RESUMO
Bioassay-guided fractionation of an extract prepared from the fruiting bodies of a Daedalea sp. has led to the isolation of daedalols A-C (1-3). The structures of these new triterpenes were elucidated based on extensive NMR spectroscopic and mass spectrometric measurements. Assignment of the relative configuration of 3 required the preparation of a suitable derivative via a Payne rearrangement. The aspartic protease BACE1, an Alzheimer's drug target, was inhibited by 3 with an IC(50) value of 14.2 µM.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Coriolaceae/química , Triterpenos/química , Triterpenos/farmacologia , Coriolaceae/metabolismo , Humanos , Modelos Moleculares , Ressonância Magnética Nuclear Biomolecular , Inibidores de Proteases/química , Inibidores de Proteases/isolamento & purificação , Inibidores de Proteases/farmacologia , Triterpenos/isolamento & purificaçãoRESUMO
An extensive study of the secondary metabolites produced by a new Sticta sp. of lichen has led to the isolation of three new compounds containing the 4-amino-3-hydroxy-5-phenylpentanoic acid residue (Ahppa). The structures of stictamides A-C (1-3) were assigned by 2D NMR spectroscopic and chemical methods. Due to extensive epimerization of the Ahppa residue observed after acid hydrolysis, the configuration of this unit was deduced through conversion of 1 to an appropriate derivative and application of our recently developed statine NMR database. Evaluation of stictamide A against a panel of disease-relevant proteases showed that it inhibited MMP12 at 2.3 µM and significantly reduced invasion in the human glioma cell line U87MG. Docking studies suggest that stictamide A inhibits MMP12 by a non-zinc-binding mechanism.
Assuntos
Aminoácidos/química , Inibidores de Metaloproteinases de Matriz , Peptídeos/química , Peptídeos/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Metaloproteinase 12 da Matriz/química , Modelos Moleculares , Invasividade Neoplásica , Conformação ProteicaRESUMO
This review focuses on recent developments in the use of natural products as therapeutics for Alzheimer's disease. The compounds span a diverse array of structural classes and are organized according to their mechanism of action, with the focus primarily on the major hypotheses. Overall, the review discusses more than 180 compounds and summarizes 400 references.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Produtos Biológicos , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Humanos , Estrutura MolecularRESUMO
Bioassay-guided fractionation of an extract prepared from the fruits of Cordia sebestena led to the isolation of sebestenoids A-D (1-4). Their structures were elucidated on the basis of extensive NMR experiments and mass spectroscopic measurements. Compounds 1-4 exhibited moderate inhibition of the aspartic protease BACE1.
Assuntos
Ácido Aspártico Proteases/antagonistas & inibidores , Cordia/química , Fenilpropionatos/isolamento & purificação , Fenilpropionatos/farmacologia , Frutas/química , Havaí , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Fenilpropionatos/químicaRESUMO
Three isopropyl steroids, topsentinols K, L, and K trisulfate (1-3), were isolated from an undescribed species of Topsentia. The structures of the new compounds were determined by extensive 1D and 2D NMR experiments and mass spectrometry measurements. Topsentinol K trisulfate (3) inhibited the aspartic protease BACE1, although in a detergent-dependent manner suggestive of nonspecific aggregation.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Poríferos/química , Esteroides/isolamento & purificação , Animais , Humanos , Biologia Marinha , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Esteroides/química , Esteroides/farmacologiaRESUMO
Eight pentacyclic compounds, xestosaprols F-M (1-8), were isolated from a marine sponge belonging to the genus Xestospongia. The structures of these new compounds were determined on the basis of extensive analyses of NMR experiments and mass spectrometric measurements. These compounds inhibited the aspartic protease BACE1 at moderate levels in a dose-dependent manner.
