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.

An efficient two‐step strategy for the synthesis of constrained C‐glycosyl amino acid derivatives from C‐vinylglycosides involving a 1,3‐dipolar cycloaddition using l‐(–)‐menthone‐derived nitrone as the key step is described. After optimization of 1,3‐dipolar cycloaddition conditions, various C‐vinylglycosides were tested leading exclusively to one diastereoisomer of the corresponding cycloadduct in good to excellent yields. The total facial selectivity observed was also studied by DFT calculations. Original conformationally restricted C‐glycosyl amino acid derivatives (8 examples) were isolated after simple cleavage of the chiral auxiliary.

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.

Bacteria from deep-sea hydrothermal vents constitute an attractive source of bioactive molecules. In particular, exopolysaccharides (EPS) produced by these bacteria become a renewable source of both biocompatible and biodegradable molecules. The low molecular weight (LMW) derivatives of the GY785 EPS produced by the deep-sea hydrothermal vent strain Alteromonas infernus have previously displayed some biological properties, similar to those of glycosaminoglycans (GAG), explored in cancer and tissue engineering. These GAG-mimetic derivatives are obtained through a free radical depolymerization process, which could, however, affect their structural integrity. In a previous study, we have shown that A. infernus produces depolymerizing enzymes active on its own EPS. In the present study, an enzymatic reaction was optimized to generate LMW derivatives of the GY785 EPS, which could advantageously replace the present bioactive derivatives obtained by a chemical process. Analysis by mass spectrometry of the oligosaccharide fractions released after enzymatic treatment revealed that mainly a lyase activity was responsible for the polysaccharide depolymerization. The repeating unit of the GY785 EPS produced by enzyme cleavage was then fully characterized.

Glycoconjugate vaccines are formed by covalently link a carbohydrate antigen to a carrier protein whose role is to achieve a long lasting immune response directed against the carbohydrate antigen. The nature of the sugar antigen, its length, its ratio per carrier protein and the conjugation chemistry impact on both structure and the immune response of a glycoconjugate vaccine. In addition it has long been assumed that the sites at which the carbohydrate antigen is attached can also have an impact. These important issue can now be addressed owing to the development of novel chemoselective ligation reactions as well as techniques such as site-selective mutagenesis, glycoengineering, or extension of the genetic code. The preparation and characterization of homogeneous bivalent pneumococcal vaccines is reported. The preparation and characterization of homogeneous bivalent pneumococcal vaccines is reported. A synthetic tetrasaccharide representative of the serotype 14 capsular polysaccharide of Streptococcus pneumoniae has been linked using the thiol/maleimide coupling chemistry to four different Pneumococcal surface adhesin A (PsaA) mutants, each harboring a single cysteine mutation at a defined position. Humoral response of these 1 to 1 carbohydrate antigen/PsaA conjugates have been assessed in mice. Our results showed that the carbohydrate antigen-PsaA connectivity impacts the anti-carrier response and raise questions about the design of glycoconjugate vaccine whereby the protein plays the dual role of immunogen and carrier.

The synthesis C-vinyl glycosides, useful intermediates for the synthesis of C-glycoconjugates, was carried out on gram-scale by controlled reduction of the corresponding ethynyl derivatives in good to excellent yields in different carbohydrate series.

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 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.

The “Journées Franco-Belges de Pharmacochimie” is a recognized annual meeting in organic and medicinal chemistry known for the quality of scientific exchange and conviviality. Young researchers were encouraged to present their work and share ideas with senior scientists. Abstracts of plenary lectures, oral communications, and posters presented during the meeting are collected in this report.

The formation of undesired glycals in this reaction is prevented by utilization of a free hydroxy group in position 2, which is deprotonated during the process.

