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1.
Nat Prod Rep ; 41(8): 1264-1293, 2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-38666377

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/química
2.
J Org Chem ; 88(13): 9306-9312, 2023 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-37314002

RESUMO

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 Molecular
3.
J Org Chem ; 88(2): 755-761, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-35235750

RESUMO

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.

4.
J Org Chem ; 87(24): 16820-16828, 2022 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-36475626

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 , Hidrazinas
5.
Bioorg Med Chem Lett ; 36: 127821, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33513387

RESUMO

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/metabolismo
6.
J Org Chem ; 85(10): 6741-6746, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32319294

RESUMO

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 química
7.
J Org Chem ; 84(11): 7219-7226, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31117573

RESUMO

This work describes an extended version of the Corey-Chaykovsky reaction to access oxazolines using sulfur ylides and stable precursors of acyl imines. The reaction proceeds through a mixture of aziridines and oxazolines, which provides the trans-oxazolines following in situ Heine-type aziridine ring expansion upon treatment with BF3·OEt2. Following the same one-pot procedure, amidine imides react with the sulfur ylides to provide imidazolines.

8.
Org Biomol Chem ; 17(10): 2734-2746, 2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30778435

RESUMO

Allosteric regulators of clinically important enzymes are gaining popularity as alternatives to competitive inhibitors. This is also the case for the proteasome, a major intracellular protease and a target of anti-cancer drugs. All clinically used proteasome inhibitors bind to the active sites in catalytic chamber and display a competitive mechanism. Unfortunately, inevitable resistance associated with this type of inhibition drives the search for non-competitive agents. The multisubunit and multicatalytic "proteolytic machine" such as the proteasome is occasionally found to be affected by agents with other primary targets. For example the immunosuppressive agent rapamycin has been shown to allosterically inhibit the proteasome albeit at levels far higher than its mTOR related efficacy. As part of an ongoing program to search for novel proteasome-targeting pharmacophores, we identified the binding domain of rapamycin as required for proteasome inhibition even without the macrocyclic context of the parent compound. By subsequent structure-activity relationship studies, we generated a pipecolic ester derivative compound 3 representing a new class of proteasome inhibitors. Compound 3 affects the core proteasome activities and proliferation of cancer cells with low micromolar/high nanomolar efficacy. Molecular modeling, atomic force microscopy imaging and biochemical data suggest that compound 3 binds into one of intersubunit pockets in the proteasomal α ring and destabilizes the α face and the gate. The α face is used as a docking area for proteasome-regulating protein modules and the gate is critical for controlling access to the catalytic chamber. Thus, the pipecolic ester template elicits a new and attractive mechanism for proteasome inhibition distinct from classical competitive drugs.


Assuntos
Ésteres/química , Ácidos Pipecólicos/química , Ácidos Pipecólicos/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/química , Inibidores de Proteassoma/farmacologia , Domínio Catalítico , Desenho de Fármacos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Ácidos Pipecólicos/metabolismo , Complexo de Endopeptidases do Proteassoma/química , Inibidores de Proteassoma/metabolismo
9.
Molecules ; 24(15)2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31387243

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.


Assuntos
Complexo de Endopeptidases do Proteassoma/metabolismo , Animais , Humanos , Proteínas Intrinsicamente Desordenadas/química , Proteínas Intrinsicamente Desordenadas/genética , Proteínas Intrinsicamente Desordenadas/metabolismo , Oxirredução , Estresse Oxidativo , Agregados Proteicos , Agregação Patológica de Proteínas , Proteostase , Relação Estrutura-Atividade
10.
Biochemistry ; 57(28): 4214-4224, 2018 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-29897236

RESUMO

The 20S proteasome is the main protease that directly targets intrinsically disordered proteins (IDPs) for proteolytic degradation. Mutations, oxidative stress, or aging can induce the buildup of IDPs resulting in incorrect signaling or aggregation, associated with the pathogenesis of many cancers and neurodegenerative diseases. Drugs that facilitate 20S-mediated proteolysis therefore have many potential therapeutic applications. We report herein the modulation of proteasome assembly by the small molecule TCH-165, resulting in an increase in 20S levels. The increase in the level of free 20S corresponds to enhanced proteolysis of IDPs, including α-synuclein, tau, ornithine decarboxylase, and c-Fos, but not structured proteins. Clearance of ubiquitinated protein was largely maintained by single capped proteasome complexes (19S-20S), but accumulation occurs when all 19S capped proteasome complexes are depleted. This study illustrates the first example of a small molecule capable of targeting disordered proteins for degradation by regulating the dynamic equilibrium between different proteasome complexes.


