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International audience; Small interfering RNAs (siRNAs) can down-regulate the expression of a target mRNA molecule in a sequence-specific manner, making them an attractive new class of drugs with broad potential for the treatment of diverse human diseases. Here, we report the synthesis of a series of cationic amphiphiles which were obtained by the coupling of amino acids and dipeptides onto a lipidic double chain. The new amphiphiles presenting a peptidic motif on a short hydrophilic spacer group were evaluated for selective gene silencing through RNA interference. Our results show that tryptophan residues boost siRNA delivery in an unexpected manner. The silencing experiments performed with very low concentrations of siRNA showed that the best formulations could induce significant death of tumor cells after silencing of polo-like kinase 1 which is implicated in cell cycle progression. In addition, these Trp containing peptide amphiphiles were highly efficient siRNA delivery vectors even in presence of competing serum proteins.

International audience; Dengue virus (DENV), a mosquito-borne flavivirus, causes severe and potentially fatal symptoms in millions of infected individuals each year. Although dengue fever represents a major global public health problem, the vaccines or antiviral drugs proposed so far have not shown sufficient efficacy and safety, calling for new antiviral developments. Here we have shown that a mannoside glycolipid conjugate (MGC) bearing a trimannose head with a saturated lipid chain inhibited DENV productive infection. It showed remarkable cell promiscuity, being active in human skin dendritic cells, hepatoma cell lines and Vero cells, and was active against all four DENV serotypes, with an IC 50 in the low micromolar range. Time-of-addition experiments and structure-activity analyses revealed the importance of the lipid chain to interfere with an early viral infection step. This, together with a correlation between antiviral activity and membrane polarization by the lipid moiety indicated that the in-hibitor functions by blocking viral envelope fusion with the endosome membrane. These finding establish MGCs as a novel class of antivirals against the DENV.

The synthesis of two molecules, B1 and B2, based on elements of norbadione A, the natural Cs + chelator in mushrooms, associated, in the case of B2, with an 18-crown-6 ether is reported. Thermodynamic and kinetic analyses performed in water, ethanol and ethanol/water 9/1 v/v (M1) show in M1 and ethanol that B1 and B2 form stable complexes with Na + , K + and Cs + . Affinity constants, measured spectrophotometrically in ethanol and M1, by the use of the S pecfit program, are in the 10 5 and 10 6 range for B1 and B2, respectively. The second-order rate constants are in the 10 6 –10 7 M −1 s −1 range and the first-order rate constants about unity. The ratios of the second-order/first-order rate constants confirm the thermodynamic results in EtOH. The kinetic processes become much too fast to allow runs in M1. Molecular simulations in EtOH imply the existence of two isomers for each of the Cs + /B1 and Cs + /B2 complexes. With B1, the more stable one is that in which the two enolates are parallel and mimic the alkali-metal inclusion cavity already envisaged for norbadione A. With B2, two similar structures are extracted, in both of which Cs + is included in the crown ether and capped by the enolate. The affinity of B1 for Cs + is comparable to that of norbadione A, whereas that of B2 is higher. These results are encouraging as they introduce a new series of alkali chelators which can lead to molecules capable of complexing 137 Cs + for radioactive decontamination.

A multi-disciplinary approach was used to identify the first pharmacophore model for KCC2 blockers: several physico-chemical studies such as XRD and NMR were combined to molecular modelling techniques, SAR analysis and synthesis of constrained analogues in order to determine a minimal conformational space regrouping few potential bioactive conformations. These conformations were further compared to the conformational space of a different series of KCC2 blockers in order to identify the common pharmacophoric features. The synthesis of more potent analogues in this second series confirmed the usefulness of this KCC2 blocker pharmacophore model.

A screening strategy based on hyphenated capillary electrophoresis and inductively coupled plasma mass spectrometry (CE–ICP-MS) was developed to classify phosphorylated ligands according to their europium(III) binding affinity in a hydro-organic medium (sodium formate, pH 3.7, H2O/MeOH 90:10, v/v). Taking advantage of the high sensibility of ICP-MS for detecting phosphorus, this method enabled to assess the affinity of a variety of phosphorylated compounds, including phosphine oxides, thiophosphines, phosphonates, and phosphinates, in less than 1 h and using less than 5 ng of substance. By varying the total europium concentration, complexation constants could be determined according to a sequential multiple run strategy, which proved to be in excellent agreement with the values obtained by UV–Vis absorption spectrophotometric titrations.

Interest in cleavable linkers is growing due to the rapid development and expansion of chemical biology. The chemical constrains imposed by the biological conditions cause significant challenges for organic chemists. In this review we will present an overview of the cleavable linkers used in chemical biology classified according to their cleavage conditions by enzymes, nucleophilic/basic reagents, reducing agents, photo-irradiation, electrophilic/acidic reagents, organometallic and metal reagents, oxidizing reagents.

