RESUMO
Synucleinopathies are a class of neurodegenerative diseases defined by the presence of α-synuclein inclusions. The location and composition of these α-synuclein inclusions directly correlate to the disease pattern. The inclusions in Multiple System Atrophy are located predominantly in oligodendrocytes and are rich in a second protein, p25α. P25α plays a key role in neuronal myelination by oligodendrocytes. In healthy oligodendrocytes, there is little to no α-synuclein present. If aberrant α-synuclein is present, p25α leaves the myelin sheaths and quickly co-aggregates with α-synuclein, resulting in the disruption of the cellular process and ultimately cell death. Herein, we report that p25α is susceptible for 20S proteasome-mediated degradation and that p25α induces α-synuclein aggregation, resulting in proteasome impairment and cell death. In addition, we identified small molecules 20S proteasome enhancers that prevent p25α induced α-synuclein fibrilization, restore proteasome impairment, and enhance cell viability.
RESUMO
The past several years have seen an increase in the discovery and isolation of natural products of the indole alkaloid class. Bis- and tris-indole alkaloids are classes of natural products that have been shown to display diverse, potent biological activities. Of particular interest are bis- and tris-indole alkaloids containing N-heterocyclic linker moieties. It has been reported that more than 85% of biologically active compounds contain one or more heterocyclic moieties; of these, N-heterocycles have been identified as the most prevalent. The goal of this review is to provide a detailed overview of the recent advances in isolation and total synthesis of bis- and tris-indole alkaloids that contain N-heterocyclic linker moieties. The known biological activities of these natural products will also be discussed.
Assuntos
Produtos Biológicos , Compostos Heterocíclicos , Alcaloides Indólicos , Estrutura Molecular , Alcaloides Indólicos/síntese química , Alcaloides Indólicos/química , Produtos Biológicos/química , Produtos Biológicos/síntese química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/químicaRESUMO
Herein, we report the total synthesis of nagelamide W (1), a pyrrole imidazole alkaloid of the nagelamide family isolated in 2013. The key approach in this work involves the construction of the 2-aminoimidazoline core of nagelamide W from alkene 6 through a cyanamide bromide intermediate. The synthesis of nagelamide W was accomplished with an overall yield of 6.0%.
Assuntos
Alcaloides , Pirróis , Estrutura MolecularRESUMO
The hydroxytetrahydropyrrolo-imidazolidinone (HTHP-I) core present in colensolide A is a synthetically intriguing scaffold as a result of its high heteroatom/carbon ratio and perceived instability. The similarity of this core to other potent biological scaffolds has led us to develop a synthetic route utilizing isocyanate chemistry to access this core and complete the first total synthesis of colensolide A.
RESUMO
The balance between protein degradation and protein synthesis is a highly choreographed process generally called proteostasis. Most intracellular protein degradation occurs through the ubiquitin-proteasome system (UPS). This degradation takes place through either a ubiquitin-dependent or a ubiquitin-independent proteasomal pathway. The ubiquitin-independent pathway selectively targets unfolded proteins, including intrinsically disordered proteins (IDPs). Dysregulation of proteolysis can lead to the accumulation of IDPs, seen in the pathogenesis of various diseases, including cancer and neurodegeneration. Therefore, the enhancement of the proteolytic activity of the 20S proteasome using small molecules has been identified as a promising pathway to combat IDP accumulation. Currently, there are a limited number of known small molecules that enhance the activity of the 20S proteasome, and few are observed to exhibit enhanced proteasome activity in cell culture. Herein, we describe the development of a high-throughput screening assay to identify cell-permeable proteasome enhancers by utilizing an AlphaLISA platform that measures the degradation of a GFP conjugated intrinsically disordered protein, ornithine decarboxylase (ODC). Through the screening of the Prestwick and NIH Clinical Libraries, a kinase inhibitor, erlotinib, was identified as a new 20S proteasome enhancer, which enhances the degradation of ODC in cells and α-synuclein in vitro.
RESUMO
A hexanucleotide repeat expansion (HRE) in an intron of gene C9ORF72 is the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. The HRE undergoes noncanonical translation (repeat-associated non-ATG translation) resulting in the production of five distinct dipeptide repeat (DPR) proteins. Arginine-rich DPR proteins have shown to be toxic to motor neurons, and recent evidence suggests this toxicity is associated with disruption of the ubiquitin-proteasome system. Here we report the ability of known 20S proteasome activator, TCH-165, to enhance the degradation of DPR proteins and overcome proteasome impairment evoked by DPR proteins. Furthermore, the 20S activator protects rodent motor neurons from DPR protein toxicity and restores proteostasis in cortical neuron cultures. This study suggests that 20S proteasome enhancers may have therapeutic efficacy in neurodegenerative diseases that display proteostasis defects.
