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1.
Cell ; 186(9): 1950-1967.e25, 2023 04 27.
Article de Anglais | MEDLINE | ID: mdl-36996814

RÉSUMÉ

Little is known about the critical metabolic changes that neural cells have to undergo during development and how temporary shifts in this program can influence brain circuitries and behavior. Inspired by the discovery that mutations in SLC7A5, a transporter of metabolically essential large neutral amino acids (LNAAs), lead to autism, we employed metabolomic profiling to study the metabolic states of the cerebral cortex across different developmental stages. We found that the forebrain undergoes significant metabolic remodeling throughout development, with certain groups of metabolites showing stage-specific changes, but what are the consequences of perturbing this metabolic program? By manipulating Slc7a5 expression in neural cells, we found that the metabolism of LNAAs and lipids are interconnected in the cortex. Deletion of Slc7a5 in neurons affects the postnatal metabolic state, leading to a shift in lipid metabolism. Additionally, it causes stage- and cell-type-specific alterations in neuronal activity patterns, resulting in a long-term circuit dysfunction.


Sujet(s)
Acides aminés neutres , Transporteur-1 d'acides aminés neutres à longue chaîne , Femelle , Humains , Grossesse , Acides aminés neutres/génétique , Acides aminés neutres/métabolisme , Encéphale/métabolisme , Transporteur-1 d'acides aminés neutres à longue chaîne/génétique , Transporteur-1 d'acides aminés neutres à longue chaîne/métabolisme , Mutation , Neurones/métabolisme , Animaux , Souris
2.
Chemistry ; 26(48): 10972-10975, 2020 Aug 26.
Article de Anglais | MEDLINE | ID: mdl-32227380

RÉSUMÉ

The metal-promoted nucleophilic addition of sulfur ylides to π-systems is a well-established reactivity. However, the driving force of such transformations, elimination of a sulfide moiety, entails stoichiometric byproducts making them unfavorable in terms of atom economy. In this work, a new take on sulfur ylide chemistry is reported, an atom-economical gold(I)-catalyzed synthesis of dihydrobenzo[b]thiepines. The reaction proceeds under mild conditions at room temperature.

3.
Angew Chem Int Ed Engl ; 57(33): 10737-10741, 2018 08 13.
Article de Anglais | MEDLINE | ID: mdl-29761878

RÉSUMÉ

We report a novel approach to the classical natural product quinine that is based on two stereoselective key steps, namely a C-H activation and an aldol reaction, to unite the two heterocyclic moieties of the target molecule. This straightforward and flexible strategy enables a concise synthesis of natural (-)-quinine, the first synthesis of unnatural (+)-quinine, and also provides access to unprecedented C3-aryl analogues, which were prepared in only six steps. We additionally demonstrate that these structural analogues exhibit improved antimalarial activity compared with (-)-quinine both in vitro and in mice infected with Plasmodium berghei.


Sujet(s)
Antipaludiques/synthèse chimique , Quinine/analogues et dérivés , Aldéhydes/composition chimique , Animaux , Antipaludiques/pharmacologie , Antipaludiques/usage thérapeutique , Carbone/composition chimique , Catalyse , Cristallographie aux rayons X , Hydrogène/composition chimique , Paludisme/traitement médicamenteux , Paludisme/médecine vétérinaire , Souris , Conformation moléculaire , Plasmodium berghei/effets des médicaments et des substances chimiques , Quinine/pharmacologie , Quinine/usage thérapeutique , Ruthénium/composition chimique , Stéréoisomérie
4.
Molecules ; 23(4)2018 Mar 24.
Article de Anglais | MEDLINE | ID: mdl-29587344

RÉSUMÉ

Efficient optimization procedures in chiral catalysis are usually linked to a straightforward strategy to access groups of structurally similar catalysts required for fine-tuning. The ease of building up such ligand libraries can be increased when the structure-modifying step (introduction of a substituent) is done at a later stage of the synthesis. This is demonstrated for the extended family of di- and tetranaphtho azepinium compounds, widely used as chiral phase transfer catalysts (PTC). Using 2,6-diiodo-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepine and 4,8-diiodo-6,7-dihydro-5H-dibenzo[c,e]azepine, respectively, as key intermediates, 18 spiro-azepinium compounds were synthesized in a total yield of 25-42% over 6-7 steps from 1,1'-binaphthyl-2,2'-dicarboxylic acid or diphenic acid, respectively. The replacement of iodo groups with aryl substituents was performed as the last or the penultimate step of the synthesis.


Sujet(s)
Azépines/composition chimique , Spiranes/synthèse chimique , Catalyse , Cristallographie aux rayons X , Ligands , Modèles moléculaires , Structure moléculaire , Spiranes/composition chimique , Stéréoisomérie
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