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1.
Brain Res ; 1838: 148991, 2024 Sep 01.
Article in English | MEDLINE | ID: mdl-38754803

ABSTRACT

BACKGROUND: The study aimed to investigate the potential pharmacological and toxicological differences between Vigabatrin (VGB) and its enantiomers S-VGB and R-VGB. The researchers focused on the toxic effects and antiepileptic activity of these compounds in a rat model. METHODS: The epileptic rat model was established by intraperitoneal injection of kainic acid, and the antiepileptic activity of VGB, S-VGB, and VGB was observed, focusing on the improvements in seizure latency, seizure frequency and sensory, motor, learning and memory deficits in epileptic rats, as well as the hippocampal expression of key molecular associated with synaptic plasticity and the Wnt/ß-catenin/GSK 3ß signaling pathway. The acute toxic test was carried out and the LD50 was calculated, and tretinal damages in epileptic rats were also evaluated. RESULT: The results showed that S-VGB exhibited stronger antiepileptic and neuroprotective effects with lower toxicity compared to VGB raceme. These findings suggest that S-VGB and VGB may modulate neuronal damage, glial cell activation, and synaptic plasticity related to epilepsy through the Wnt/ß-catenin/GSK 3ß signaling pathway. The study provides valuable insights into the potential differential effects of VGB enantiomers, highlighting the potential of S-VGB as an antiepileptic drug with reduced side effects. CONCLUSION: S-VGB has the highest antiepileptic effect and lowest toxicity compared to VGB and R-VGB.


Subject(s)
Anticonvulsants , Epilepsy , Vigabatrin , Wnt Signaling Pathway , Animals , Anticonvulsants/pharmacology , Vigabatrin/pharmacology , Rats , Male , Epilepsy/drug therapy , Epilepsy/chemically induced , Stereoisomerism , Wnt Signaling Pathway/drug effects , Kainic Acid/toxicity , Rats, Sprague-Dawley , Seizures/chemically induced , Seizures/drug therapy , Hippocampus/drug effects , Hippocampus/metabolism , Neuronal Plasticity/drug effects , Disease Models, Animal , Neuroprotective Agents/pharmacology , Glycogen Synthase Kinase 3 beta/metabolism
2.
Chem Sci ; 14(9): 2330-2335, 2023 Mar 01.
Article in English | MEDLINE | ID: mdl-36873834

ABSTRACT

Azonaphthalenes have been verified as a class of effective arylation reagents in a variety of asymmetric transformations. Here a highly efficient approach to construct triaryl-substituted all-carbon quaternary stereocenters through chiral phosphoric acid-catalyzed enantioselective arylation of 3-aryl-2-oxindoles with azonaphthalenes is disclosed. This chemistry is scalable and displays excellent functional group tolerance, furnishing a series of 3,3-disubstituted 2-oxindole derivatives in good yields with excellent enantiocontrol. Preliminary mechanistic data suggest that the initially formed direct addition intermediate undergoes intramolecular annulation under acidic reaction conditions.

3.
Angew Chem Int Ed Engl ; 60(52): 26978-26985, 2021 12 20.
Article in English | MEDLINE | ID: mdl-34665909

ABSTRACT

A divergent synthesis of skeletally distinct arboridinine and arborisidine was achieved. The central divergent strategy was inspired by the divergent biosynthetic cyclization mode of arboridinine and arborisidine and their hidden topological connection. The branch point was reached through a Michael and Mannich cascade process. A site-selective intramolecular Mannich reaction was developed to construct the tetracyclic core of arboridinine, while a site-selective intramolecular α-amination of ketone was used to access the tetracyclic core of arborisidine. A strategic Peterson olefination through intramolecular nucleophile delivery was able to set up the exocyclic olefin of arboridinine.

4.
Angew Chem Int Ed Engl ; 60(10): 5512-5518, 2021 03 01.
Article in English | MEDLINE | ID: mdl-33206427

ABSTRACT

We describe herein the assembly of the cis-decalin framework through radical cyclization initiated by metal-catalyzed hydrogen atom transfer (MHAT), further applied it in the asymmetric synthesis of dankasterones A and B and periconiastone A. Position-selective C-H oxygenation allowed for installation of the necessary functionality. A radical rearrangement was adopted to create 13(14→8)abeo-8-ergostane skeleton. Interconversion of dankasterone B and periconiastone A was realized through biomimetic intramolecular aldol and retro-aldol reactions. The MHAT-based approach, serves as a new dissection means, is complementary to the conventional ways to establish cis-decalin framework.

5.
Org Lett ; 19(21): 5756-5759, 2017 11 03.
Article in English | MEDLINE | ID: mdl-29072076

ABSTRACT

An unprecedented strategy for the highly effective synthesis of γ-lactones from homoallylic alcohols was achieved by palladium catalysis in one step. The protocol affords aryl, alkyl, and spiro γ-lactones directly from readily available homoallylic alcohols in good yields with excellent functional group tolerance and high chemoselectivity under mild conditions.

6.
Chem Asian J ; 12(23): 2991-2995, 2017 Dec 05.
Article in English | MEDLINE | ID: mdl-29058778

ABSTRACT

A domino carbopalladation reaction of haloalkynes is presented. Remarkably, the four-time carbopalladation process converts the carbon-carbon triple bonds of haloalkynes stepwise into carbon-carbon double bonds, and finally to carbon-carbon single bonds. Features of this reaction are that the carbon-carbon double bonds of stable vinyl palladium intermediates are transformed into carbon-carbon single bonds with the generation of unstable alkyl palladium intermediates. The subsequently formed π-allylpalladium species are independently trapped by N-tosylhydrazones, boronic acids, and B2 pin2 in a highly diastereoselective manner, delivering the corresponding polycyclic and twisted products with a bicyclo[3.2.1]oct-2-en-3-yl)tricyclo[3.2.1.02,4 ]octane core skeleton in moderate to good yields via C-C and C-B bond formations. Significantly, the dual roles of norbornenes, ring construction and ring expansion, and the identification of electron-rich tri(2-furyl)phosphine as the ligand are found to be critical for the success of these transformations.