An efficient one-pot four-step domino reaction of substituted β-ketoesters has been optimized giving rise to a large panel of C2-substituted 3-methylcyclohex-2-enones, an important scaffold for the preparation of various initiators for cationic or radical cyclizations. The developed methodology is quite general and applicable to a wide range of β-ketoester substrates, allowing the introduction of various functionalities at the C2 position of the 3-methylcyclohex-2-enones, in good to excellent yields.

TMSNTf 2 has been used efficiently as a promoter in glycosidation reaction involving permethacrylated Schmidt reagents. While TMSNTf 2 is known to be a powerful activator for C O double bonds, we have discovered that this reagent can activate C N double bond selectively, even in the presence of excess C O groups of permethacrylated O -glycosyl trichloroacetimidate substrates. Glycosides are synthesized in moderate to reasonable yields with an excellent overall β-stereoselectivity.

The discovery and optimization of a novel class of selective submicromolar KCC2 blockers is described. Details of synthesis and SAR are given together with ADME properties of selected compounds. A methylsulfone residue on the R(1) phenyl group improved the overall general profile of these prolinate derivatives.

A convenient synthesis of functionalized propargylic alcohols arising from the 1,2-addition of lithium alkynyl-trimethyl borate onto aldehydes under transition metal free mild conditions is reported. The reaction tolerates a wide range of functional groups, is highly chemoselective and the propargylic alcohols are isolated in good to excellent yields.

The synthesis of various permethacrylated mono- and disaccharides in acceptable yields is reported. The reactivity of these unusual polymerizable compounds has been investigated in diverse glycosidation reaction conditions. New original polymerizable donor sugars have been prepared successfully in good to excellent yields.

At the beginning of the 15th century a systematic programme of maritime exploration masterminded by prince Henry the Navigator of Portugal sparked the technological, scientific and cultural revolutions that connected Europe to the rest of the world. What made the Portuguese initiative different from their contemporaries’—and from the dawn of the space age—is a limited set of explicit, broad rationales. We have assessed some maritime and space exploration programmes against these rationales, and we infer that these programmes are successful when they are driven by a balanced combination of these rationales. With the appropriate caution linked to transposing historical parallels, this exercise may help bring into focus some factors that may help shaping a lunar initiative to open up the solar system.

A novel solid-phase synthesis of tetrasubstituted 2-imino-1,3-thiazolines using a functionalizing cleavage strategy is described. The synthetic route utilized the ambident reactivity of a dithiocarbamate functionality to synthesize the key resin-bound electrophilic thiazolium intermediate. The desired products were efficiently obtained in high purity by the reaction of various amines with the thiazolium salt.

Herein, we describe short and efficient syntheses of isoxazole-3-carboxylic acid 3a and imino-oxopentanoic acid 8 achiral precursors of 4-hydroxyisoleucine. The developed procedures involve readily available and cheap starting materials and can easily be transposed to the large scale.

International audience; A straightforward mono-selective and C-specific alkylation of phloroglucinol with activated alkyl halides is presented. The use of water as solvent limits the amount of over-alkylated by-products. Provided some minor changes in the experimental conditions, hydrophobic cinnamyl halides can also be reacted, thus giving a direct access to advanced intermediates of natural flavonoids.

An effective traceless solid-phase synthesis of chloro-diaminopyrimidines via an amino-de-chlorination reaction of polymer-bound 4-alkoxycarbonylamino-2,6-dichloropyrimidines has been developed. After release from the polymer the target molecules were obtained in good to excellent purity, although with modest regiocontrol. Further reaction of solid-supported N -alkoxycarbonyl-chloro-diaminopyrimidines with secondary amines afforded triaminopyrimidines in good purity under mild conditions, whereas less nucleophilic primary amines did not perform well under the conditions explored so far.

The use of DCC, triethylamine, and 4-dimethylaminopyridine in dichloromethane provides a general and standard one-pot procedure for the C-acylation of cyclic 1,3-diones with a wide range of carboxylic acids, giving rise to β-triketones in good to excellent yields.

(Chloro-phenylthio-methylene)dimethylammonium chloride reacts smoothly with a variety of alcohols, to afford the corresponding alkyl chloride in good yields. In the presence of tetrabuthylammonium bromide the corresponding bromide is obtained. Selective halogenation of primary hydroxyl groups in the presence of an unprotected secondary one is described. The mild reaction conditions involved are compatible with the major alcohol protecting groups as well as with acid sensitive functions like epoxides.

4-N-Alkoxycarbonyl-2,6-dichloropyrimidines have been synthesized with good to excellent regioselectivity and yields from 2,4,6-trichloropyrimidine and N-sodium carbamates in DMF, at room temperature, in 15–30 minutes.

