The dysregulation of RAC1 activity is associated with neoplastic transformation, metastasis, and poor prognosis in several cancers. Here, we discover in silico a series of RAC1 inhibitors. The most potent of them, A41, specifically inhibits RAC1 with an original mechanism of action. We characterize A41 as a reversible inhibitor that competes with guanine nucleotide binding specifically on RAC proteins. A41 efficiently blocks RAC1 activity and RAC1-dependent cell functions including cell adhesion and migration. Chronic administration of A41 exhibits anti-metastatic effects in mouse models of triple-negative breast cancer, leading to an increase in the survival rate. Our findings suggest that this molecule, A41, could be a promising and powerful therapeutic agent for limiting invasive cancers in patients.

This paper describes the versatility of substituted [(allyl-oxy)methyl]phosphonates to open the way to the synthesis of original phosphonated molecules with heterocyclic architectures. In 1,3-dipolarcycloaddition reactions with nitrile oxides, nitrile imines, and nitrones, these [(allyloxy)methyl]phosphonates react as dipolarophiles to give, regioselectively, the corresponding isoxazolines, pyrazolines, and isox-azolidines. Transition-metal-catalyzed reactions, including inter- or in-tramolecular Heck coupling, provided access to cinnamyl- and indenyl-linked moieties and phosphonated benzo-fused oxacycles, respectively. Additionally, ring-closing metathesis reactions enabled the synthesis of2,5-dihydrofurans with the phosphonate group at the anomeric position. In this work, 51 novel phosphorylated heterocyclic compounds, which may find significance in the pharmaceutical and agrochemical fields, were prepared.

Since the decline of the use of bisphenol A, the chemistry of the varnishes and coatings which are applied to the inner surfaces of metallic food contact materials is poorly documented. We hypothesised that can coatings are now diverse and bring forth various non-intentionally added substances (NIAS) to be described. Investigating complex components such as NIAS requires demanding non-targeted approaches. We investigated the coatings of 12 vegetable cans from the French market. More than 125 substances were pinpointed, among them 84 oligoester combinations from 8 diols and 4 diacids. Thus, oligoesters were the dominant family. Additives such as epoxidised soybean oil, bisphenol A diglycidyl ether and benzoguanamine derivatives and phenol-formaldehyde oligomers were also identified. A software for exploring databases of theoretical combinations of polyester and phenol-formaldehyde resin components (NIAS-db 1.0) was made available. The stepwise organic synthesis of native and deuterated combinations of neopentyl glycol and isophthalic acid (4 and 8 units, linear and cyclic) enabled a higher confidence level and monitoring in vegetable extracts. Migration of oligoesters averaged 330 mu g/kg in the drained vegetables (43-1600 mu g/kg). This study sheds light on the need to fulfil a proper risk assessment on this NIAS family (exposure and hazard characterisation).

A new solvent/ligand-controlled switchable C-H arylation of 1-methyl-4-nitro-1H-indazole catalyzed by Pd(OAc)(2) was achieved. A bidentate ligand in DMA promoted the activation at C7 position, while a phosphine ligand in H2O oriented the arylation at C3 position. The C3 and C7 arylation products were obtained in moderate to good yields and with high regioselectivity.

The expedient syntheses of small libraries of ((β-ethoxycarbonyl, -cyano and -acetyl)propyloxy) methylphosphonate scaffolds bearing olefin, sulfanyl, or amine functions are described. All these new derivatives are readily produced from easily available starting reagents (aldehydes, electron-poor olefins, and dialkylphosphites) following a three steps reaction sequence of condensations, SN2′-type reaction and a conjugated thia- or aza-Michael 1,4-addition with aromatic and aliphatic thiol or amine nucleophiles.

Interleukin (IL)-15 is a pleiotropic cytokine structurally close to IL-2 and sharing with the IL-2Rβ and γc receptor (R) subunits. IL-15 plays important roles in innate and adaptative immunity, supporting the activation and proliferation of NK, NK-T, and CD8+ T cells. Over-expression of IL-15 has been shown to participate to the development of inflammatory and autoimmune diseases and diverse T cell malignancies. This study is in continuity of our previous work through which a family of small-molecule inhibitors impeding IL-15/IL-2Rβ interaction with sub-micromolar activity has been identified using pharmacophore-based virtual screening and hit optimization methods. With the aim to improve the efficacy and selectivity of our lead inhibitor, specific modifications have been introduced on the basis of optimized SAR and modelisation. The new series of compounds generated have been evaluated for their capacity to inhibit the proliferation as well as the down-stream signaling of IL-15-dependent cells and to bind to IL-15.

