RESUMO
Lysosomal degradation pathways coordinate the clearance of superfluous and damaged cellular components. Compromised lysosomal degradation is a hallmark of many degenerative diseases, including lysosomal storage diseases (LSDs), which are caused by loss-of-function mutations within both alleles of a lysosomal hydrolase, leading to lysosomal substrate accumulation. Gaucher's disease, characterized by <15% of normal glucocerebrosidase function, is the most common LSD and is a prominent risk factor for developing Parkinson's disease. Here, we show that either of two structurally distinct small molecules that modulate PIKfyve activity, identified in a high-throughput cellular lipid droplet clearance screen, can improve glucocerebrosidase function in Gaucher patient-derived fibroblasts through an MiT/TFE transcription factor that promotes lysosomal gene translation. An integrated stress response (ISR) antagonist used in combination with a PIKfyve modulator further improves cellular glucocerebrosidase activity, likely because ISR signaling appears to also be slightly activated by treatment by either small molecule at the higher doses employed. This strategy of combining a PIKfyve modulator with an ISR inhibitor improves mutant lysosomal hydrolase function in cellular models of additional LSD.
Assuntos
Fibroblastos , Glucosilceramidase , Doenças por Armazenamento dos Lisossomos , Lisossomos , Fosfatidilinositol 3-Quinases , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Lisossomos/metabolismo , Lisossomos/efeitos dos fármacos , Glucosilceramidase/metabolismo , Glucosilceramidase/genética , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Doenças por Armazenamento dos Lisossomos/tratamento farmacológico , Doenças por Armazenamento dos Lisossomos/genética , Doenças por Armazenamento dos Lisossomos/metabolismo , Doença de Gaucher/tratamento farmacológico , Doença de Gaucher/genética , Doença de Gaucher/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologiaRESUMO
Herein, we describe our synthetic efforts toward the pupukeanane natural products, in which we have completed the first enantiospecific route to 2-isocyanoallopupukeanane in 10 steps (formal synthesis), enabled by a key Pd-mediated cyclization cascade. This subsequently facilitated an unprecedented bio-inspired "contra-biosynthetic" rearrangement, providing divergent access to 9-isocyanopupukeanane in 15 steps (formal synthesis). Computational studies provide insight into the nature of this rearrangement.
RESUMO
The all-cis stereoisomers of tetrasubstituted azetidine-2-carboxylic acids and derivatives that possess three chiral centers have been prepared in high yield and stereocontrol from silyl-protected Z-γ-substituted enoldiazoacetates and imido-sulfur ylides by asymmetric [3+1]-cycloaddition using chiral sabox copper(I) catalysis followed by Pd/C catalytic hydrogenation. Hydrogenation of the chiral p-methoxybenzyl azetine-2-carboxylates occurs with both hydrogen addition to the C=C bond and hydrogenolysis of the ester.
RESUMO
Enoldiazoimides, a new subclass of enoldiazo compounds, generate enol-substituted carbonyl ylides whose reactions with sulfur ylides enable an unprecedented formal [4+2]â cycloaddition. The resulting multifunctionalized indolizidinones, which incorporate sulfur, are formed in good yields under mild reaction conditions. The uniqueness of this transformation stems from the role of the silyl-protected enol, since the corresponding acetyldiazoimide failed to provide any cross-products in metal-catalyzed reactions with sulfur ylides. This copper-catalyzed cycloaddition is initiated with the generation of enol-substituted carbonyl ylides and sulfur ylides from enoldiazoimides and sulfonium salts, respectively, and proceeds through stepwise six-membered ring formation, C-O and C-S bond cleavage, and silyl and acetyl group migration.
Assuntos
Compostos Azo/química , Cobre/química , Imidas/química , Compostos Organometálicos/química , Enxofre/química , Catálise , Reação de Cicloadição , Estrutura MolecularRESUMO
The first asymmetric [3+1]-cycloaddition was successfully achieved by copper(I) triflate/double-sidearmed bisoxazoline complex catalyzed reactions of ß-triisopropylsilyl-substituted enoldiazo compounds with sulfur ylides. This methodology delivered a series of chiral cyclobutenes in good yields with high enantio- and diastereoselectivities (up to 99 %â ee, and >20:1â d.r.). Additionally, the [3+1]-cycloaddition of catalytically generated metallo-enolcarbenes was successfully extended to reaction with a stable benzylidene dichlororuthenium complex.
RESUMO
Highly selective divergent cycloaddition reactions of enoldiazo compounds and α-diazocarboximides catalyzed by copper(I) or dirhodium(II) have been developed. With tetrakis(acetonitrile)copper(I) tetrafluoroborate as the catalyst epoxypyrrolo[1,2-a]azepine derivatives were prepared in good yields and excellent diastereoselectivities through the first reported [3+3]-cycloaddition of a carbonyl ylide. Use of Rh2 (pfb)4 or Rh2 (esp)2 directs the reactants to regioselective [3+2]-cycloaddition generating cyclopenta[2,3]pyrrolo[2,1-b]oxazoles with good yields and excellent diastereoselectivities.
RESUMO
The condition of having a healthy, functional proteome is known as protein homeostasis, or proteostasis. Establishing and maintaining proteostasis is the province of the proteostasis network, approximately 2,700 components that regulate protein synthesis, folding, localization, and degradation. The proteostasis network is a fundamental entity in biology that is essential for cellular health and has direct relevance to many diseases of protein conformation. However, it is not well defined or annotated, which hinders its functional characterization in health and disease. In this series of manuscripts, we aim to operationally define the human proteostasis network by providing a comprehensive, annotated list of its components. We provided in a previous manuscript a list of chaperones and folding enzymes as well as the components that make up the machineries for protein synthesis, protein trafficking into and out of organelles, and organelle-specific degradation pathways. Here, we provide a curated list of 838 unique high-confidence components of the autophagy-lysosome pathway, one of the two major protein degradation systems in human cells.
RESUMO
Coupling reactions of amines and alcohols are of central importance for applications in chemistry and biology. These transformations typically involve the use of a reagent, activated as an electrophile, onto which nucleophile coupling results in the formation of a carbon-nitrogen or a carbon-oxygen bond. Several promising reagents and procedures have been developed to achieve these bond forming processes in high yields with excellent stereocontrol, but few offer direct coupling without the intervention of a catalyst. Herein, we report the synthesis of chiral donor-acceptor azetines by highly enantioselective [3 + 1]-cycloaddition of enoldiazoacetates with aza-ylides and their selective coupling with nitrogen and oxygen nucleophiles via 3-azetidinones to form amino acid derivatives, including those of peptides and natural products. The overall process is general for a broad spectrum of nucleophiles, has a high degree of electronic and steric selectivity, and retains the enantiopurity of the original azetine.