RESUMO
A rare example of a structurally characterized metal quinoline complex was prepared using a non-covalent quinoline-based proteasome inhibitor (Quin1), and a related complex bearing an inactive quinoline ligand (Quin2) was also synthesized. The quinolines are prepared by a one-pot procedure involving titanium-catalyzed alkyne iminoamination and are bound to ruthenium by reaction with CpRu(NCMe)3+ PF6- in CH2Cl2. The arene of the quinoline is η6-bonded to the ruthenium metal center. The kinetics of quinoline displacement were investigated, and reactivity with deuterated solvents follows the order acetonitrile > DMSO > water. Quinolines with more methyl groups on the arene are more kinetically stable, and RuCp(Quin1)+ PF6- (1), which has two methyl groups on the arene, is stable for days in DMSO. In contrast, a very similar complex (2) made with Quin2 having no methyl groups on the arene was readily displaced by DMSO. Both 1 and 2 are stable in 9 : 1 water/DMSO for days with no measurable displacement of the quinoline. The cytotoxicity of the quinolines, their CpRu+-complexes, and CpRu(DMSO)3+ PF6- was investigated towards two multiple myeloma cell lines: MC/CAR and RPMI 8226. To determine whether the activity of the complexes was related to the nature of the quinoline ligands, two structurally similar quinoline ligands with vastly different biological properties were investigated. Quin1 is a cytotoxic proteasome inhibitor, whereas Quin2 is not a proteasome inhibitor and showed no discernable cytotoxicity. The ruthenium complexes showed poor cellular proteasome inhibition. However, both 1 and 2 showed good cytotoxicity towards RPMI 8226 and MC/CAR, with 1 being slightly more cytotoxic. For example, 1 has a CC50 = 2 µM in RPMI 8226, and 2 has a CC50 = 5 µM for the same cell line. In contrast, CpRu(DMSO)3+ PF6- was quite active towards MC/CAR with CC50 = 2.8 µM but showed no discernible cytotoxicity toward RPMI 8226. The mechanism of action responsible for the observed cytotoxicity is not known, but the new Ru(Cp)(Quin)+ PF6- complexes do not cross-link DNA as found for platinum-based drugs. It is concluded that the Ru(Cp)(Quin)+ PF6- complexes remain intact in the cellular assays and constitute a new class of cytotoxic metal complexes.
Assuntos
Antineoplásicos , Complexos de Coordenação , Quinolinas , Rutênio , Inibidores de Proteassoma/farmacologia , Rutênio/farmacologia , Rutênio/química , Dimetil Sulfóxido , Antineoplásicos/química , Complexos de Coordenação/química , Quinolinas/farmacologia , LigantesRESUMO
The indole-oxazole scaffold is found in a range of biologically active natural products, including the breitfussin family. Divergent methods that provide access to the indole-oxazole template are relatively scarce, which impedes the wider exploration of these natural products and their exciting biological activity. Herein, we describe a highly divergent synthesis of the indole-oxazole scaffold via a one-pot Friedel-Crafts/Robinson-Gabriel synthesis and the application of this methodology to the synthesis of breitfussins C, G, and H.
RESUMO
Here, we report the synthesis of 3,4-disubstituted 1H-pyrazoles and 3,5-disubstituted pyridines from the reaction of epoxides with hydrazine and ammonia, respectively. Both reactions utilize Sc(OTf)3 as a Lewis acid. The pyrazole synthesis utilizes N-bromosuccinimide to convert the intermediate pyrazolines to the pyrazoles, whereas the pyridine synthesis utilizes FeCl3 as a cocatalyst.
Assuntos
Amônia , Piridinas , Compostos de Epóxi , Pirazóis , HidrazinasRESUMO
A Rh(III)-catalyzed C-H activation/annulation with an imidazolone as alkene partner is reported to access dihydroisoquinolone-fused imidazolin-2-ones. These bicycles are reminiscent of scaffolds belonging to the pyrrole alkaloid family of natural products. This approach facilitates construction of a variety of urea-fused dihydroisoquinolone scaffolds including heterocyclic moieties.
