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1.
Ann Agric Environ Med ; 26(3): 508-510, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31559812

RESUMO

Rare diseases, almost by definition, present us with diagnostic as well as therapeutic difficulties as. They also include infectious diseases outside endemic areas. Without expecting them, we are not preparing to fight them. Like Macbeth, we feel safe, convinced that tropical diseases do not reach us, like Birnam forest towards his castle. Nevertheless, the forest moved according to the prophecy of the three witches, and in a similar way tropical flora is moving towards us according to the predictions of environmentalists. This is illustrated by the history of the presented patient, who was admitted to hospital because of sepsis caused by Chromobacterium violaceum (CV), a Gram-negative facultatively anaerobic, oxidase-positive bacterium producing a dark violet antioxidant pigment called violacein. This is probably the first documented case report of sepsis in this part of the world. To the best of the authors' knowledge, the patient is the first to require dialysis after Chromobacterium violaceum infection.


Assuntos
Chromobacterium/isolamento & purificação , Infecções por Bactérias Gram-Negativas/microbiologia , Sepse/microbiologia , Chromobacterium/classificação , Chromobacterium/genética , Chromobacterium/metabolismo , Europa (Continente) , Humanos , Indóis/metabolismo , Masculino , Pessoa de Meia-Idade
2.
Bioresour Technol ; 291: 121866, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31374417

RESUMO

The study was to explore the feasibility of polyurethane (PU), Fe3O4@PU, powdered activated carbon (PAC), Fe(OH)3@PAC, biochar, and Fe(OH)3@biochar as biological carriers in strengthening anaerobic degradation of quinoline, pyridine, and indole. When the concentrations of pollutants were 25 mg/L and 50 mg/L, reactors based on PAC and Fe(OH)3@PAC had higher degradation ratios than the other reactors. However, when the concentrations of pollutants were 75 mg/L and 100 mg/L, with the addition of PU and Fe3O4@PU, reactors began to show their superiority in the degradation of the selected NHCs. Among these, the reactor based on Fe3O4@PU had the optimal degradation ratio on quinoline, pyridine, and indole. PU, PAC, Fe(OH)3@PAC, biochar, and Fe(OH)3@biochar benefited the enrichment of Acinetobacter, Comamonas, Levilinea, Longilinea, and Desulfomicrobium. The reactor with the carrier of Fe3O4@PU had some specificity, which benefited the enrichment of Zoogloea, Thiobacillus, Anaeromyxobacter, Sphingobium, Terrimonas, Parcubacteria genera incertae sedis, Bdellovibrio, Rhizobium, and Acidovorax.


Assuntos
Carvão Vegetal/metabolismo , Compostos Férricos/química , Indóis/metabolismo , Poliuretanos/química , Piridinas/metabolismo , Quinolinas/metabolismo , Anaerobiose
3.
Chem Commun (Camb) ; 55(58): 8402-8405, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31257385

RESUMO

A proof-of-principle for the application of hemi-indigo derivatives as RNA binders with photocontrollable fluorescence is presented. The photoswitch binds to the human immunodeficiency virus type 1 (HIV-1) RNA with a significant light-up effect. The fluorescence of the RNA-bound ligand can be reversibly switched ON and OFF by light without destroying the ligand-RNA associates.


Assuntos
Corantes Fluorescentes/metabolismo , HIV-1/genética , Indóis/metabolismo , RNA/metabolismo , Fluorescência , Corantes Fluorescentes/química , Corantes Fluorescentes/efeitos da radiação , Indóis/química , Indóis/efeitos da radiação , Ligantes , Luz , Estudo de Prova de Conceito , RNA/genética , Elementos de Resposta , Estereoisomerismo
4.
Food Chem ; 299: 125099, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31299513

RESUMO

Applying methyl jasmonate can mimic the defense response to insect damage in broccoli and enhances the production of glucosinolates, especially inducible indolyl GS-neoglucobrassicin. Previous studies have suggested that glucosinolates and their hydrolysis products are anti-carcinogenic. Therefore, MeJA treatment may increase the nutritional quality of broccoli. However, there are few reports on the sensory evaluation and consumer acceptance of MeJA-treated broccoli. In this study, an untrained consumer panel could not detect any taste differences between steamed MeJA-treated and untreated broccoli, even though the steamed MeJA-treated broccoli contained 50% more glucosinolates than untreated broccoli. The partial least square-regression model suggested that neoglucobrassicin-derived hydrolysis compounds were the major metabolites that determined overall preference for raw MeJA-treated broccoli potentially due to their potential negative sensory qualities. The results imply that MeJA treatment can increase the nutritional quality of broccoli without sacrificing taste in precooked meals or frozen vegetables.