A new strategy for the synthesis of acyl β-C-glycosides is described. The reactivity of glyconitriles toward organometallic reagents such as organomagnesium or organolithium derivatives was studied, affording acyl β-C-glycosides in moderate to good yields. In this study, glycal formation was efficiently prevented by deprotonating the hydroxyl group in position 2 of the glyconitriles during the process.

The synthesis and evaluation of new extractants for spent nuclear fuel reprocessing are described. New bitopic ligands constituted of phenanthroline and 1,3,5-triazine cores functionalized by picolinamide groups were designed. Synthetic routes were investigated and optimized to obtain twelve new polyaza-heterocyclic ligands. In particular, an efficient and versatile methodology was developed to access non-symmetric 2-substituted-4,6-di(6-picolin-2-yl)-1,3,5-triazines from the 1,3,5-triazapentadiene precursor in the presence of anhydride reagents. Extraction studies showed the ability of both ligand series to extract and separate actinides selectively at different oxidation states (U(VI), Np(V,VI), Am(III), Cm(III), and Pu(IV)) from an acidic solution (3 M HNO3). Phenanthroline-based ligands show the most promising efficiency for use in the group actinide extraction (GANEX) process due to a higher number of donor nitrogen atoms and a suitable pre-organization of the dipicolinamide-1,10-phenanthroline architecture.

Starting from a previously described aromatic oligoamide helically folded capsule that binds tartaric acid with high affinity and diastereoselectivity, we demonstrate the feasibility of the direct in situ modification of the helix backbone, which results in a conformational change that reduces its affinity for guests by two orders of magnitude. Specifically, ring contraction of the central pyridazine unit into a pyrrole in the full helical sequence was investigated by using electrochemical and chemical processes. The sequence containing the pyrrole was synthesized independently in a convergent manner to ascertain its structure. The conformation of the pyrrolic folded capsule was elucidated in the solid state by X-ray crystallography and in solution by using (1)H and (13)C NMR spectroscopy. Solution studies revealed an unanticipated solvent-dependent equilibrium between the anti-anti and syn-syn conformations of the pyrrole ring with respect to its two adjacent pyridine units. Titrations of the pyrrole-containing sequence monitored by (1)H NMR spectroscopy confirmed the expected drop in affinity for tartaric acid and malic acid that arises from the conformation change in the backbone that follows the replacement of the pyridazine by a pyrrole. The reduction of the pyridazine to a pyrrole was characterized by cyclic voltammetry both on the entire sequence and on a shorter precursor. The lower cathodic potential of the precursor made its preparative-scale electroreduction possible. Direct in situ modification of the pyridazine within the entire capsule sequence was achieved chemically by using zinc in acetic acid.

The title compound, C15H20O5, presents a bis-norsesquiterpene skeleton, with a trans-deca-line backbone constrained by the lactone bridge. The α-hy-droxy substituent and the methyl group belonging to the two deca-line rings are in axial positions, whereas the other methyl group and the acyl group occupy the sterically preferred equatorial positions. The mol-ecular structure is stabilized by an intra-molecular C-H⋯O hydrogen bond. In the crystal, mol-ecules are linked into chains along [010] by O-H⋯O hydrogen bonds.

We have developed an efficient diastereoselective synthetic route towards a nardosinane sesquiterpene scaffold. The strategy used a key bicyclic diene intermediate 11a , and allowed access to valuable polyoxygenated sesquiterpenes 21 and 22 , which may be regarded as analogues of the natural sesquiterpenes laevinol B and fulvol acetate, respectively.

3-Amino-6-aryl- and 3-amino-6-heteroarylpyridazines have been obtained in generally good yield using a nickel-catalyzed electrochemical cross-coupling between 3-amino-6-chloropyridazines and aryl or heteroaryl halides at room temperature. Comparative experiments involving classical palladium-catalyzed reactions, such as Suzuki, Stille, or Negishi cross-couplings, reveal that the electrochemical method can constitute a reliable alternative tool for biaryl formation. A possible reaction mechanism is proposed on the basis of electrochemical analyses.