Synthèse totale asymétrique des L-allose, L-talose, D-allonojirimycine et désoxypolyoxine C

Derivatives of 7-oxabicyclo[2.2.l]hept-5-en-2-yl ("naked sugars") are readily available through Diels-Alder cycloaddition of furan to an appropriate dienophile. Several methods allow one to obtain these molecules in optically pure form. They have been used as starting material for the syntheses of numerous natural products. In order to fully exploit the synthetic potential of "naked sugars", one must be able to functionalize regio- and stereoselectively their C(5)=C(6) double bond, as well as their C(3) position. Although several means for functionalizing the double bond had already been developed, no method was available for the C(3) center manipulation. The first objective of this work was to develop two stereoselective pathways for the functionalization of the C(3) atom by oxygen-containing groups, illustrated by the total syntheses of L-allose and L-talose. In the case of L-talose, which formally corresponds to the introduction of an hydroxyl group on C(3) by the endo face of (+)-5,6-(isopropylidenedioxy)-7-oxanorboman-2-one (+)-29, the synthesis is based on the exo α-bromation of the ketone and is followed by an intramolecular substitution, with inversion of the configuration at C(3). L-talose ((-)-13) was obtained in five steps starting from ketone (+)-29 with a 42% overall yield. In the case of L-allose, the introduction of the oxygen-containing function came from the oxidation of the double bond of the (-)-5,6-(isopropy1idenedioxy)-7-oxanorboman-2-one silylenolether ((+)-30) with a peracid. The direct precursor of this rare sugar, (+)-methyl 2,3-O-isopropylidène-L-allofuranoside (+)-61, was obtained in six steps from (-)-29 with a 30% overall yield. In the second part of this work, the objective was to introduce a nitrogen-containing function on the C(3) center of the "naked sugars" stereoselectively. The total syntheses of 5-amino-5-deoxy-D-allopyranose (-)-107 (allonojirimycin) and of deoxypolyoxin C (+)-123 are applications of the method developed. Allonojirimycin was the last isomer of gluconojirimycin which had not yet been characterized; it belongs to a class of potential glycosidase inhibitors. The starting molecule was a brominated intermediate from the synthesis of L-talose, to which a nitrogen-containing function was introduced by substitution with retention of configuration at C(3). Allonojirimycin was obtained in seven steps from (+)-29, in a 9.7% overall yield. The same principle was used in the synthesis of deoxypolyoxin C, the core structure of polyoxin and nikkomycin antibiotics. Deoxypolyoxin C was synthesized in nine steps from (+)-29 with an overall yield of 5.8%

Blockade of NR2A-Containing NMDA Receptors Induces Tau Phosphorylation in Rat Hippocampal Slices

Physiological activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors has been proposed to play a key role in both neuronal cell function and dysfunction. In the present study, we used selective NMDA receptor antagonists to investigate the involvement of NR2A and NR2B subunits in the modulatory effect of basal NMDA receptor activity on the phosphorylation of Tau proteins. We observed, in acute hippocampal slice preparations, that blockade of NR2A-containing NMDA receptors by the NR2A antagonist NVP-AAM077 provoked the hyperphosphorylation of a residue located in the proline-rich domain of Tau (i.e., Ser199). This effect seemed to be Ser199 specific as there was no increase in phosphorylation at Ser262 and Ser409 residues located in the microtubule-binding and C-terminal domains of Tau proteins, respectively. From a mechanistic perspective, our study revealed that blockade of NR2A-containing receptors influences Tau phosphorylation probably by increasing calcium influx into neurons, which seems to rely on accumulation of new NR1/NR2B receptors in neuronal membranes and could involve the cyclin-dependent kinase 5 pathway

Enhanced Astrocytic Ca\u3csup\u3e2+\u3c/sup\u3e Signals Contribute to Neuronal Excitotoxicity after Status Epilepticus