Assuntos
Acetatos/farmacologia , Brassica/efeitos dos fármacos , Brassica/metabolismo , Comportamento do Consumidor , Ciclopentanos/farmacologia , Glucosinolatos/metabolismo , Oxilipinas/farmacologia , Adolescente , Adulto , Feminino , Glucosinolatos/análise , Humanos , Hidrólise , Indóis/metabolismo , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Valor Nutritivo , Vapor , Paladar
5.
J Plant Physiol ; 239: 10-17, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31177026

RESUMO

Auxin is one of the crucial plant hormones which stimulates and controls cell and plant growth. The effects of auxin IBA (indole-3-butyric acid) during 10-days on maize plants growth in controlled conditions (hydroponic, 16-h photoperiod, 70% humidity, 25/20 °C temperature), depended on its concentration in the substrate. A high concentration (10-7 M) of IBA inhibited root growth, evoked the development of apoplasmic barriers (Casparian bands and suberin lamellae) closer to the root apex, and elevated the amount of lignin in roots. A low concentration (10-11 M) of IBA stimulated root growth but affected neither the development of apoplasmic barriers, nor the amount of lignin. Auxin in a 10-8 M concentration influenced the root growth to a minimal extent compare to the control, and it was the non-effective concentration. Plant cell walls as cell structures ensure cell enlargement and plant growth, and have to react to auxin stimulus by modification of their components. We found the most significant changes in the composition of the PF III fraction (lignocellulosic complex) of the cell wall. The presence of auxin in the substrate affected all three components of this fraction - Klason lignin and both the by acid (2 M TFA) non-hydrolysable and the hydrolysable parts of this complex. The ratio of the non-hydrolysable part to the Klason lignin increased from 1.3 to 3.3 with increasing auxin concentrations in the substrate. This may be related to the deposition of polysaccharides and lignin in the cell wall, which help maintain the specific tensile stress of, and turgor pressure on, the cell walls.


Assuntos
Indóis/metabolismo , Reguladores de Crescimento de Planta/metabolismo , Zea mays/efeitos dos fármacos , Zea mays/fisiologia , Parede Celular/efeitos dos fármacos , Parede Celular/fisiologia , Relação Dose-Resposta a Droga , Ácidos Indolacéticos/administração & dosagem , Ácidos Indolacéticos/farmacologia , Indóis/administração & dosagem , Lipídeos/química , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/fisiologia , Xilema/efeitos dos fármacos , Xilema/fisiologia
6.
Comput Biol Chem ; 80: 512-523, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31185422

RESUMO

A new series of N'-(substituted phenyl)-5-chloro/iodo-3-phenyl-1H-indole-2-carbohydrazide (5, 6) and N-[2-(substituted phenyl)-4-oxo-1,3-thiazolidin-3-yl]-5-iodo/chloro-3-phenyl-1H-indole-2-carboxamide (7, 8) derivatives were synthesized and evaluated for their anticancer properties. Compounds 5a and 6b, selected as prototypes by the National Cancer Institute for screening against the full panel of 60 human tumor cell lines at a minimum of five concentrations at 10-fold dilutions, demonstrated remarkable antiproliferative activity against leukemia, non-small cell lung cancer, colon cancer, central nervous system (CNS) cancer, melanoma, ovarian cancer, renal cancer, and breast cancer (MCF-7) cell lines with GI50 values < 0.4 µM. A subset of the compounds was then tested for their potential to inhibit tubulin polymerization. Compounds 6f and 6g showed significant cytotoxicity at the nM level on MCF-7 cells and exhibited significant inhibitory activity on tubulin assembly and colchicine binding at about the same level as combretastatin A-4. Finally, docking calculations were performed to identify the binding mode of these compounds. Group 5 and 6 compounds interacted with the colchicine binding site through hydrophobic interactions similar to those of colchicine. These compounds with antiproliferative activity at high nanomolar concentration can serve as scaffolds for the design of novel microtubule targeting agents.