The B-BOP instrument developed for the SPICA observatory will use a new generation of submillimeter in pixel polarization sensitive bolometers cooled at 50mK. An ultra-low background testbed for these bolometers has been developed for the M5 phase A at ESA. The main challenge is there to combine a very low flux on the detectors (ifW) a "flat" spectrum around 100 mu m, and a very high dynamic range (up to 10 pW), in the volume of a commercial dilution cryostat. All these constraints were achieved by the use of an inverted telescope optics that dilutes a multi emitter source through a rotatice polariser. This allowed us to perform the first measurements on bolometer arrays produced by CEA-Leti.

Small Conductance Calcium (Ca2+)-activated potassium (K+) channels (SKCa) are now proved to be involved in many cancer cell behaviors such as proliferation or migration. The SK3 channel isoform was particularly described in breast cancer where it can be associated with the Orai1 Ca2+ channel to form a complex that regulates the Ca2+ homeostasis during tumor development and acts as a potent mediator of bone metastases development in vivo. Until now, very few specific blockers of Orai1 and/or SK3 have been developed as potential anti-metastatic compounds. In this study, we illustrated the synthesis of new families of lipophilic pyridine and tetrahydropyridine derivatives designed as potential modulators of SK3 channel. The toxicity of the newly synthesized compounds and their migration effects were evaluated on the breast cancer cell line MDA-MB-435s. Two molecules (7a and 10c) demonstrated a significant decrease in the SK3 channel-dependent migration as well as the SK3/Orai1-related Ca2+ entry. Current measurements showed that these compounds are more likely SK3-selective. Taken all together these results suggest that such molecules could be considered as promising anti-metastatic drugs in breast cancer.

A new Ru complex containing the deprotonated 2,2':6 ',2 ''-terpyridine-6,6 ''-diphosphonic acid (H(4)tPa) and pyridine (py) of general formula [Ru-II(H(3)tPa-kappa-(NO)-O-3)(py)(2)](+), 2(+), has been prepared and thoroughly characterized by means of spectroscopic and electrochemical techniques, X-ray diffraction analysis, and density functional theory (DFT) calculations. Complex 2+ presents a dynamic behavior in the solution that involves the synchronous coordination and the decoordination of the dangling phosphonic groups of the tPa(4-) ligand. However, at oxidation state IV, complex 2(+) becomes seven coordinated with the two phosphonic groups now bonded to the metal center. Further, at this oxidation state at neutral and basic pH, the Ru complex undergoes the coordination of an exogenous OH- group from the solvent that leads to an intramolecular aromatic O atom insertion into the CH bond of one of the pyridyl groups, forming the corresponding phenoxo-phosphonate Ru complex [Ru-III(tPaO-kappa-(NOPOC)-O-2)(py)(2)](2-), 4(2-), where tPaO(5-) is the 3-(hydroxo-[2,':6 ',2 ''-terpyridine]-6,6 ''-diyl)bis(phosphonate) ligand. This new in situ generated Ru complex, 4(2-), has been isolated and spectroscopically and electrochemically characterized. In addition, a crystal structure has been also obtained using single-crystal X-ray diffraction techniques. Complex 42- turns out to be an exceptional water oxidation catalyst achieving record maximum turnover frequencies (TOFmax) on the order of 16 000 s(-1). A mechanistic analysis complemented with DFT calculations has also been carried out, showing the critical role of intramolecular second coordination sphere effects exerted by the phosphonate groups in lowering the activation energy at the rate-determining step.