Assuntos
Alcaloides , Produtos Biológicos , Ródio , Alcenos , Catálise , Ciclização , Imidazóis , Pirróis , UreiaRESUMO
Despite the addition of several new agents to the armamentarium for the treatment of multiple myeloma (MM) in the last decade and improvements in outcomes, the refractory and relapsing disease continues to take a great toll, limiting overall survival. Therefore, additional novel approaches are needed to improve outcomes for MM patients. The oncogenic transcription factor MYC drives cell growth, differentiation and tumor development in many cancers. MYC protein levels are tightly regulated by the proteasome and an increase in MYC protein expression is found in more than 70% of all human cancers, including MM. In addition to the ubiquitin-dependent degradation of MYC by the 26S proteasome, MYC levels are also regulated in a ubiquitin-independent manner through the REGγ activation of the 20S proteasome. Here, we demonstrate that a small molecule activator of the 20S proteasome, TCH-165, decreases MYC protein levels, in a manner that parallels REGγ protein-mediated MYC degradation. TCH-165 enhances MYC degradation and reduces cancer cell growth in vitro and in vivo models of multiple myeloma by enhancing apoptotic signaling, as assessed by targeted gene expression analysis of cancer pathways. Furthermore, 20S proteasome enhancement is well tolerated in mice and dogs. These data support the therapeutic potential of small molecule-driven 20S proteasome activation for the treatments of MYC-driven cancers, especially MM.
RESUMO
While neurodegenerative diseases affect millions of patients worldwide, there are insufficient available therapeutics to halt or slow down the progression of these diseases. A key pathological feature of several neurodegenerative diseases is the oligomerization and aggregation of specific intrinsically disordered proteins (IDPs) creating neuronal deposits, such as Lewy bodies in Parkinson's disease. Clearance of these pathogenic, aggregation-prone IDPs is mediated by the 20S isoform of the human proteasome. Thus, enhancing the 20S proteasome-mediated proteolysis could be a very useful therapeutic pathway to prevent neurotoxicity. Here, we report the successful development of sub-microM 20S proteasome activators based on a phenothiazine scaffold. This class of compounds prevented the accumulation of pathologically relevant IDPs, such as the pathogenic A53T mutated α-synuclein, in vitro and in mammalian cell lines.
Assuntos
Proteínas Intrinsicamente Desordenadas , Doenças Neurodegenerativas , Doença de Parkinson , Sinucleinopatias , Animais , Humanos , Proteínas Intrinsicamente Desordenadas/metabolismo , Mamíferos/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , alfa-Sinucleína/metabolismoRESUMO
The proteasome system is a large and complex molecular machinery responsible for the degradation of misfolded, damaged, and redundant cellular proteins. When proteasome function is impaired, unwanted proteins accumulate, which can lead to several diseases including age-related and neurodegenerative diseases. Enhancing proteasome-mediated substrate degradation with small molecules may therefore be a valuable strategy for the treatment of various neurodegenerative diseases such as Parkinson's, Alzheimer's, and Huntington's diseases. In this review, we discuss the structure of proteasome and how proteasome's proteolytic activity is associated with aging and various neurodegenerative diseases. We also summarize various classes of compounds that are capable of enhancing, directly or indirectly, proteasome-mediated protein degradation.
Assuntos
Envelhecimento/metabolismo , Doenças Neurodegenerativas/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Humanos , Inibidores de Proteassoma/farmacologia , Dobramento de Proteína , Proteólise/efeitos dos fármacosRESUMO
The main protease (Mpro) plays a crucial role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication and is highly conserved, rendering it one of the most attractive therapeutic targets for SARS-CoV-2 inhibition. Currently, although two drug candidates targeting SARS-CoV-2 Mpro designed by Pfizer are under clinical trials, no SARS-CoV-2 medication is approved due to the long period of drug development. Here, we collect a comprehensive list of 817 available SARS-CoV-2 and SARS-CoV Mpro inhibitors from the literature or databases and analyze their molecular mechanisms of action. The structure-activity relationships (SARs) among each series of inhibitors are discussed. Additionally, we broadly examine available antiviral activity, ADMET (absorption, distribution, metabolism, excretion, and toxicity), and animal tests of these inhibitors. We comment on their druggability or drawbacks that prevent them from becoming drugs. This Perspective sheds light on the future development of Mpro inhibitors for SARS-CoV-2 and future coronavirus diseases.
Assuntos
Proteases 3C de Coronavírus , Inibidores de Proteases , Antivirais/farmacologia , HumanosRESUMO
Nortopsentin D is part of a class of bis(indole) alkaloids known for their biological activity, including inhibitory activity in tumoral cells and antifungal activity. Herein we describe the first total synthesis of nortopsentin D, in which amidine and dione undergo a pivotal condensation and subsequent cyclization via a pinacol-like rearrangement. This synthesis represents a unique strategy for the formation of 5,5-disubstituted (4H)-imidazol-4-one containing natural products, many of which have yet to succumb to total synthesis.