Assuntos
Antineoplásicos/farmacologia , Hidrazinas/farmacologia , Indóis/farmacologia , Tiazolidinas/farmacologia , Moduladores de Tubulina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazinas/síntese química , Hidrazinas/química , Hidrazinas/metabolismo , Indóis/síntese química , Indóis/química , Indóis/metabolismo , Células MCF-7 , Simulação de Acoplamento Molecular , Ligação Proteica , Tiazolidinas/síntese química , Tiazolidinas/química , Tiazolidinas/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Moduladores de Tubulina/metabolismo
7.
BMC Plant Biol ; 19(1): 264, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31215396

RESUMO

BACKGROUND: Brassica napus L. has little or no primary dormancy, but exhibits great variation in secondary dormancy. Secondary dormancy potential in oilseed rape can lead to the emergence of volunteer plants that cause genetic contamination, reduced quality and biosafety issues. However, the mechanisms underlying secondary dormancy are poorly understood. In this study, cultivars Huaiyou-WSD-H2 (H) and Huaiyou-SSD-V1 (V), which exhibit low (approximately 5%) and high (approximately 95%) secondary dormancy rate, respectively, were identified. Four samples, before (Hb and Vb) and after (Ha and Va) secondary dormancy induction by polyethylene glycol (PEG), were collected to identify the candidate genes involved in secondary dormancy via comparative transcriptome profile analysis. RESULTS: A total of 998 differentially expressed genes (DEGs), which are mainly involved in secondary metabolism, transcriptional regulation, protein modification and signaling pathways, were then detected. Among these DEGs, the expression levels of those involved in the sulfur-rich indole glucosinolate (GLS)-linked auxin biosynthesis pathway were markedly upregulated in the dormant seeds (Va), which were validated by qRT-PCR and subsequently confirmed via detection of altered concentrations of indole-3-acetic acid (IAA), IAA conjugates and precursors. Furthermore, exogenous IAA applications to cultivar H enhanced secondary dormancy. CONCLUSION: This study first (to our knowledge) elucidated that indole GLS-linked auxin biosynthesis is enhanced during secondary dormancy induced by PEG, which provides valuable information concerning secondary dormancy and expands the current understanding of the role of auxin in rapeseed.


Assuntos
Brassica napus/metabolismo , Ácidos Indolacéticos/metabolismo , Dormência de Plantas , Reguladores de Crescimento de Planta/metabolismo , Brassica napus/genética , Brassica napus/fisiologia , Perfilação da Expressão Gênica , Genes de Plantas/genética , Genes de Plantas/fisiologia , Glucosinolatos/metabolismo , Indóis/metabolismo , Redes e Vias Metabólicas , Dormência de Plantas/genética , Dormência de Plantas/fisiologia , Metabolismo Secundário/genética , Metabolismo Secundário/fisiologia
8.
Eur J Med Chem ; 177: 414-424, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158754

RESUMO

Due to the role of butyrylcholinesterase (BChE) in acetylcholine hydrolysis in the late stages of the Alzheimer's disease (AD), inhibitors of butyrylcholinesterase (BChE) have been recently envisaged, besides acetylcholinesterase (AChE) inhibitors, as candidates for treating mild-to-moderate AD. Herein, synthesis and AChE/BChE inhibition activity of some twenty derivatives of 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (HHAI) is reported. Most of the newly synthesized HHAI derivatives achieved the inhibition of both ChE isoforms with IC50s in the micromolar range, with a structure-dependent selectivity toward BChE. Apparently, molecular volume and lipophilicity do increase selectivity toward BChE, and indeed the N2-(4-phenylbutyl) HHAI derivative 15d, which behaves as a mixed-type inhibitor, resulted the most potent (IC50 0.17 µM) and selective (>100-fold) inhibitor toward either horse serum and human BChE. Moreover, 15d inhibited in vitro self-induced aggregation of neurotoxic amyloid-ß (Aß) peptide and displayed neuroprotective effects in neuroblastoma SH-SY5Y cell line, significantly recovering (P < 0.001) cell viability when impaired by Aß1-42 and hydrogen peroxide insults. Overall, this study highlighted HHAI as useful and versatile scaffold for developing new small molecules targeting some enzymes and biochemical pathways involved in the pathogenesis of AD.


