Florence Fauvelle

Physicochemical properties and membrane interactions of anti-apoptotic derivatives 2-(4-fluorophenyl)-3-(pyridin-4-yl)imidazo[1,2-a]pyridine depending on the hydroxyalkylamino side chain length and conformation: an NMR and ESR study.

Three imidazo[1,2-a]pyridine derivatives 3a-c have been synthesized from p38 kinase inhibitor structures and evaluated as anti-apoptosis agents. These drugs were designed to interact with nucleic acids and membrane interactions by varying the chain length in position 6, from hydroxyethylamino (3a), to hydroxybutylamino (3b) and hydroxyhexylamino (3c). First experiments showed that 3a and 3b were insoluble in water while 3c could be solubilized in water despite its partition coefficient (logP=3.2). This latter feature was explained by the formation of a fifth intramolecular cycle thus allowing supramolecular structure formation (NMR and MD calculations). The interactions with membranes have been studied using (1)H, (2)H, (31)P Nuclear Magnetic Resonance (NMR), Electron Spin Resonance (ESR) and High Resolution-Magic Angle Spinning (HR-MAS). Despite the insolubility of 3a and 3b in water, these derivatives could be partially solubilized by synthetic phospholipidic model membranes (small unilamellar vesicles, SUV). (1)H NMR paramagnetic broadening experiments performed on the same models showed that 3a was located in the external layer, probably close to the surface while 3b only formed external superficial adducts. Supplementary (31)P, (2)H NMR and ESR experiments on phospholipid dispersions confirmed the location of 3a close to the polar headgroup of the external layer of the membrane, this resulting in a 2K lowering of the transition temperature. Moreover, no significant interaction was detected on the deep part of the layer ((2)H NMR and 16NS ESR experiments). This binding was also found in the presence of cell cultures, as revealed by HR-MAS NMR experiments. Conversely, no significant interaction with membranes was found with 3b or 3c. From both the unexpected solubility of 3c and 3a interactions with membranes, further chemical modifications were finally proposed.

(Hetero)Arylation of 6‐Halogenoimidazo[1,2‐a]pyridines Differently Substituted at C(2): Influence of the 2‐Substituent on the Suzuki Cross‐Coupling Reaction

We previously reported that reactivity towards the Suzuki cross-coupling reaction of 3-iodoimidazo[1,2-a]pyridines substituted at C(2) is largely influenced by the nature of this 2-substituent. Hence, with the aim to expand the scope of this coupling process to the 6-position of this series, it seemed important to similarly determine the influence of the nature of the 2-substituent (H, alkyl, or aryl) on the rate of coupling. From this work, the Suzuki-type cross-coupling was shown to proceed efficiently on 6-bromo-2-methyl- and 2-(4-fluorophenyl)imidazo[1,2-a]pyridines, whereas the 6-Br derivative unsubstituted at C(2) appeared to be poorly reactive. By modifying the reaction conditions in terms of catalyst and base, and the nature of the halogen, the reactivity of the unsubstituted series was largely enhanced. Finally, this work led us to establish efficient and convenient Suzuki reaction conditions for the 6-(hetero)arylation of 6-halogenoimidazo[1,2-a]pyridines depending on the nature of the 2-substituent and boronic acid.

Synthesis of polyfused heterocycle derivatives containing the dipyridoimidazole core by Friedländer's reaction : Access to analogs of ellipticine

Reaction of 3-amino-2-formylimidazo[l,2-a]pyridine with various aldehydes and ketones by Friedlanders methodology afforded an entry to dipyridoimidazole, tri(tetra)azacyclopenta[b]fluorene, tri(tetra)azabenzo[b]-fluorene and triazaindeno[2,1-b]phenanthrene derivatives. Intercalation with a synthetic oligodeoxynucleotide was examined.

Synthesis and Antiviral Activity of 2 and 3-Substituted Imidazo[1,2-a]pyrimidine

Abstract Synthesis of acyclo-C-nucleoside derivatives in the imidazo[1,2-a]pyrimidine series was reported. None of the evaluated compounds showed appreciable antiviral activity.

Investigation of the α-cyclodextrin-myo-inositol phosphate inclusion complex by NMR spectroscopy and molecular modeling

Abstract 1 H- 31 P NMR spectroscopy and molecular dynamics (MD) have been used to investigate the myo -inositol 2-phosphate (MY2P) inclusion complex in α-cyclodextrin (α-CD). From spectral analyses, it has not been possible to estimate the stoichiometric ratio of MY2P to α-CD, however several geometrical constraints between the two molecules have been deduced from nuclear Overhauser effects and chemical shift measurements. Based on a MD study, a model for the α-CD-MY2P interaction is proposed showing the possible coexistence of loose and tight inclusion of MY2P into α-CD.

