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International audience; Small Conductance Calcium (Ca 2-)-activated potassium (K-) channels (SKCa) are now proved to be involved in many cancer cell behaviors such as proliferation or migration. The SIG channel isoform was particularly described in breast cancer where it can be associated with the Orai 1 Ca 2-channel to form a complex that regulates the ca 2-homeostasis during tumor development and acts as a potent mediator of bone metastases development in vivo. Until now, very few specific blockers of Orail and/or SIG have been developed as potential anti-metastatic compounds. ln 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 toc) demonstrated a significant decrease in the SK3 channel-dependent migration as well as the SK3/Orai1-related Ca 2-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.

20 iNKT cells recognize CD1d/-galactosylceramide (-GalCer) complexes via their invariant 21 TCR receptor and stimulate the immune response. Many -GalCer analogues have been 22 investigated to interrogate this interaction. Following our previous work related to the 23 modification of the hydrogen bond network between -GalCer and CD1d, we have now 24 focused our attention on the synthesis of 3-deoxy-3,3-difluoro-and 3,4-dideoxy-3,3,4,4-25 tetrafluoro-α-GalCer analogues, and studied their ability to stimulate human iNKT cells. In 26 2 each case, deoxygenation at the indicated positions was accompanied by difluoro introduction 1 in order to evaluate the resulting electronic effect on the stability of the ternary 2 CD1d/Galcer/TCR complex which has been rationalized by modeling study. With deoxy-3 difluorination at the 3-position, the two epimeric 4-OH analogues were investigated to establish 4 their capacity to compensate for the lack of the hydrogen bond donating group at the 3-position. 5 The 3,4-dideoxytetrafluoro analogue was of interest to highlight the amide NH-bond hydrogen 6 bond properties. 7 8

International audience; 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

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 efficient synthesis of novel polyhydroxy-tetrahydropyrano-pyrroles from acetylenic carbohydrate precursors in three to four steps is described. The methodology involves, as key steps, the ring contraction of pyridazine intermediates obtained by an inverse-demand Diels–Alder reaction and subsequent intramolecular lactonization. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

The stereoselective access to original polyhydroxylated tetrahydropyranopyrroles is described. The key steps involve an inverse-demand Diels-Alder reaction and a ring contraction of a pyridazine heterocycle.

The synthesis of novel substituted pyrroloquinolinones is described by concomitant ring contraction cyclization form 2-(2-amino-5-nitro-phenyl)-[4 H ]-1,3-thiazines, which were derived from N -substituted 5-nitro-anthranilonitrile. An easy access to novel 4-thiono-1,4-dihydro-1,3-quinazoline heterocycles is also mentioned.

The syntheses of thiazinone, thiazinedione and thiazolinone base modified nucleoside analogues have been discussed in both the deoxy- and ribosyl series. Both inter- and intramolecular N-glycosylations were evaluated.

Pig organs transplanted into primates are rapidly rejected because of the interaction between Gal alpha(1-->3)Gal epitopes carried by the graft and natural antibodies (anti-alphaGal antibodies) present in the blood of the recipient. This report describes a simplified synthesis of the xenogeneic disaccharide and its linkage to activated gel matrices. The digalactosides alpha-D-Galp-(1-->3)-alpha,beta-D-Galp-OAll were synthesized by the condensation of the trichloroacetimidoyl 2,3,4,6-tetra-O-benzyl-beta-D-galactopyranoside donor with the 3,4-unprotected allyl 2,6-di-O-benzyl-alpha- or beta-D-galactopyranoside acceptor precursor. Deallylation and hydrogenolysis led to the free digalactoside, whereas hydrogenolysis alone resulted in the 1-O-propyl digalactoside. Both products were tested by inhibition ELISA of natural anti-Gal alpha(1-->3)Gal antibodies. The alpha-D-Galp-(1-->3)-beta-D-Galp-OPr was found to be the best inhibitor. Thus, the allyl group of the partially benzylated alpha-D-Galp-(1-->3)-beta-D-Galp-OAll was engineered, via the hydroxy-, the tosyloxy- and the azidopropyl intermediates, into an aminopropyl group amenable to binding to N-hydroxysuccinimide-activated agarose gel matrices in order to obtain specific immunoabsorption columns. Columns made of gel substituted with 5 micromol of disaccharide per milliliter were found efficient for the immunoabsorption of anti-alphaGal antibodies from human plasma.

The synthesis of 3'-O2-(azaheterocycle)-thymidines is presented from 1-thia-3-aza- 1,3-butadiene precursors (N-thioacylamidines). A variety of heterocycles is accessible using the dienic, the electrophilic or the nucleophilic reactivity of these thia-azabutadiene systems. 3'-O2-(azaheterocycle)-thymidine analogues are regarded as potential substrates to interfere with the DNA-polymerization process.

Racemic on the outside, but not inside: Aromatic-foldamer hosts are enantiomers and as such prefer to co-crystallize even though the guests (e.g. L-tartaric acid, see picture) in each host are not present as enantiomers. This behavior allows a one-step structure elucidation of diastereomeric and quasi-racemic structures in the solid state.

The electrochemical method for the synthesis of 3-amino-6-arylpyridazines is complementary to the classic Suzuki-, Stille- or Nigishi-cross-coupling reactions and provides the products with higher yields.

Novel methods are developed for the preparation of the synthetically important bismuth agents.

Solvent-free techniques were successfully and efficiently applied under mild conditions to the perbenzylation of methyl α- d -glucopyranoside and methyl 6-bromo(and 6-chloro)-6-deoxy-α- d -glucopyranoside, and to the selective monobenzylation of diethyl (R,R)-tartrate. Selective 2-O- or 3-O-benzylation of methyl 4,6-O-benzylidene-α- d -galactopyranoside, requiring CH2Cl2 as solvent, was observed depending on the nature of the ammonium catalyst.