Assuntos
Azepinas/farmacologia , Inibidores da Colinesterase/farmacologia , Indóis/farmacologia , Fármacos Neuroprotetores/farmacologia , Peptídeos beta-Amiloides/metabolismo , Azepinas/síntese química , Azepinas/química , Azepinas/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Relação Dose-Resposta a Droga , Desenho de Drogas , Depuradores de Radicais Livres/síntese química , Depuradores de Radicais Livres/química , Depuradores de Radicais Livres/metabolismo , Depuradores de Radicais Livres/farmacologia , Humanos , Indóis/síntese química , Indóis/química , Indóis/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fragmentos de Peptídeos/metabolismo , Ligação Proteica/efeitos dos fármacos , Multimerização Proteica/efeitos dos fármacos , Relação Estrutura-Atividade
9.
J Sci Food Agric ; 99(13): 5792-5798, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31162672

RESUMO

BACKGROUND: Recently, a producer of fermented ciders observed 'vinyl' off-odors formed during fermentation of pear juice previously depectinized at ≥ 49 °C but not if depectinized at lower temperatures. The objective of this study was to investigate the source of this spoilage and evaluate factors that affect formation. RESULTS: Analysis of untainted and tainted samples obtained from the producer determined the causative agent to be indole, a compound sometimes produced by yeast (Saccharomyces cerevisiae) during fermentation. To mimic commercial depectinization conditions, pectinases were added to pear juices held at 35 °C for 45 min (Treatment A), 49 °C for 45 min (Treatment B), or 49 °C for 90 min (Treatment C). Juice processing conditions did not affect yeast growth nor progress of alcoholic fermentation. Although neither yeast strain (DV10 or MERIT) synthesized indole during fermentation of Treatment A juices, the compound was produced by MERIT in Treatments B (27.05 µg L-1 ) and C (469.9 µg L-1 ). Supplementation of Treatment C juice with pyridoxine (vitamin B6 ) prior to fermentation resulted in no detectable indole formed. However, juices from Treatments A, B, or C contained similar concentrations of pyridoxine and non-detectable amounts of tryptophan, a potential precursor to indole. Furthermore, indole was not detected during fermentations of a synthetic pear juice medium without pyridoxine. CONCLUSION: Supplementation of cider musts with pyridoxine prior to fermentation and choice of yeast strain can lower the risk of formation of off-odors caused by indole. However, other unidentified factors are present which affect its formation in perry. © 2019 Society of Chemical Industry.


Assuntos
Bebidas Alcoólicas/análise , Etanol/metabolismo , Manipulação de Alimentos/métodos , Indóis/metabolismo , Pectinas/metabolismo , Pyrus/química , Saccharomyces cerevisiae/metabolismo , Bebidas Alcoólicas/microbiologia , Etanol/análise , Fermentação , Sucos de Frutas e Vegetais/análise , Sucos de Frutas e Vegetais/microbiologia , Indóis/análise , Malus/química , Malus/microbiologia , Odorantes/análise , Poligalacturonase/química , Pyrus/microbiologia
10.
Comput Biol Chem ; 80: 374-383, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31103918

RESUMO

Colony-stimulating factor 1 receptor is a type III receptor protein tyrosine kinase belonging to PDGFR family. CSF1R signaling is essential for differentiation, proliferation and survival of macrophages. Aberrant expression of CSF1R appears to be an attractive target in several cancer types. Higher expression of CSF1R ligands correlates to tumor progression. CSF1R inhibitors have been shown to suppress cancers. We have attempted an in silico fragment derived drug discovery approach by screening ˜25,000 in-house compounds as potential CSF1R inhibitors. Using FBDD approach we have identified six diverse fragments that exhibit affinity towards hinge region of CSF1R. Some of the fragments 5-nitroindole and 7-azaindole and their derivatives were synthesized for further evaluation. The in silico and in vitro enzyme activity studies reveal moderate inhibition of CSF1R kinase activity by 5-nitroindole and good inhibition by 7-azaindole fragments. Bio and chemiinformatics studies have shown that 7-azaindole compounds have better membrane permeability and enzyme inhibition properties. Molecular docking studies show that the amino acid residues 664-666 in the hinge region of the cytosolic domain of CSF1R to be the preferred region of binding for nitroindole and azaindole derivatives. Further optimization and biological analysis would identify these fragments as potential and promising leads as CSF1R inhibitors.