CD1d restricted T lymphocytes, a subclass of human lymphocytes, appears to be major players of the immune response. A subpopulation of the CD1d restricted lymphocytes, called iNKT cells, bears a TCR receptor and reacts against ii-galactosylceramides (ii-GalCer). Recognition of ii-GalCer (KRN7000) bound to CD1d molecule of an antigen presenting cell, leads to the fast and strong secretion of a large panel of cytokines. These cytokines can stimulate the maturation of dendritic cells, activate the proliferation of IFNi§ synthesis and stimulate cytotoxic CD8 lymphocytes. These mechanisms contribute to the control of tumor progression. In view to highlight the potency of deoxy-analogues of ii-GalCers to modulate the iNKT response, we evaluated the effect of combined alterations of the sphingoid base devoid of both 4-OH1 and 3-OH groups by substitution with one or two fluorine atoms.2,3 We shown that, despite suppression of the H-bond donating capacity with CD1d, electron isoelectronic effect of one or two fluorine atoms, vs. oxygen, can modulate the lack of the sphingosine 3-OH on the destabilisation of the CD1d/GalCer/TCR complex by reinstating favourable interactions. In our continuing efforts to improve iNKT activation, we recently discovered novel a-GalCer analogues proved to be more potent by several orders of magnitude than a-GalCer for IFN-i§ secretion. Intriguingly, unlike a-GalCer, they also proved to be active when loaded on several human cancer cell lines known as not expressing CD1d. This latter result reveals a paramount effect of modified a-GalCer on CD1d/TCR complex stabilization that occurs on cancer cell bed without recruitment of usual APCs. With the aim to mediate a local immune response close to tumour environment, selected a-GalCer derivatives have been associated to the anti-EGFR monoclonal antibody. We found that monoclonal antibody glycoconjugates are able to restore iNKT stimulation at a nM range while keeping antibody cytotoxicity

iNKT cells recognize CD1d/α-galactosylceramide (α-GalCer) complexes via their invariant TCR receptor and stimulate the immune response. Many α-GalCer analogues have been investigated to interrogate this interaction. Following our previous work related to the modification of the hydrogen bond network between α-GalCer and CD1d, we have now focused our attention on the synthesis of 3-deoxy-3,3-difluoro- and 3,4-dideoxy-3,3,4,4-tetrafluoro-α-GalCer analogues, and studied their ability to stimulate human iNKT cells. In each case, deoxygenation at the indicated positions was accompanied by difluoro introduction in order to evaluate the resulting electronic effect on the stability of the ternary CD1d/Galcer/TCR complex which has been rationalized by modeling study. With deoxy-difluorination at the 3-position, the two epimeric 4-OH analogues were investigated to establish their capacity to compensate for the lack of the hydrogen bond donating group at the 3-position. The 3,4-dideoxytetrafluoro analogue was of interest to highlight the amide NH-bond hydrogen bond properties.

Addition of Reformatsky-type or allylic zinc reagents to 2,3,4,6-tetra-O-benzylglycopyranosyl cyanides led to keto ester-C-glycosides or unsaturated acyl-C-glycosides in moderate to excellent yields in the galactose, glucose, and mannose series.

A family of Ru complexes based on the pentadentate ligand t5a(3-) ((2,5-bis(6-carboxylatopyridin-2-yl)pyrrol-1-ide) and pyridine (py) that includes {Ru-II(Ht5a-kappa-(NO)-O-2)(py)(3)} (1H(II)(kappa-(NO)-O-2)), {Ru-III(t5a-kappa-(NO1.5)-O-3)(py)(2)} (2(III)(kappa-(NO1.5)-O-3)), and {Ru-IV(t5a-kappa-(NO2)-O-3)(py)(2)}(+) ({2(IV)(kappa-(NO2)-O-3)}(+)) has been prepared and thoroughly characterized. Complexes 1H(II)(kappa-(NO)-O-2), 2(III)(kappa-(NO1.5)-O-3), and {2(IV)(kappa-(NO2)-O-3)}(+) have been investigated in solution by spectroscopic methods (NMR, UV-vis) and in the solid state by single-crystal X-ray diffraction analysis and complemented by density functional theory (DFT) calculations. The redox properties of complex 2(III)(kappa-(NO1.5)-O-3) have been studied by electrochemical methods (CV and DPV), showing its easy access to high oxidation states, thanks to the trianionic nature of the t5a(3-) ligand. Under neutral to basic conditions complex {2(IV)(kappa-(NO2)-O-3)}(+) undergoes aquation, generating {Ru-IV(OH)(t5a-kappa-(NO)-O-2)(py)(2)} (2(IV)(OH)(kappa-(NO)-O-2)). Further oxidation of the complex forms {Ru-V(O)(t5a-kappa-(NO)-O-2)(py)(2)} (2(V)(O)(kappa-(NO)-O-2)), which is a very efficient water oxidation catalyst, reaching a TOFMAX value of 9400 s(-1) at pH 7.0, as measured via foot of the wave analysis. The key to fast kinetics for the catalytic oxidation of water to dioxygen by 2(V)(O)(kappa-(NO)-O-2) is due not only to the easy access to high oxidation states but also to the intramolecular hydrogen bonding provided by the noncoordinated dangling carboxylate at the transition state, as corroborated by DFT calculations.

