Catalytic Enantioselective Allylboration and Related Reactions of Isatins Promoted by Chiral BINOLs: Scope and Mechanistic Studies.

An improvement in the catalytic enantioselective allylboration of isatins with 2-allyl-1,3,2-dioxaborolane in the presence of chiral BINOL derivatives is reported, offering an efficient one-step access to enantioenriched N-unprotected 3-allyl-3-hydroxy-2-oxindoles. This catalytic process is also effective for the crotylboration reaction with enantiomeric ratios (er) up to 97:3, as well as for the asymmetric synthesis of homopropargylic alcohols via an allenyl addition to indoline-2,3-diones. Origins of the high enantioselectivity in chiral BINOL-catalyzed allylboration of isatins were examined by DFT calculations. A hypothetical scenario suggested a crucial internal hydrogen bonding between the amide group (C═O···H-O) and the ethylene hydroxyl of the transient chiral mixed boronate ester, generating a rigid and stabilized system that favors the addition of the allylboron species to the Re face of the ketone function. The key role of the alcohol additive (t-BuOH or t-AmOH) in the enantioselective allylboration reaction of isatins has also been shown on the basis of a kinetics study and computational calculations by favoring the transesterification of the 2-allyl-1,3,2-dioxaborolane with BINOL via proton transfer processes.

Structure-Activity Relationship in the Leucettine Family of Kinase Inhibitors.

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.

Design and Microwave Synthesis of New (5Z) 5-Arylidene-2-thioxo-1,3-thiazolinidin-4-one and (5Z) 2-Amino-5-arylidene-1,3-thiazol-4(5H)-one as New Inhibitors of Protein Kinase DYRK1A.

Here, we report on the synthesis of libraries of new 5-arylidene-2-thioxo-1,3-thiazolidin-4-ones 3 (twenty-two compounds) and new 2-amino-5-arylidene-1,3-thiazol-4(5H)-ones 5 (twenty-four compounds) with stereo controlled Z-geometry under microwave irradiation. The 46 designed final compounds were tested in order to determine their activity against four representative protein kinases (DYR1A, CK1, CDK5/p25, and GSK3α/ß). Among these 1,3-thiazolidin-4-ones, the molecules (5Z) 5-(4-hydroxybenzylidene)-2-thioxo-1,3-thiazolidin-4-one 3e (IC50 0.028 µM) and (5Z)-5-benzo[1,3]dioxol-5-ylmethylene-2-(pyridin-2-yl)amino-1,3-thiazol-4(5H)-one 5s (IC50 0.033 µM) were identified as lead compounds and as new nanomolar DYRK1A inhibitors. Some of these compounds in the two libraries have been also evaluated for their in vitro inhibition of cell proliferation (Huh7 D12, Caco2, MDA-MB 231, HCT 116, PC3, and NCI-H2 tumor cell lines). These results will enable us to use the 1,3-thiazolidin-4-one core as pharmacophores to develop potent treatment for neurological or oncological disorders in which DYRK1A is fully involved.

Structural and molecular bases to IRE1 activity modulation.

The Unfolded Protein response is an adaptive pathway triggered upon alteration of endoplasmic reticulum (ER) homeostasis. It is transduced by three major ER stress sensors, among which the Inositol Requiring Enzyme 1 (IRE1) is the most evolutionarily conserved. IRE1 is an ER-resident type I transmembrane protein exhibiting an ER luminal domain that senses the protein folding status and a catalytic kinase and RNase cytosolic domain. In recent years, IRE1 has emerged as a relevant therapeutic target in various diseases including degenerative, inflammatory and metabolic pathologies and cancer. As such several drugs altering IRE1 activity were developed that target either catalytic activity and showed some efficacy in preclinical pathological mouse models. In this review, we describe the different drugs identified to target IRE1 activity as well as their mode of action from a structural perspective, thereby identifying common and different modes of action. Based on this information we discuss on how new IRE1-targeting drugs could be developed that outperform the currently available molecules.

Synthetic alkyl-ether-lipid promotes TRPV2 channel trafficking trough PI3K/Akt-girdin axis in cancer cells and increases mammary tumour volume.