Assuntos
Indóis/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Sequência de Aminoácidos , Sítios de Ligação , Biologia Computacional , Desenho de Drogas , Humanos , Indóis/síntese química , Indóis/química , Simulação de Acoplamento Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Receptores Proteína Tirosina Quinases/química , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/química , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo
11.
MBio ; 10(3)2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088928

RESUMO

Marine sponges are recognized as valuable sources of bioactive metabolites and renowned as petri dishes of the sea, providing specialized niches for many symbiotic microorganisms. Sponges of the family Dysideidae are well documented to be chemically talented, often containing high levels of polyhalogenated compounds, terpenoids, peptides, and other classes of bioactive small molecules. This group of tropical sponges hosts a high abundance of an uncultured filamentous cyanobacterium, Hormoscilla spongeliae Here, we report the comparative genomic analyses of two phylogenetically distinct Hormoscilla populations, which reveal shared deficiencies in essential pathways, hinting at possible reasons for their uncultivable status, as well as differing biosynthetic machinery for the production of specialized metabolites. One symbiont population contains clustered genes for expanded polybrominated diphenylether (PBDE) biosynthesis, while the other instead harbors a unique gene cluster for the biosynthesis of the dysinosin nonribosomal peptides. The hybrid sequencing and assembly approach utilized here allows, for the first time, a comprehensive look into the genomes of these elusive sponge symbionts.IMPORTANCE Natural products provide the inspiration for most clinical drugs. With the rise in antibiotic resistance, it is imperative to discover new sources of chemical diversity. Bacteria living in symbiosis with marine invertebrates have emerged as an untapped source of natural chemistry. While symbiotic bacteria are often recalcitrant to growth in the lab, advances in metagenomic sequencing and assembly now make it possible to access their genetic blueprint. A cell enrichment procedure, combined with a hybrid sequencing and assembly approach, enabled detailed genomic analysis of uncultivated cyanobacterial symbiont populations in two chemically rich tropical marine sponges. These population genomes reveal a wealth of secondary metabolism potential as well as possible reasons for historical difficulties in their cultivation.


Assuntos
Cianobactérias/genética , Metagenômica , Poríferos/microbiologia , Simbiose/genética , Animais , Produtos Biológicos/metabolismo , Cianobactérias/metabolismo , Genômica , Éteres Difenil Halogenados/metabolismo , Indóis/metabolismo , Família Multigênica , Filogenia , Pirróis/metabolismo , Clima Tropical
12.
Eur J Med Chem ; 176: 326-342, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31112893

RESUMO

Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-activated transcription factors that govern lipid and glucose homeostasis playing a central role in cardiovascular disease, obesity, and diabetes. These receptors show a high degree of stereoselectivity towards several classes of drugs. This review covers the most relevant findings that have been made in the last decade and takes into consideration only those compounds in which stereochemistry led to unexpected results or peculiar interactions with the receptors. These cases are reviewed and discussed with the aim to show how enantiomeric recognition originates at the molecular level. The structural characterization by crystallographic methods and docking experiments of complexes formed by PPARs with their ligands turns out to be an essential tool to explain receptor stereoselectivity.


Assuntos
Derivados de Benzeno/química , Derivados de Benzeno/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Acetatos/química , Acetatos/metabolismo , Animais , Sítios de Ligação , Cristalografia por Raios X , Humanos , Indóis/química , Indóis/metabolismo , Ligantes , Simulação de Acoplamento Molecular , Oxazóis/química , Oxazóis/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/antagonistas & inibidores , Receptores Ativados por Proliferador de Peroxissomo/química , Fenilpropionatos/química , Fenilpropionatos/metabolismo , Ligação Proteica , Estereoisomerismo , Relação Estrutura-Atividade , Tirosina/análogos & derivados , Tirosina/metabolismo
13.
Nat Chem Biol ; 15(6): 589-597, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31086330

