RESUMO
O-GlcNAc hydrolase (OGA) removes O-linked N-acetylglucosamine (O-GlcNAc) from a myriad of nucleocytoplasmic proteins. Through co-expression and assembly of OGA fragments, we determined the three-dimensional structure of human OGA, revealing an unusual helix-exchanged dimer that lays a structural foundation for an improved understanding of substrate recognition and regulation of OGA. Structures of OGA in complex with a series of inhibitors define a precise blueprint for the design of inhibitors that have clinical value.
Assuntos
Modelos Moleculares , beta-N-Acetil-Hexosaminidases/química , Acetilglucosamina/metabolismo , Sítios de Ligação , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Células HEK293 , Humanos , Ligantes , Ligação Proteica , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Estrutura Terciária de Proteína , beta-N-Acetil-Hexosaminidases/genética , beta-N-Acetil-Hexosaminidases/metabolismoRESUMO
Pyrrolidine-based iminocyclitols are a promising class of glycosidase inhibitors. Reported herein is a convenient epimerization strategy that provides direct access to a range of stereoisomeric iminocyclitol inhibitors of O-GlcNAcase (OGA), the enzyme responsible for catalyzing removal of O-GlcNAc from nucleocytoplasmic proteins. Structural details regarding the binding of these inhibitors to a bacterial homologue of OGA reveal the basis for potency. These compounds are orally available and permeate into rodent brain to increase O-GlcNAc, and should prove useful tools for studying the role of OGA in health and disease.
Assuntos
Encéfalo/metabolismo , Ciclitóis/farmacocinética , Inibidores Enzimáticos/farmacocinética , beta-N-Acetil-Hexosaminidases/antagonistas & inibidores , Animais , Ciclitóis/química , Inibidores Enzimáticos/química , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , EstereoisomerismoRESUMO
A short synthesis of ent-hydromorphone has been achieved in twelve steps from ß-bromoethylbenzene. The key transformations involved the enzymatic dihydroxylation of the arene to the corresponding cis-dihydrodiol, Mitsunobu coupling with the ringâ A fragment, oxidative dearomatization of the C3 phenol, and the subsequent [4+2] cycloaddition to form ring B of the morphinan. The synthesis was completed by intramolecular amination at C9.
Assuntos
Analgésicos Opioides/síntese química , Reação de Cicloadição , Dioxigenases/metabolismo , Hidromorfona/síntese química , Aminação , Ciclização , Estrutura Molecular , Oxirredução , EstereoisomerismoRESUMO
Homoenolates generated from α,ß-unsaturated aldehydes using NHC catalysis underwent facile addition to dibenzylidene cyclohexanone to afford bicyclic cyclopentenes as single diastereomers.
RESUMO
Homoenolate generated from alpha,beta-unsaturated aldehydes by NHC catalysis underwent facile addition to conjugated sulfonimines, generated in situ, and subsequent methanolysis to afford protected GABA derivatives stereoselectively and in high yields, thus constituting a novel pseudo four component reaction.
RESUMO
A facile NHC-mediated reaction of aromatic aldehydes with carbon dioxide leading to carboxylic acids is described. The present protocol is mechanistically important, and it can serve as a tool for the sequestration of carbon dioxide.
Assuntos
Aldeídos/química , Dióxido de Carbono/química , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Catálise , Metano/análogos & derivados , Metano/química , Estrutura MolecularRESUMO
Homoenolates generated from enals by nucleophilic heterocyclic carbene (NHC) catalysis undergo annulation with chalcones in methanol to afford methyl beta-hydroxycyclopentanecarboxylates, stereoselectively. Construction of four contiguous stereocenters in a stereoselective manner is noteworthy.
RESUMO
A stereoselective Michael addition of homoenolate, generated from enals by nucleophilic heterocyclic carbene (NHC) catalysis, to beta-nitrostyrenes is reported for the first time. The products of this reaction obtained in good yields are of potential value in the synthesis of a variety of acyclic and heterocyclic compounds.