Various 3-amino-, 3-aryloxy- and alkoxy-6-arylpyridazines have been synthesized by an electrochemical reductive cross-coupling between 3-amino-, 3-aryloxy- or 3-alkoxy-6-chloropyridazines and aryl or heteroaryl halides. In vitro antiproliferative activity of these products was evaluated against a representative panel of cancer cell lines (HuH7, CaCo-2, MDA-MB-231, HCT116, PC3, NCI-H727, HaCaT) and oncogenicity prevention of the more efficient derivatives was highlighted on human breast cancer cell line MDA-MB 468-Luc prior establishing their interaction with p44/42 and Akt-dependent signaling pathways.

The SEPAGE spectrometer (Spectrometre Electrons Protons A Grandes Energies) was realized within the PETAL+ project funded by the French ANR (French National Agency for Research). This plasma diagnostic, installed on the LMJ-PETAL laser facility, is dedicated to the measurement of charged particle energy spectra generated by experiments using PETAL (PETawatt Aquitaine Laser). SEPAGE is inserted inside the 10-meter diameter LMJ experimental chamber with a SID (Diagnostic Insertion System) in order to be close enough to the target. It is composed of two Thomson Parabola measuring ion spectra and more particularly proton spectra ranging from 0.1 to 20 MeV and from 8 to 200 MeV for the low and high energy channels respectively. The electron spectrum is also measured with an energy range between 0.1 and 150 MeV. The front part of the diagnostic carries a film stack that can be placed as close as 100 mm from the target center chamber. This stack allows a spatial and spectral characterization of the entire proton beam. It can also be used to realize proton radiographies.

Interleukin (IL)-15 is a pleiotropic cytokine, which is structurally close to IL-2 and shares with it the IL-2 β and γ receptor (R) subunits. By promoting the activation and proliferation of NK, NK-T, and CD8+ T cells, IL-15 plays important roles in innate and adaptative immunity. Moreover, the association of high levels of IL-15 expression with inflammatory and autoimmune diseases has led to the development of various antagonistic approaches targeting IL-15. This study is an original approach aimed at discovering small-molecule inhibitors impeding IL-15/IL-15R interaction. A pharmacophore and docking-based virtual screening of compound libraries led to the selection of 240 high-scoring compounds, 36 of which were found to bind IL-15, to inhibit the binding of IL-15 to the IL-2Rβ chain or the proliferation of IL-15-dependent cells or both. One of them was selected as a hit and optimized by a structure-activity relationship approach, leading to the first small-molecule IL-15 inhibitor with sub-micromolar activity.

The development of foldamer-based receptors is driven by the design of monomers with specific properties. Herein, we introduce a pyridazine-pyridine-pyridazine diacid monomer and its incorporation into helical aromatic oligoamide foldamer containers. This monomer codes for a wide helix diameter and can sequester metal ions on the inner wall of the helix cavity. Crystallographic studies and NMR titrations show that part of the metal coordination sphere remains available and may then promote the binding of a guest within the cavity. In addition to metal coordination, binding of the guest is assisted by cooperative interactions with the helix host, thereby resulting in significant enhancements depending on the foldamer sequence, and in slow guest capture and release on the NMR time scale. In the absence of metal ions, the pyridazine-pyridine-pyridazine monomer promotes an extended conformation of the foldamer that results in aggregation, including the formation of an intertwined duplex.

High dynamic range dust continuum map of the NGC 6334 star-forming complex at 350 microns obtained by combining high-resolution ground-based observations taken with the ArTeMiS camera on the APEX telescope and Herschel Space Observatory data from the HOBYS key project (Motte et al., 2010AA Russeil et al. 2013A&A...554A..42R). The effective angular resolution is ~ 8 (HPBW). (2 data files).

We report the first comprehensive study of the reactivity in organic media of (3-glycidyloxypropyl)trialkoxysilanes towards common nucleophiles. Their reactivity have to be emphasized in order to design and to improve new sol–gel hybrid synthesis.