RESUMO

To maximize a desired product, metabolic engineers typically express enzymes to high, constant levels. Yet, permanent pathway activation can have undesirable consequences including competition with essential pathways and accumulation of toxic intermediates. Faced with similar challenges, natural metabolic systems compartmentalize enzymes into organelles or post-translationally induce activity under certain conditions. Here we report that optogenetic control can be used to extend compartmentalization and dynamic control to engineered metabolisms in yeast. We describe a suite of optogenetic tools to trigger assembly and disassembly of metabolically active enzyme clusters. Using the deoxyviolacein biosynthesis pathway as a model system, we find that light-switchable clustering can enhance product formation six-fold and product specificity 18-fold by decreasing the concentration of intermediate metabolites and reducing flux through competing pathways. Inducible compartmentalization of enzymes into synthetic organelles can thus be used to control engineered metabolic pathways, limit intermediates and favor the formation of desired products.


Assuntos
Luz , Engenharia Metabólica , Redes e Vias Metabólicas/efeitos da radiação , Optogenética/métodos , Organelas/metabolismo , Organelas/efeitos da radiação , Biologia Sintética , Indóis/metabolismo , Organelas/química , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/efeitos da radiação , Synechocystis/efeitos da radiação
14.
Eur J Med Chem ; 175: 357-372, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31096156

RESUMO

Lysine-specific demethylase 1 (LSD1), demethylase against mono- and di - methylated histone3 lysine 4, has emerged as a promising target in oncology. More specifically, it has been demonstrated as a key promoter in acute myeloid leukemia (AML), and several LSD1 inhibitors have already entered into clinical trials for the treatment of AML. In this paper, a series of new indole derivatives were designed and synthesized based on a lead compound obtained by a high-throughput screening with our in-house compound library. Among the synthetic compounds, 9e was characterized as a potent LSD1 inhibitor with an IC50 of 1.230 µM and can inhibit the proliferation of THP-1 cells effectively. And most importantly, this is the first irreversible LSD1 inhibitor that is not derived from monoamine oxidase inhibitors. Hence, the discovery of 9e may serve as a proof of concept work for AML treatment.


Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Indóis/síntese química , Indóis/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Furanos/química , Ensaios de Triagem em Larga Escala , Histona Desmetilases/metabolismo , Humanos , Indóis/química , Indóis/metabolismo , Concentração Inibidora 50 , Leucemia Mieloide Aguda/patologia , Proteínas Recombinantes/efeitos dos fármacos , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
15.
C R Biol ; 342(3-4): 58-80, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31088733

RESUMO

Indole glucosinolates are plant secondary metabolites derived from the amino acid tryptophan. They are part of a large group of sulfur-containing molecules almost exclusively found among Brassicales, which include the mustard family (Brassicaceae) with many edible plant species of major nutritional importance. These compounds mediate numerous interactions between these plants and their natural enemies and are therefore of major biological and economical interest. This literature review aims at taking stock of recent advances of our knowledge about the biosynthetic pathways of indole glucosinolates, but also about the defense strategies and ecological processes involving these metabolites.


Assuntos
Brassicaceae/química , Glucosinolatos/metabolismo , Indóis/metabolismo , Ecologia
16.
J Photochem Photobiol B ; 194: 96-106, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30953915

RESUMO

Photodynamic therapy (PDT) is a promising approach for the treatment of different types of cancer and has been brought into focus for its synergy, compatibility, repeatability, relatively inexpensive cost and it's typically more efficacious nature. Photosensitizers (PSs) play a major role in PDT and are the core of this specific therapy. Al (III) Phthalocyanine Chloride Tetra sulfonic Acid (AlPcS4Cl) PS is an aromatic macrocyclic metal-based compound that is synthetically derived. It aids in deep tissue penetration due to its far red light activation wavelength, low photo bleaching, increased quantum yields and stability. Lung cancer is a leading cause of cancer related deaths worldwide accounting for approximately 1 in 5 of all cancer-related deaths. In this study, we explored the photochemical properties of AlPcS4Cl, its uptake into lung cancer, the intracellular localization and photodynamic action on lung cancer (A549 cells). Results indicated that AlPcS4Cl is a stable PS that localizes in intracellular organelles including the mitochondrion and lysosomes. PDT using AlPcS4Cl indicated an increase in cell death and decrease in cell proliferation and viability. AlPcS4Cl showed to be effective in treating lung cancer in vitro, however the resulting PDT efficacy will finally depend on the biological features such as tumour vasculature and tumour specific accumulation when used as a clinical application. It is noted that PDT can be considered as an adjunct therapy until standard protocols for various tumour types along with a relevant PS has been validated.