The Transient Receptor Potential Vanilloid type 2 (TRPV2) channel is highly selective for Ca2+ and can be activated by lipids, such as LysoPhosphatidylCholine (LPC). LPC analogues, such as the synthetic alkyl-ether-lipid edelfosine or the endogenous alkyl-ether-lipid Platelet Activating Factor (PAF), modulates ion channels in cancer cells. This opens the way to develop alkyl-ether-lipids for the modulation of TRPV2 in cancer. Here, we investigated the role of 2-Acetamido-2-Deoxy-l-O-Hexadecyl-rac-Glycero-3-PhosphatidylCholine (AD-HGPC), a new alkyl-ether-lipid (LPC analogue), on TRPV2 trafficking and its impact on Ca2+ -dependent cell migration. The effect of AD-HGPC on the TRPV2 channel and tumour process was further investigated using calcium imaging and an in vivo mouse model. Using molecular and pharmacological approaches, we dissected the mechanism implicated in alkyl-ether-lipids sensitive TRPV2 trafficking. We found that TRPV2 promotes constitutive Ca2+ entry, leading to migration of highly metastatic breast cancer cell lines through the PI3K/Akt-Girdin axis. AD-HGPC addresses the functional TRPV2 channel in the plasma membrane through Golgi stimulation and PI3K/Akt/Rac-dependent cytoskeletal reorganization, leading to constitutive Ca2+ entry and breast cancer cell migration (without affecting the development of metastasis), in a mouse model. We describe, for the first time, the biological role of a new alkyl-ether-lipid on TRPV2 channel trafficking in breast cancer cells and highlight the potential modulation of TRPV2 by alkyl-ether-lipids as a novel avenue for research in the treatment of metastatic cancer.

BINOL derivatives-catalysed enantioselective allylboration of isatins: application to the synthesis of (R)-chimonamidine.

The asymmetric synthesis of the 3-allyl-3-hydroxyoxindole skeleton was accomplished in yields up to 99% via a metal-free and enantioselective allylation of isatins (90-96% ee) using BINOL derivatives as catalysts and an optimized allylboronate. This methodology was applied at a gram-scale to the synthesis of the natural product (R)-chimonamidine.

Inhibition of DYRK1A proteolysis modifies its kinase specificity and rescues Alzheimer phenotype in APP/PS1 mice.

Recent evidences suggest the involvement of DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1 A) in Alzheimer's disease (AD). Here we showed that DYRK1A undergoes a proteolytic processing in AD patients hippocampus without consequences on its kinase activity. Resulting truncated forms accumulate in astrocytes and exhibit increased affinity towards STAT3ɑ, a regulator of inflammatory process. These findings were confirmed in APP/PS1 mice, an amyloid model of AD, suggesting that this DYRK1A cleavage is a consequence of the amyloid pathology. We identified in vitro the Leucettine L41 as a compound able to prevent DYRK1A proteolysis in both human and mouse protein extracts. We then showed that intraperitoneal injections of L41 in aged APP/PS1 mice inhibit STAT3ɑ phosphorylation and reduce pro-inflammatory cytokines levels (IL1- ß, TNF-ɑ and IL-12) associated to an increased microglial recruitment around amyloid plaques and decreased amyloid-ß plaque burden. Importantly, L41 treatment improved synaptic plasticity and rescued memory functions in APP/PS1 mice. Collectively, our results suggest that DYRK1A may contribute to AD pathology through its proteolytic process, reducing its kinase specificity. Further evaluation of inhibitors of DYRK1A truncation promises a new therapeutic approach for AD.

Stereodivergent approach in the protected glycal synthesis of L-vancosamine, L-saccharosamine, L-daunosamine and L-ristosamine involving a ring-closing metathesis step.

In this paper, a new access to several chiral 3-aminoglycals as potential precursors for glycosylated natural products is reported from a common starting material, (-)-methyl-L-lactate. The stereodivergent strategy is based on the implementation of a ring-closing metathesis of vinyl ethers as key step of reaction sequences developed.

1,3-Dioxa-[3,3]-sigmatropic Oxo-Rearrangement of Substituted Allylic Carbamates: Scope and Mechanistic Studies.