Metyrapone effects on systemic and cerebral energy metabolism.

Metyrapone is a cytochrome P(450) inhibitor that protects against ischemia- and excitotoxicity-induced brain damages in rodents. This study examines whether metyrapone would act on energy metabolism in a manner congruent with its neuroprotective effect. In a first investigation, the rats instrumented with telemetric devices measuring abdominal temperature, received i.p. injection of either metyrapone or saline. One hour after injection, their blood and hippocampus were sampled. Hippocampus metabolite concentrations were measured using (1)H high-resolution magic angle spinning-magnetic resonance spectroscopy ((1)H HRMAS-MRS). The hippocampus levels in phosphorylated mammalian target of rapamycin (mTOR) and adenosine monophosphate-activated protein kinase (AMPK) were measured by Western Blot analysis and those of c-fos and HSP70-2 mRNA were quantified by RT-PCR. In a second investigation, the rats received the same treatment and were sacrificed 1h after. The functioning of mitochondria was immediately studied on their whole brain. Metyrapone provoked a slight hypothermia which was correlated to the increase in blood glucose concentration. Metyrapone also increased blood lactate concentrations without modifying hippocampus lactate content. In the hippocampus, metyrapone decreased γ-aminobutyric acid (GABA) and glutamate levels but increased glutamine and N-acetyl-aspartate contents (NAA). Phosphorylated mTOR and AMPK and the c-fos and HSP70-2 mRNA levels were similar between treatment groups. Metyrapone did not modify blood corticosterone levels. Mitochondrial oxygen consumption was similar in both groups whatever the substrate used. These metabolic modifications, which take place without modifying blood glucocorticoid levels, are consistent with the neuroprotective properties of metyrapone as demonstrated in animal models.

Acidic Derivative of Per(3,6-anhydro)-α-cyclodextrin: Preparation and a First Evaluation of Its Affinity for Lanthanides by 1 H NMR

We report on the first synthesis ofhexakis(2-O-carboxymethyl-3,6-anhydro)-α-cyclodextrin,an acidic derivative of per(3,6-anhydro)-α-cyclodextrin.Preliminary qualitative tests showed that thisnew compound would have greater affinity for lanthanides,cobalt and uranyl cations, thanfor sodium, potassium and calcium physiological ions.

2-O-Substituted-3,6-per-anhydro-α-Cyclodextrin as Potential Biocompatible Agents for the Selective Complexation of Heavy Metal Ions with Special Attention to Lead

We report on the synthesis,characterization and ionic complexation properties ofhexakis (2-O-acetyl-3,6-anhydro)cyclomaltohexaose and hexakis (2-O-methyl-3,6-anhydro) cyclomaltohexaose usingthin-layer chromatography and Nuclear MagneticResonance spectroscopy. The selectivity towardscations depends on chemical modification of thehydroxyl groups and a very high specificity can beobtained in the case of lead for methylatedderivatives.

Synthesis of original pyrrolonaphthyridines by 1,3-dipolar cycloaddition reactions of naphthyridinium dicyanomethylides with dimethyl acetylene-dicarboxylate

The pyrrolo[2,1-f][1,6]naphthyridine, pyrrolo[1,2-a][1,8]- and [1,5]naphthyridines along with their corresponding 2,3- and 1,2-dihydrocompounds are synthesized from naphthyridinium dicyanomethylides and dimethyl acetylenedicarboxylate

Interaction and translocation of cysteamine (mercaptoethylamine) with model membranes: a 15N-NMR and 1H-NMR study

Abstract We investigated by 15 N-NMR (nuclear magnetic resonance) spectroscopy the interactions of 15 N-labeled cysteamine ([ 15 N]mercaptoethylamine (MEA)), a radioprotecting aminothiol, with model membranes of egg yolk phosphatidylcholine (EPC) and phosphatidic acid (EPA). We prepared large unilamellar vesicles (LUVs) with a pH gradient between the intravesicular space and the bulk medium. Over the pH range from 4.8 to 8.1, the observations show a MEA incorporation into the vesicles. This result is consistent with a specific dissociation balance at the lipid-water interface. We carried out another 1 H-NMR experiment with unlabeled MEA in the presence of small unilamellar vesicles (SUVs). It revealed that the interactions of MEA within the hydrophobic core of the phospholipidic bilayer vary with external pH value over the range 4.0–7.1. Through these experiments, and others compiled from the literature, it was concluded that 15 N-NMR spectroscopy is particularly successful for transmembrane transport analysis.