The direct azidation of various heterocyclic β-ketoesters, lactones, and lactams is reported. By using tosylazide and an organic base such as l -proline or TBD, the direct α-insertion of azide into these substrates was achieved in moderate to good yields, without competitive deacylating diazo transfer. This procedure represents an interesting alternative to the usual two-step approach of α-halogenation and subsequent displacement with azide ion.

The use of TMSCl in methanol under microwave irradiation allows the facile intramolecular condensation of a large panel of triketones, giving rise to 4-keto-4,5,6,7-tetrahydrobenzofurans in good to excellent yields.

Treatment of a vinyl resin with 9-BBN affords a polymer bound alkylborane that undergoes palladium-catalyzed Suzuki cross coupling reactions with a variety of aromatic, vinylic and aliphatic halides. The mild reaction conditions are compatible with several functional groups and allow carboncarbon bond formation at non-activated positions.

Nitroacetic esters are prepared in good yield by reaction, at 0 °C, of nitroacetic acid with various alcohols in the presence of DCC. These reaction conditions were applied to the preparation of Merrifield resin-bound nitroacetate.

A wide range of alkoxycarbonyl protected benzylic amines have been synthesized in a three component reaction involving a carbamate an aldehyde and an aromatic substrate. This reaction proceeds through electrophilic substitution of the aromatic compound by a N-carbamoyl iminium which is generated in situ by condensation of the carbamate with the aldehyde.

Orginal dehydrating reagents for the efficient formation of nitrile oxides from primary nitro compounds are reported. Burgess salt, DAST, acetic anhydride and oxalyl chloride were shown to be useful reagents to perform this transformation.

A mild and efficient two-step synthesis of a polystyrene thiol resin is reported. Firstly, a polystyrene resin was reacted with an activated sulfoxide to afford the resin bound bis-(2-methoxy-carbonylethyl)-sulfonium trifluoromethanesulfonate. Smooth β-elimination based dealkylations afforded the polystyrene thiol resin with good and controlled loading. Its reactivity was assessed through a derivatisation step.

A new safety-catch linker has been developed for combinatorial solid-phase chemistry. Azidomethyl-polystyrene, obtained by nucleophilic substitution of chloromethyl-polystyrene, undergoes an acid promoted Schmidt rearrangement. The resulting polymer-bound iminium participates in an aza Diels–Alder cycloaddition, which leads to a supported dihydroquinoline (DHQ resin). The acylated form of the DHQ resin is stable under basic, acidic and mild reducing agents. The cleavage proceeds in two steps (i) oxidative aromatization leading to an activated quinolinium and (ii) nucleophilic displacement of the quinoline resin. The overall process is high yielding and efficient.

We introduce benzylsulfonyl (Bns) as a valuable protecting group in phenol chemistry. Bns proved to be stable under drastic reaction conditions and towards many common reagents. The deprotection proceeds quantitatively using catalytic hydrogenolysis. Additionally the Bns deactivating properties make this protecting group useful for tuning the reactivity of phenolic substrates.

Azidomethyl–polystyrene, obtained by nucleophilic substitution of chloromethyl–polystyrene, undergoes a Schmidt rearrangement when treated with trifluoromethanesulfonic acid, affording amino–polystyrene. To assess its loading and reactivity the resin is used as a support for the preparation of triazene-linked amine.

The synthesis of two α-aminocyclopropanone hydrates is reported. These synthons could find biological applications by acting as transition-state analog inhibitors of hydrolytic enzymes, such as serine proteases.

The first regioselective resin-anchoring reaction of 2,4,6-trichloropyrimidine has been achieved through 4-amino-de-chlorination by solid-supported Boc-like N -potassium carbamates. Excellent regioselectivities together with high coupling efficiency were obtained with aliphatic, aromatic and α-amino-ester derived carbamates. The scope and limits of the reaction are described with the view of its applications to the solid-phase synthesis of combinatorial libraries of aminopyrimidine-based structures.

1-Bromo-1-alkynes are prepared in high yields under very mild conditions by treatment of primary alkynes with PPh3/CBr4.

(Vinyl)polystyrene resin is prepared in one step by treatment of Merrifield resin with an excess dimethylsulfonium methylide.

ozone is a versatile reagent which is well adapted to solid phase synthesis: terminal double bonds can be efficiently converted into alcohols, aldehydes or carboxylic acids depending on the reaction conditions.

Substituted tetrahydropyrans are prepared in good yields by PPh3/CBr4 induced cyclization of acetals. The utility of this new procedure is illustrated by the synthesis of cis-2-(2-methyl-1 propenyl)- 4 methyltetrahydropyran (rose oxide).

Various tetrahydro-2 pyranyl protected alcohols are converted into the corresponding bromides by PPh3 / CBr4, with inversion of configuration, and in high yield.