Assuntos
Alumínio/química , Interações Hidrofóbicas e Hidrofílicas , Indóis/química , Indóis/farmacologia , Neoplasias Pulmonares/patologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Células A549 , Transporte Biológico , Morte Celular/efeitos dos fármacos , Morte Celular/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Relação Dose-Resposta a Droga , Humanos , Indóis/metabolismo , Espaço Intracelular/metabolismo , Cinética , Fotoquimioterapia , Fármacos Fotossensibilizantes/metabolismo
17.
Eur J Med Chem ; 174: 56-65, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31029944

RESUMO

A zinc(II) phthalocyanine substituted with three 2,4-dinitrobenzenesulfonate (DNBS) groups and a cyclic arginine-glycine-aspartic acid (cRGDfK) moiety was prepared and characterized. With three strongly electron-withdrawing DNBS groups, this compound was fully quenched in terms of fluorescence emission and singlet oxygen generation in N,N-dimethylformamide and phosphate buffered saline due to the strong photoinduced electron transfer effect. In the presence of glutathione (GSH), which is the most abundant intracellular thiol particularly in tumor cells, the DNBS moieties were cleaved, thereby restoring these photoactivities and making the conjugate as a GSH-activated photosensitizer. Being a well-known integrin antagonist, the cyclic RGD peptide sequence could enhance the localization of the conjugate in integrin-upregulated tumor cells. As shown by confocal laser scanning microscopy and flow cytometry, the intracellular fluorescence intensity of the conjugate was significantly higher in the integrin-positive A549 and MDA-MB-231 cells than in the integrin-negative MCF-7 and HEK293 cells. The photocytotoxicity of the conjugate against MDA-MB-231 cells was also higher than that toward MCF-7 cells. The results suggest that this dual-functional photosensitizer is a promising candidate for targeted photodynamic therapy.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Glutationa/metabolismo , Indóis/farmacologia , Peptídeos Cíclicos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/efeitos da radiação , Benzenossulfonatos/síntese química , Benzenossulfonatos/metabolismo , Benzenossulfonatos/farmacologia , Benzenossulfonatos/efeitos da radiação , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , Complexos de Coordenação/efeitos da radiação , Fluorescência , Células HEK293 , Humanos , Indóis/síntese química , Indóis/metabolismo , Indóis/efeitos da radiação , Integrinas/metabolismo , Luz , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/metabolismo , Peptídeos Cíclicos/efeitos da radiação , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/metabolismo , Fármacos Fotossensibilizantes/efeitos da radiação , Oxigênio Singlete/metabolismo , Zinco/química
18.
Anal Chim Acta ; 1063: 99-109, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-30967192

RESUMO

The ability of LC-MS/MS for high coverage metabolite analysis lags behind the requirements of global metabolomics. The introduction of chemical derivatizations could significantly extend the ability of LC-MS/MS with enhanced MS response and improved LC separation, which has been serving as a promising quantitative tool for metabolomic analysis. However, as one specific derivatization reagent usually targets to a certain moiety, only a single chemical-group-based submetabolome could be analyzed in one injection. Therefore, the coverage of detected metabolites by derivatization-based LC-MS/MS is largely limited. To overcome this technical obstacle of derivatization-based LC-MS and increase submetabolome coverage, we proposed an extendable all-in-one injection LC-MS/MS strategy. 5-dimethylamino-naphthalene-1-sulfonyl chloride (Dns-Cl)/5-diethylamino-naphthalene-1-sulfonyl chloride (Dens-Cl) and 5-dimethylamino-naphthalene-1-sulfonyl piperazine (Dns-PP)/5-diethylamino-naphthalene-1-sulfonyl piperazine (Dens-PP) were used as twins labeling reagents for amino/phenol and carboxyl submetabolomes, respectively. "Series Mode" and "Parallel Mode" were proposed and investigated using eight representative standards with the consideration of interaction between different derivatization systems, time-consumption, and extendability. As a result, we found that "Series Mode" led to yield reduction, while "Parallel Mode" gave identical results with those of individual derivatization. Finally, a "Parallel Mode" was chosen to develop an extendable all-in-one injection twin derivatization LC-MS/MS strategy to quantify eighty metabolites assigned to five classes of microbial metabolites, including polyamines, amino acids, indole derivatives, bile acids, and free fatty acids. This well-validated method quantified 67 metabolites absolutely and discovered additional 40 differential metabolites compared with the untargeted method in rat serum from irinotecan (CPT-11)-induced gastrointestinal toxicity model.