7.
J Org Chem ; 82(23): 12746-12756, 2017 12 01.
Article in English | MEDLINE | ID: mdl-28861996

ABSTRACT

A novel one-step strategy for the synthesis of aminocyclopropanephosphonates containing adjacent quaternary-tetrasubstituted carbon centers under transition-metal-free catalysis via [3+2] cycloaddition process has been developed. A series of aminocyclopropanephosphonates with adjacent quaternary-tetrasubstituted carbon centers including spirocyclopropyl adducts were obtained in moderate to excellent yields under mild reaction conditions. This protocol would find the potential applications in biochemistry and medicinal chemistry.

8.
Chem Asian J ; 12(15): 1875-1878, 2017 Aug 04.
Article in English | MEDLINE | ID: mdl-28661583

ABSTRACT

A catalyst-free oxidative radical sulfonylation of haloalkynes with sulfonyl hydrazides is reported. It represents an example of C(sp)-S bond formation using sulfonyl hydrazides as sulfonyl radical sources. Various alkynyl sulfones were synthesized in moderate to good yields. Having MnO2 as the oxidant is very critical for this transformation. Remarkably, the self-coupling reaction of haloalkynes through C(sp)-C(sp) bond formation is significantly inhibited under the standard reaction conditions.

9.
Chem Commun (Camb) ; 53(18): 2697-2700, 2017 Feb 28.
Article in English | MEDLINE | ID: mdl-28197556

ABSTRACT

A new example of C[double bond, length as m-dash]N double bond formation in metal carbene insertion reactions is reported. Remarkably, the general 1,2-migration process of the corresponding ylide intermediates in X-H carbene insertion reactions that leads to C-X single bond formation is completely inhibited by replacing the H atom with a nitrogen atom. This palladium-catalyzed carbene insertion reaction with N[double bond, length as m-dash]N double bonds gave various N,N-disubstituted hydrazone products in high yields.

10.
Org Biomol Chem ; 15(5): 1228-1235, 2017 Feb 01.
Article in English | MEDLINE | ID: mdl-28094400

ABSTRACT

A palladium-catalyzed cyclopropanation of internal alkenes with N-tosylhydrazones is presented. This gram-scale cyclopropanation reaction of maleimides provides a wide spectrum of 3-azabicyclo[3.1.0]hexane derivatives in high yields and diastereoselectivities. The major diastereoisomers could be easily isolated by chromatography on silica gel. This protocol provides a practical route to the mu opioid receptor antagonist CP-866,087.


Subject(s)
Azabicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Cyclopropanes/chemical synthesis , Hexanes/chemical synthesis , Hydrazones/chemistry , Maleimides/chemistry , Palladium/chemistry , Tosyl Compounds/chemistry , Azabicyclo Compounds/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Catalysis , Cyclopropanes/chemistry , Hexanes/chemistry , Molecular Structure
11.
Org Lett ; 18(16): 4008-11, 2016 08 19.
Article in English | MEDLINE | ID: mdl-27504788

ABSTRACT

The first example of the epoxidation reaction of trifluoromethylketones with N-tosylhydrazones under transition-metal free conditions is reported. This epoxidation reaction provided tetrasubstituted trifluoromethylated oxiranes with excellent yields and diastereoselectivities. The salient features of this reaction include readily available starting materials, mild conditions, broad substrate scope, high efficiency, and valuable further applications. Remarkably, this reaction proceeded through an unprecedented nucleophilic addition process, and the ammonium O-anion intermediate was detected and characterized by NMR and HRMS analysis.

12.
Org Lett ; 18(6): 1470-3, 2016 Mar 18.
Article in English | MEDLINE | ID: mdl-26958741

ABSTRACT

Cyclopropanation of 2-aminoacrylates with N-tosylhydrazones could proceed smoothly under transition-metal-free conditions via a [3 + 2] cycloaddition process. This robust protocol exhibits excellent generality, delivering a wide spectrum of cyclopropane α-amino acid esters bearing contiguous quaternary carbon centers in high yields and diastereoselectivities. With these readily available products, the steric convergence of cyclopropane α-amino acids could be readily obtained.


Subject(s)
Amino Acids/chemical synthesis , Carbon/chemistry , Cyclopropanes/chemical synthesis , Hydrazones/chemistry , Tosyl Compounds/chemistry , Amino Acids/chemistry , Catalysis , Cycloaddition Reaction , Cyclopropanes/chemistry , Molecular Structure , Stereoisomerism , Transition Elements
13.
Chem Commun (Camb) ; 52(1): 84-7, 2016 Jan 04.
Article in English | MEDLINE | ID: mdl-26496814

ABSTRACT

We describe herein a palladium-catalyzed Heck-type reaction of O-acetyl ketoximes and allylic alcohols to synthesise pyridines. This protocol allows the robust synthesis of pyridines and azafluorenones in good to excellent yields with tolerance of various functional groups under mild conditions. The reaction is supposed to go through an oxidative addition of oximes to palladium(0) complexes, generating an alkylideneamino-palladium(II) species, which is utilized as a key intermediate to capture the nonbiased alkenes for carbon-carbon bond formation.

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