An unexpected 1,3-dioxa-[3,3]-sigmatropic rearrangement during the treatment of aryl- and alkenyl-substituted allylic alcohols with activated isocyanates is reported. The reorganization of bonds is highly dependent on the electron density of the aromatic ring and the nature of isocyanate used. This metal-free tandem reaction from branched allyl alcohols initiated by a carbamoylation reaction and followed by a sigmatropic rearrangement thus offers a new access to ( E)-cinnamyl and conjugated ( E, E)-diene carbamates, such as N-acyl and N-sulfonyl derivatives. A computational study was conducted in order to rationalize this phenomenon, and a rearrangement progress kinetic analysis was performed.

Correction of cognitive deficits in mouse models of Down syndrome by a pharmacological inhibitor of DYRK1A.

Growing evidence supports the implication of DYRK1A in the development of cognitive deficits seen in Down syndrome (DS) and Alzheimer's disease (AD). We here demonstrate that pharmacological inhibition of brain DYRK1A is able to correct recognition memory deficits in three DS mouse models with increasing genetic complexity [Tg(Dyrk1a), Ts65Dn, Dp1Yey], all expressing an extra copy of Dyrk1a Overexpressed DYRK1A accumulates in the cytoplasm and at the synapse. Treatment of the three DS models with the pharmacological DYRK1A inhibitor leucettine L41 leads to normalization of DYRK1A activity and corrects the novel object cognitive impairment observed in these models. Brain functional magnetic resonance imaging reveals that this cognitive improvement is paralleled by functional connectivity remodelling of core brain areas involved in learning/memory processes. The impact of Dyrk1a trisomy and L41 treatment on brain phosphoproteins was investigated by a quantitative phosphoproteomics method, revealing the implication of synaptic (synapsin 1) and cytoskeletal components involved in synaptic response and axonal organization. These results encourage the development of DYRK1A inhibitors as drug candidates to treat cognitive deficits associated with DS and AD.

Stereospecific C-Glycosylation by Mizoroki-Heck Reaction: A Powerful and Easy-to-Set-Up Synthetic Tool to Access α- and ß-Aryl-C-Glycosides.

A stereospecific Mizoroki-Heck cross-coupling of differently substituted glycals with haloarenes resulting in the exclusive formation of either α- or ß-aryl-C-glycosides depending solely on the configuration at C3 was achieved. The reaction was easy to set up because no specific precautions were required concerning moisture or oxygen, and it proceeded by a chirality transfer from C3 to C1. After optimization of cross-coupling conditions, various prepared glycals (7 examples) and arenes (10 examples) were tested, leading stereospecifically to the corresponding aryl-C-glycosides with a carbonyl group at C3, thus opening up new horizons for the total synthesis of glycosylated natural products.

Marine-Derived 2-Aminoimidazolone Alkaloids. Leucettamine B-Related Polyandrocarpamines Inhibit Mammalian and Protozoan DYRK & CLK Kinases.

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.

Total Synthesis of γ-Indomycinone and Kidamycinone by Means of Two Regioselective Diels-Alder Reactions.

An efficient access for the synthesis of pluramycinones is described. Total syntheses of racemic γ-indomycinone and kidamycinone were achieved by means of two Diels-Alder reactions. A first Diels-Alder condensation followed by a Stille cross-coupling is used for the elaboration of the desired substituted dienes which will be involved in the second pericyclic reaction with juglone to construct the tetracyclic core of pluramycinones.

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

An 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.

[3,3]-Sigmatropic Rearrangement/Allylboration/Cyclization Sequence: Enantioenriched Seven-Membered-Ring Carbamates and Ring Contraction to Pyrrolidines.

The combination of in situ generated α-isocyanato allylboronic esters and aldehydes afforded seven-membered-ring enecarbamates with high levels of diastereo- and enantiocontrol. They were easily converted into diversely substituted 1,3-oxazepan-2-ones. An unprecedented rearrangement of 5-acetoxy-7-aryl or styryl derivatives led to tetrasubstituted pyrrolidines. A computational study provides evidence on the feasibility of the proposed mechanism of this unusual ring contraction.

Leucettine L41, a DYRK1A-preferential DYRKs/CLKs inhibitor, prevents memory impairments and neurotoxicity induced by oligomeric Aß25-35 peptide administration in mice.

Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) are implicated in the onset and progression of Down syndrome (DS) and Alzheimer's disease (AD). DYRK1A has emerged as a possible link between amyloid-ß (Aß) and Tau, the major pathological proteins in AD. We here assessed the neuroprotective potential of a novel inhibitor of DYRKs/CLKs. The Leucettine L41, acting preferentially on DYRK1A, was tested in Aß25-35-treated mice, a nontransgenic model of AD-like toxicity. We co-injected intracerebroventricularly oligomeric Aß25-35 peptide and L41 in Swiss male mice. After 7 days, they were submitted to behavioral tests addressing spatial and non-spatial, short- and long-term memories. The oxidative stress, apoptotic markers, kinases involved in Tau phosphorylation, and synaptic integrity were analyzed by Western blot and ELISA in the hippocampus. L41, tested at 0.4, 1.2, 4 µg, prevented the Aß25-35-induced memory deficits in the Y-maze, passive avoidance and water-maze tests, with the most active dose being 4 µg. The inhibitor prevented the Aß25-35-induced oxidative stress, as revealed by measures of lipid peroxidation levels and reactive oxygen species accumulation, and abolished Aß25-35-induced expression of pro-apoptotic markers. L41 prevented the Aß25-35-induced decrease of AKT activation and increase of glycogen synthase kinase-3ß (GSK-3ß) activation, resulting in a decrease of Tau phosphorylation. Finally, L41 restored Aß25-35-reduced levels of synaptic markers. The novel DYRK1A-preferential inhibitor L41 therefore prevented Aß25-35-induced memory impairments and neurotoxicity in the mouse hippocampus. These in vivo data highlighted particularly DYRK1A as a major kinase involved in Aß pathology and suggested therapeutic developments for DYRK1A inhibitors in AD.

Microwave-Assisted Condensation Reactions of Acetophenone Derivatives and Activated Methylene Compounds with Aldehydes Catalyzed by Boric Acid under Solvent-Free Conditions.

We here disclosed a new protocol for the condensation of acetophenone derivatives and active methylene compounds with aldehydes in the presence of boric acid under microwave conditions. Implementation of the reaction is simple, healthy and environmentally friendly owing to the use of a non-toxic catalyst coupled to a solvent-free procedure. A large variety of known or novel compounds have thus been prepared, including with substrates bearing acid or base-sensitive functional groups.

Cross-metathesis/isomerization/allylboration sequence for a diastereoselective synthesis of anti-homoallylic alcohols from allylbenzene derivatives and aldehydes.

We describe a highly diastereoselective approach to anti-homoallylic alcohols from allylbenzene derivatives and aldehydes. The strategy is based on a cross-metathesis/isomerization/allylboration sequence catalyzed successively by ruthenium and iridium. This methodology provides another way to access this class of compounds, which leads to the preparation of hitherto-unknown homoallylic alcohols without the requirement to control the stereochemistry of the 1-alkenyl boronate intermediates. Our study towards an enantioselective version of this sequential reaction is also reported.

New 5-ylidene rhodanine derivatives based on the dispacamide A model.

A practical approach for the preparation of (5Z) 5-ylidene rhodanine derivatives bearing the (4,5-dihalogeno-pyrrol-2-yl)carbamoyl fragment of dispacamide A is reported. The new compounds were obtained in good yields (19-88 %) by Knoevenagel condensation according to a solution-phase microwave dielectric heating protocol in the presence of organic bases (piperidine, TEA, and AcONa) from a set of N-substituted rhodanines 2(a-i). The ten synthetic products 3(a-j) have been synthesized with a Z-geometry about their exocyclic double bond and the structure of one of these compounds (3) was confirmed by a single X-ray diffraction analysis. The new (5Z) 5-ylidene rhodanine derivatives 3(a-j) were tested against eight protein kinases.

Boron-substituted 1,3-dienes and heterodienes as key elements in multicomponent processes.

In the last few years, multicomponent reactions involving boron substituted 1,3-dienes have emerged as important tools in synthetic organic chemistry. The most significant recent results and developments obtained in this area are reported in this review.