell death in cultured HT22 hippocampal cells. It also provides neuroprotection against APP-induced cell death in mouse brain slices. Finally it prevents in vivo cognitive impairments due to icv injection of amyloid-β 25-35. Leucettines should be further explored as pharmacological tools to study and modulate pre-RNA splicing. Leucettines should also be investigated as potential therapeutic drugs in Alzheimer's disease and in diseases involving abnormal pre-mRNA splicing

    Selectivity, cocrystal structures, and neuroprotective properties of leucettines, a family of protein kinase inhibitors derived from the marine sponge alkaloid leucettamine B.

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    DYRKs (dual specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) are implicated in the onset and development of Alzheimer's disease and Down syndrome. The marine sponge alkaloid leucettamine B was recently identified as an inhibitor of DYRKs/CLKs. Synthesis of analogues (leucettines) led to an optimized product, leucettine L41. Leucettines were cocrystallized with DYRK1A, DYRK2, CLK3, PIM1, and GSK-3β. The selectivity of L41 was studied by activity and interaction assays of recombinant kinases and affinity chromatography and competition affinity assays. These approaches revealed unexpected potential secondary targets such as CK2, SLK, and the lipid kinase PIKfyve/Vac14/Fig4. L41 displayed neuroprotective effects on glutamate-induced HT22 cell death. L41 also reduced amyloid precursor protein-induced cell death in cultured rat brain slices. The unusual multitarget selectivity of leucettines may account for their neuroprotective effects. This family of kinase inhibitors deserves further optimization as potential therapeutics against neurodegenerative diseases such as Alzheimer's disease

    Structure-Activity Relationship in the Leucettine Family of Kinase Inhibitors

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    International audienceThe 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 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
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