GluN2C selective inhibition is a target to develop new antiepileptic compounds.

OBJECTIVE: Many early-onset epilepsies present as developmental and epileptic encephalopathy associated with refractory seizures, altered psychomotor development, and disorganized interictal cortical activity. Abnormal upregulation of specific N-methyl-d-aspartate receptor (NMDA-R) subunits is being disentangled as one of the mechanisms of severe early-onset epilepsies. In tuberous sclerosis complex (TSC), upregulation of the GluN2C subunit of the NMDA-R with slow deactivation kinetic results in increased neuronal excitation and synchronization. METHODS: Starting from an available GluN2C/D antagonist, NMDA-R-modulating compounds were developed and screened using a patch clamp on neuronal culture to select those with the strongest inhibitory effect on glutamatergic NMDA currents. For these selected compounds, blood pharmacokinetics and passage through the blood-brain barrier were studied. We tested the effect of the most promising compounds on epileptic activity in Tsc1+/- mice brain slices with multielectrode array, and then in vivo at postnatal ages P14-P17, comparable with the usual age at epilepsy onset in human TSC. RESULTS: Using a double-electrode voltage clamp on isolated NMDA currents, we identified the most prominent antagonists of the GluN2C subunit with no effect on GluN2A as a means of preventing side effects. The best compound passing through the blood-brain barrier was selected. Applied in vivo in six Tsc1+/- mice at P14-P17, this compound reduced or completely stopped spontaneous seizures in four of them, and decreased the background activity disorganization. Furthermore, ictal-like discharges stopped on a human brain sample from an infant with epilepsy due to TSC. INTERPRETATION: Subunit-selective inhibition is a valuable target for developing drugs for severe epilepsies resulting from an upregulation of NMDA-R subunit-mediated transmission.

Conversion of 3-Bromo-2H-coumarins to 3-(Benzofuran-2-yl)-2H-coumarins under Palladium Catalysis: Synthesis and Photophysical Properties Study.

An intriguing conversion of 3-bromo-2H-coumarins to 3-(benzofuran-2-yl)-2H-coumarins under palladium catalysis is reported. The process involves, from only one single starting material, three transformations and two bond formations in one pot: C-C bond formation via C-H activation and C-O bond formation through 2H-coumarin-to-benzofuran ring contraction under palladium catalysis. Moreover, the photophysical properties of all synthesized compounds were studied.

Alkoxyallene-ynes: Selective Preparation of Bicyclo[5.3.0] Ring Systems Including a δ-Alkoxy Cyclopentadienone.

The development of an intramolecular rhodium(I)-catalyzed Pauson-Khand reaction of alkoxyallene-ynes with a proximal alkoxy group is reported. This reaction, in the presence of a [Rh(cycloocta-1,5-diene)Cl]2/propane-1,3-diylbis(diphenylphosphane) system under a CO atmosphere, constitutes a powerful tool for selectively accessing carbo- and heterobicyclo[5.3.0] frameworks featuring an enol ether moiety. Through this procedure, a straightforward access to guaiane skeletons with a tertiary hydroxy group at the C10 position was achieved.

Diversity-oriented synthesis of fused thioglycosyl benzo[e][1,4]oxathiepin-5-ones and benzo[f][1,4]thiazepin-5(2H)-ones by a sequence of palladium-catalyzed glycosyl thiol arylation and deprotection-lactonization reactions.

An efficient synthesis of thioglycosylated benzo[e][1,4]oxathiepin-5-one and benzothiazepinone derivatives by a sequence of palladium-catalyzed glycosyl thiol arylation followed by deprotection-lactonization reactions has been reported. This diversity-oriented strategy enabled access to unknown complex cyclic scaffolds with polyhydroxylated appendages of biological interest.

Regio- and stereochemical studies on the nitroso-Diels-Alder reaction with 1,2-disubstituted dienes.

The regioselectivity of the nitroso-Diels-Alder reaction between unsymmetrical acyclic dienes and Boc-nitroso (Boc=tert-butoxycarbonyl) reagent or the Wightman chiral chloronitroso reagents has been studied. With the Boc-nitroso reagent, the selectivity is a consequence of steric effects at the C1-position in the diene and electronic effects at the C2-position in the diene. The combination of an unprotected hydroxyethyl side chain at C1 and an electron-withdrawing group at C2 allows complete regioselectivity in favour of the proximal isomer. The same isomer was obtained exclusively with the chiral nitroso reagent with high enantioselectivities. A model based on steric effects is proposed.

Asymmetric synthesis of a highly functionalized enantioenriched system close to thapsigargin framework.

A straightforward approach to a highly functionalized enantioenriched bicyclo[5.3.0]decadienone system close to the thapsigargin framework has been achieved. The developed synthetic route involves two main stages: installation of the chains on either side of the quaternary center at C7 starting from a central enantiopure epoxide and formation of the bicyclic octahydroazulene through subsequent Pauson-Khand annelation.

Efficient cleavage of the N-O bond of 3,6-dihydro-1,2-oxazines mediated by some alpha-hetero substituted carbonyl compounds in mild conditions.

The efficient cleavage of the N-O bond of some nitroso Diels-Alder cycloadducts has been achieved in mild conditions, mediated either by 2,2-dimethyl-1,3-dioxan-5-one or 1,3-dithiolane-2-carboxaldehyde. These new and purely organic conditions allow an excellent tolerance with respect to many functional groups that would have been affected by previous reductive cleavage conditions.