Assuntos
Glicóis/química , Imidazóis/síntese química , Alcaloides Indólicos/síntese química , Indóis/síntese química , Produtos Biológicos/síntese química , Imidazóis/química , Alcaloides Indólicos/química , Indóis/química , Estrutura MolecularRESUMO
Oligomerization of aggregation-prone intrinsically disordered proteins (IDPs), such as α-synuclein, amyloid ß, and tau, has been shown to be associated with the pathogenesis of several neurodegenerative diseases, including Parkinson's and Alzheimer's disease. The proteasome is charged with regulating cellular levels of IDPs, but this degradation pathway can become dysregulated leading to their accumulation and subsequent aggregation. Although the pathogenesis of these neurodegenerative diseases is still under intense investigation, it has been shown that the oligomeric forms of IDPs, including α-synuclein and amyloid ß, can impair proteasome function. This leads to additional accumulation of the IDPs, further promoting disease progression. Herein, we report the use of small molecule activators of the 20S subcomplex of the proteasome to restore impaired 20S proteasome activity and prevent IDP accumulation and oligomerization. We found that fluspirilene and its new synthetic analog (16) show strong 20S proteasome enhancement (doubling 20S proteolytic activity at â¼2 µM, with maximum fold enhancement of â¼1000%), overcome impaired proteasome function, and prevent the accumulation of pathogenic IDPs. These findings provide support for the use of 20S enhancers as a possible therapeutic strategy to combat neurodegenerative diseases.
Assuntos
Proteínas Intrinsicamente Desordenadas , Peptídeos beta-Amiloides , Fluspirileno , Complexo de Endopeptidases do Proteassoma , alfa-SinucleínaRESUMO
Aggregates or oligomeric forms of many intrinsically disordered proteins (IDPs), including α-synuclein, are hallmarks of neurodegenerative diseases, like Parkinson's and Alzheimer's disease, and key contributors to their pathogenesis. Due to their disordered nature and therefore lack of defined drug-binding pockets, IDPs are difficult targets for traditional small molecule drug design and are often referred to as "undruggable". The 20S proteasome is the main protease that targets IDPs for degradation and therefore small molecule 20S proteasome enhancement presents a novel therapeutic strategy by which these undruggable IDPs could be targeted. The concept of 20S activation is still relatively new, with few potent activators having been identified thus far. Herein, we synthesized and evaluated a library of dihydroquinazoline analogues and discovered several promising new 20S proteasome activators. Further testing of top hits revealed that they can enhance 20S mediated degradation of α-synuclein, the IDP associated with Parkinson's disease.
Assuntos
Proteínas Intrinsicamente Desordenadas/antagonistas & inibidores , Doença de Parkinson/tratamento farmacológico , Complexo de Endopeptidases do Proteassoma/metabolismo , Quinazolinas/farmacologia , alfa-Sinucleína/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Proteínas Intrinsicamente Desordenadas/metabolismo , Estrutura Molecular , Doença de Parkinson/metabolismo , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade , alfa-Sinucleína/metabolismoRESUMO
Here, we report the first synthesis of 2,3-disubstituted quinolines from anilines and aromatic or aliphatic epoxides. This reaction utilizes Sc(OTf)3 as a Lewis acid and TEMPO as an oxygen scavenger. A wide variety of highly substituted quinolines were obtained with moderate to excellent yields (up to 96%).
Assuntos
Quinolinas , Compostos de Anilina , Compostos de Epóxi , Ácidos de Lewis , Quinolinas/síntese químicaRESUMO
The 20S proteasome is a valuable target for the treatment of a number of diseases including cancer, neurodegenerative disease, and parasitic infection. In an effort to discover novel inhibitors of the 20S proteasome, many reseaarchers have looked to natural products as potential leads for drug discovery. The following review discusses the efforts made in the field to isolate and identify natural products as inhibitors of the proteasome. In addition, we describe some of the modifications made to natural products in order to discover more potent and selective inhibitors for potential disease treatment.
RESUMO
Loss of proteome fidelity leads to the accumulation of non-native protein aggregates and oxidatively damaged species: hallmarks of an aged cell. These misfolded and aggregated species are often found, and suggested to be the culpable party, in numerous neurodegenerative diseases including Huntington's, Parkinson's, Amyotrophic Lateral Sclerosis (ALS), and Alzheimer's Diseases (AD). Many strategies for therapeutic intervention in proteotoxic pathologies have been put forth; one of the most promising is bolstering the efficacy of the proteasome to restore normal proteostasis. This strategy is ideal as monomeric precursors and oxidatively damaged proteins, so called "intrinsically disordered proteins" (IDPs), are targeted by the proteasome. This review will provide an overview of disorders in proteins, both intrinsic and acquired, with a focus on susceptibility to proteasomal degradation. We will then examine the proteasome with emphasis on newly published structural data and summarize current known small molecule proteasome activators.