Solvent-free techniques were successfully and efficiently applied under mild conditions to the perbenzylation of methyl α- d -glucopyranoside and methyl 6-bromo(and 6-chloro)-6-deoxy-α- d -glucopyranoside, and to the selective monobenzylation of diethyl (R,R)-tartrate. Selective 2-O- or 3-O-benzylation of methyl 4,6-O-benzylidene-α- d -galactopyranoside, requiring CH2Cl2 as solvent, was observed depending on the nature of the ammonium catalyst.

A new synthesis and the reactivity of stable selenaazadienes are discussed. Their dienic, electrophilic and nucleophilic character are used to prepare five and six membered selenoheterocycles. The easy access to selenazine, selenazinone, selenopyran, selenazoline, selenazole and selenophene heterocycles from N-selenoacylamidines is described. An interpretation of the reactivity of the selenaazadiene systems, experimentaly compared to their thia analogues, is based on their physico-chemical parameters and correlated to the theoretical calculations of their frontier molecular orbital energy levels.

The synthesis of 6-deoxy-D-myo-inositol-1,3,4,5-tetrakisphosphates is described. The access to opticaly pure Ins(1,3,4,5)P4 analogues was carried out from deoxy myo inositol precursors derived from d -galactose. Modification of Ins(1,3,4,5)P4 analogues by lipophilic substituents has been investigated in order to produce neutral phosphate derivatives aimed to be incorporated in cell membrane for in vivo evaluation.

The synthesis of opticaly pure deoxy- myo -inositol mono, bis and trisphosphate analogues is described from 4- O -benzyl-2,3-di- O -cyclohexylidene-6-deoxy- myo -inositol and corresponding 1,5 epimer chiro -inositol. These precursors, which derive from galactose, are used to accede to a variety of cyclitol intermediates employing protection/deprotection sequence. The phosphorylation procedure was performed to produce free and original substituted phosphate derivatives aimed to be incorporated through the lipidic cell membrane for in vivo evaluation.

The preparation of 2-phenyl-4-dimethylamino-1-aza-, 1-oxa-, 1-thia-, 1-selena-3-azabuta-1,3-dienes as well as their 4-methyl derivatives is described following a new heteroatom interchange reaction process. Heteronucleophilic attack at one particular reactive site of bis-electrophilic amidinium salts is the key feature of the process. In addition, we also disclose that the substituted 1-oxa-3-aza- and 1,3-diazabuta-1,3-dienes can be obtained by a reactional transformation cascade initiated by either silver acetate addition or tosyl azide [3+2] cycloaddition onto the CS or CSe double bonds of the 1-thia- and 1-selena-3-azabuta-1,3-diene analogues.

The bielectronic electrochemical reduction of pyridazines, substituted by electron-withdrawing groups, leads to their corresponding 1,2-dihydro derivatives. Depending on the nature of the ring substitution, these intermediates can either rearrange into 1,4-dihydropyridazine isomers or be further electrochemically reduced into activated pyrroles.

The synthesis of monoglycosyl imidazoles and 1,1′-di- O -glycosides is described by direct glycosylation process from reducing sugar in the presence of 1,1′-thiocarbonyldiimidazole. Novel anomeric groups as 1- O -(imidazolyl)thiocarbonyl and 1- O -(imidazolyl)carbonyl are presented as potent glycosidic activators.

The syntheses of thiazinone, thiazinedione and thiazolinone base modified nucleoside analogues have been discussed in both the deoxy- and ribosyl series. Both inter- and intramolecular N-glycosylations were evaluated.

When compounds 3a and 3b were subjected to a Mitsunobu reaction with benzoylthymine, the expected substitution products were formed together with the regioisomers corresponding to benzyloxy group migrations.

A sensitive LC-MS-MS assay for the quantitative determination of bromocriptine has been developed and validated and is described in this work. The assay involved the extraction of the analyte from 1 ml of human plasma using a solid phase extraction on Oasis MCX cartridges. Chromatography was performed on a Symmetry C18 (2.1 mm x 100 mm, 3.5 microm) column using a mobile phase consisting of 25:75:01 acetonitrile-water-formic acid with a flow rate of 250 microl/min. The linearity was within the concentration range of 2-500 pg/ml. The lower limit of quantification was 2 pg/ml. This method has been demonstrated to be an improvement over existing methods due to its greater sensitivity and specificity.

Dichlorovinyl glycopyranosides are obtained from peracetylated glycopyranoses by a Wittig-type reaction with Ph 3 P/CCl 4 on anomeric acetate. This new type of glycosides has been used to get rapid access to the corresponding perbenzylated glycopyranoses.

Pyridazine C-nucleosides have been synthesized by [4+2] cycloaddition of alkynyl C-nucleosides with substituted tetrazines. These pyridazines on extrusion of a nitrogen atom afforded novel pyrrole C-nucleosides with good yields. The results of electrochemical and chemical reduction are compared.

The synthesis of 3'-O2-(azaheterocycle)-thymidines is presented from 1-thia-3-aza- 1,3-butadiene precursors (N-thioacylamidines). A variety of heterocycles is accessible using the dienic, the electrophilic or the nucleophilic reactivity of these thia-azabutadiene systems. 3'-O2-(azaheterocycle)-thymidine analogues are regarded as potential substrates to interfere with the DNA-polymerization process.

0022-3263; International audience; A general efficient electrochemical method for the preparation of aryl- and heteroarylpyridazines in a nickel-catalyzed cross-coupling reaction of 3-chloro-6-methoxypyridazine and 3-chloro-6-methylpyridazine with a range of functionalized aryl or heteroaryl halides is reported.