Status epilepticus (SE), an unremitting seizure, is known to cause a variety of traumatic responses including delayed neuronal death and later cognitive decline. Although excitotoxicity has been implicated in this delayed process, the cellular mechanisms are unclear. Because our previous brain slice studies have shown that chemically induced epileptiform activity can lead to elevated astrocytic Ca2+ signaling and because these signals are able to induce the release of the excitotoxic transmitter glutamate from these glia, we asked whether astrocytes are activated during status epilepticus and whether they contribute to delayed neuronal death in vivo. Using two-photon microscopy in vivo, we show that status epilepticus enhances astrocytic Ca2+ signals for 3 d and that the period of elevated glial Ca2+ signaling is correlated with the period of delayed neuronal death. To ask whether astrocytes contribute to delayed neuronal death, we first administered antagonists which inhibit gliotransmission: MPEP [2-methyl-6-(phenylethynyl)pyridine], a metabotropic glutamate receptor 5 antagonist that blocks astrocytic Ca2+ signals in vivo, and ifenprodil, an NMDA receptor antagonist that reduces the actions of glial-derived glutamate. Administration of these antagonists after SE provided significant neuronal protection raising the potential for a glial contribution to neuronal death. To test this glial hypothesis directly, we loaded Ca2+ chelators selectively into astrocytes after status epilepticus.We demonstrate that the selective attenuation of glial Ca2+ signals leads to neuronal protection. These observations support neurotoxic roles for astrocytic gliotransmission in pathological conditions and identify this process as a novel therapeutic target

Double Dissociation of Spike Timing–Dependent Potentiation and Depression by Subunit-Preferring NMDA Receptor Antagonists in Mouse Barrel Cortex

Spike timing–dependent plasticity (STDP) is a strong candidate for an N-methyl-D-aspartate (NMDA) receptor-dependent form of synaptic plasticity that could underlie the development of receptive field properties in sensory neocortices. Whilst induction of timing-dependent long-term potentiation (t-LTP) requires postsynaptic NMDA receptors, timing-dependent long-term depression (t-LTD) requires the activation of presynaptic NMDA receptors at layer 4-to-layer 2/3 synapses in barrel cortex. Here we investigated the developmental profile of t-LTD at layer 4-to-layer 2/3 synapses of mouse barrel cortex and studied their NMDA receptor subunit dependence. Timing-dependent LTD emerged in the first postnatal week, was present during the second week and disappeared in the adult, whereas t-LTP persisted in adulthood. An antagonist at GluN2C/D subunit–containing NMDA receptors blocked t-LTD but not t-LTP. Conversely, a GluN2A subunit–preferring antagonist blocked t-LTP but not t-LTD. The GluN2C/D subunit requirement for t-LTD appears to be synapse specific, as GluN2C/D antagonists did not block t-LTD at horizontal cross-columnar layer 2/3-to-layer 2/3 synapses, which was blocked by a GluN2B antagonist instead. These data demonstrate an NMDA receptor subunit-dependent double dissociation of t-LTD and t-LTP mechanisms at layer 4-to-layer 2/3 synapses, and suggest that t-LTD is mediated by distinct molecular mechanisms at different synapses on the same postsynaptic neuron

Reflections on 2018-2020

Reflections on three years of EFMC presidenc

Editorial - In vivo molecular imaging tools facilitates Drug Discovery

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EFMC, medicinal chemistry and chemical biology in Europe

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Medicinal Chemists Don't Just Make Drugs – The Art of Developing Low Molecular Weight Imaging Agents in Switzerland

Radiolabeled molecular imaging agents are useful to study drug distribution, target engagement and disease progression in human patients. Medicinal chemists often develop them in parallel to drug discovery programs, to facilitate clinical development or to better understand physiological and pathological processes. While the properties required for imaging agents differ from those of drug candidates, their optimization follows similar principles. Developing them for clinical use also requires a multidisciplinary approach, and is best conducted in a close partnership between pharmaceutical and academic research centers. This article reviews recent scientific advances towards the identification and development of low molecular weight imaging agents in Switzerland