Assuntos
Metabolômica/instrumentação , Metabolômica/métodos , Aminoácidos/sangue , Aminoácidos/metabolismo , Animais , Ácidos e Sais Biliares/sangue , Ácidos e Sais Biliares/metabolismo , Cromatografia Líquida , Modelos Animais de Doenças , Ácidos Graxos não Esterificados/sangue , Ácidos Graxos não Esterificados/metabolismo , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Indóis/sangue , Indóis/metabolismo , Irinotecano/toxicidade , Poliaminas/sangue , Poliaminas/metabolismo , Ratos , Espectrometria de Massas em Tandem
19.
Chem Biodivers ; 16(6): e1900087, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30994253

RESUMO

An efficient diastereoselective synthesis of spirocyclopropaneoxindoles is reported using three-component reactions of various phenacylidenetriphenylphosphorane, isatins and phenacyl bromide under ultrasonic irradiation. The structures of synthesized spirocyclopropaneoxindoles were characterized by their spectral data. The antioxidant activities of the synthesized compounds were evaluated by 1,1-diphenyl-2-picrylhydrazyl radical scavenging assay. Among the products, those with NH group in their structure exhibited higher antioxidant activities than other derivatives. Also, in vitro cytotoxicity of compounds 4b, 4e, 4j, 4k were examined against heLa cancer cell lines using MTT assay. The results revealed that compound 4j with chlorine substituent on phenyl group displayed higher cytotoxicity activity (IC50 =4.50±0.30 µg/mL) after 48 h.


Assuntos
Antioxidantes/síntese química , Indóis/química , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Células HeLa , Humanos , Indóis/metabolismo , Indóis/farmacologia , Conformação Molecular , Compostos de Espiro/química , Estereoisomerismo
20.
Spectrochim Acta A Mol Biomol Spectrosc ; 216: 190-201, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-30901704

RESUMO

Spectral-fluorescent properties of polymethine dye probes anionic 3,3'-di(sulfopropyl)-4,5,4',5'-dibenzo-9-ethylthiacarbocyanine-betaine (DEC) and cationic 3,3',9-trimethylthiacarbocyanine iodide (Cyan 2) in the presence of biological surfactants, bile salts sodium cholate (NaC), sodium deoxycholate (NaDC) and sodium taurocholate (NaTC), as well as sodium dodecyl sulfate (SDS), have been studied in a wide range of surfactant concentrations. When a surfactant is introduced into a solution of DEC, changes of the spectral-fluorescent properties are observed due to decomposition of dye dimers into cis-monomers and cis-trans conversion of the resulting monomers. In the presence of SDS, both processes occur in parallel, caused by noncovalent interaction of dye monomers with micelles, and mainly occur near the critical micelle concentration (CMC). In contrast, upon the introduction of increasing concentrations of bile salts, decomposition of dye dimers into the monomers begins at lower concentrations than cis-trans conversion. The former process is almost completed at concentrations close to CMC of secondary micelles (CMC2), while the latter process occurs even at concentrations of bile salts much higher than CMC2. Hence, DEC can serve as a probe that permits estimating the value of CMC2 and is indicative of reorganization of secondary micelles upon an increase in bile salt concentration. Aggregation of DEC and Cyan 2 on bile salts is also observed. Since it is observed at relatively low concentrations of bile salts (

Assuntos
Carbocianinas/metabolismo , Ácido Desoxicólico/metabolismo , Indóis/metabolismo , Colato de Sódio/metabolismo , Tensoativos/metabolismo , Ácido Taurocólico/metabolismo , Betaína/análogos & derivados , Betaína/metabolismo , Carbocianinas/química , Ácido Desoxicólico/química , Dimerização , Indóis/química , Micelas , Colato de Sódio/química , Dodecilsulfato de Sódio/química , Dodecilsulfato de Sódio/metabolismo , Espectrometria de Fluorescência , Tensoativos/química , Ácido Taurocólico/química
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