Assuntos
Proteínas Intrinsicamente Desordenadas/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Células HEK293 , Humanos , Simulação de Acoplamento Molecular , Ornitina Descarboxilase/metabolismo , Ubiquitinação/efeitos dos fármacos , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo
11.
J Org Chem ; 83(16): 9250-9255, 2018 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-29969032

RESUMO

Electrophilic bromination of pyrroles bearing carbonyl substituents at C-2 typically results in a mixture of the 4- and 5-brominated species, generally favoring the 4-position. Herein, we describe a substrate-controlled regioselective bromination in which tetra-butyl ammonium tribromide (TBABr3) reacts with pyrrole-2-carboxamide substrates to yield the 5-brominated species as the predominant (up to >10:1) product.

12.
Bioorg Med Chem ; 24(11): 2441-50, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27112450

RESUMO

Screening of a library of diverse heterocyclic scaffolds identified substituted quinolines as inhibitors of the human proteasome. The heterocyclic library was prepared via a novel titanium-catalyzed multicomponent coupling reaction, which rendered a diverse set of isoxazoles, pyrimidines, pyrroles, pyrazoles and quinolines. SAR of the parent lead compound indicated that hydrophobic residues on the benzo-moiety significantly improved potency. Lead compound 25 inhibits the chymotryptic-like proteolytic activity of the proteasome (IC50 5.4µM), representing a new class of nonpeptidic, noncovalent proteasome inhibitors.


Assuntos
Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Quinolinas/farmacologia , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Estrutura Molecular , Inibidores de Proteassoma/síntese química , Inibidores de Proteassoma/química , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade
13.
J Org Chem ; 80(3): 1440-5, 2015 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-25574949

RESUMO

The hydroxyamination reagent Br-N-(CO2Me)2 underwent Markovnikov addition to various olefins in the presence of catalytic BF3·OEt2 and provides efficient access to aminoalcohols. The reaction provided the trans-1-bromo, 2-N-bis-carbamate adduct stereoisomer in all cases. The resulting adduct underwent cyclization to give an oxazolidinone, which could be readily hydrolyzed to an oxazolidin-2-one or an amino alcohol.


Assuntos
Alcenos/química , Amino Álcoois/química , Amino Álcoois/síntese química , Carbamatos/química , Carbamatos/síntese química , Oxazolidinonas/química , Oxazolidinonas/síntese química , Aminação , Catálise , Ciclização , Indicadores e Reagentes/química , Espectroscopia de Ressonância Magnética , Estereoisomerismo
14.
Angew Chem Int Ed Engl ; 54(9): 2830-3, 2015 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-25581903

RESUMO

The proteasome represents an invaluable target for the treatment of cancer and autoimmune disorders. The application of proteasome inhibitors, however, remains limited to blood cancers because their reactive headgroups and peptidic scaffolds convey unfavorable pharmacodynamic properties. Thus, the discovery of more drug-like lead structures is indispensable. In this study, we present the first structure of the proteasome in complex with an indolo-phakellin that exhibits a unique noncovalent binding mode unparalleled by all hitherto reported inhibitors. The natural product inspired pentacyclic alkaloid binds solely and specificially into the spacious S3 subpocket of the proteasomal ß5 substrate binding channel, gaining major stabilization through halogen bonding with the protein backbone. The presented compound provides an ideal scaffold for the structure-based design of subunit-specific nonpeptidic proteasome-blockers.


Assuntos
Indóis/farmacologia , Piperazinas/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Relação Dose-Resposta a Droga , Humanos , Indóis/química , Modelos Moleculares , Conformação Molecular , Piperazinas/química , Inibidores de Proteassoma/síntese química , Inibidores de Proteassoma/química , Relação Estrutura-Atividade
15.
iScience ; 27(7): 110166, 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-38974969

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.

16.
Org Lett ; 25(20): 3698-3701, 2023 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-37184387

RESUMO

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.

17.
Dalton Trans ; 52(3): 721-730, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36562335

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 , Ligantes
18.
ACS Chem Neurosci ; 2023 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-37015082

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.

19.
ACS Omega ; 8(17): 15650-15659, 2023 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-37151549

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.

20.
Bioorg Med Chem Lett ; 22(22): 6821-4, 2012 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-23083981

RESUMO

The pathogenesis of rheumatoid arthritis is mainly driven by NF-κB-mediated production of cytokines, such as TNF-α. We report herein that the orally available imidazoline-based NF-κB inhibitor, TCH-013, was found to significantly reduce TNF-α signaling and attenuate collagen antibody induced arthritis in BALB/c mice.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Imidazóis/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Administração Oral , Animais , Artrite Reumatoide/induzido quimicamente , Colágeno , Relação Dose-Resposta a Droga , Imidazóis/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , NF-kappa B/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismo
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