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1.
Molecules ; 26(5)2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33673443

RESUMO

Keto piperazines and aminocoumarins are privileged building blocks for the construction of geometrically constrained peptides and therefore valuable structures in drug discovery. Combining these two heterocycles provides unique rigid polycyclic peptidomimetics with drug-like properties including many points of diversity that could be modulated to interact with different biological receptors. This work describes an efficient multicomponent approach to condensed chromenopiperazines based on the novel enol-Ugi reaction. Importantly, this strategy involves the first reported post-condensation transformation of an enol-Ugi adduct.


Assuntos
Peptidomiméticos/síntese química , Piperazinas/síntese química , Aminocumarinas/química , Ciclização , Descoberta de Drogas , Modelos Moleculares , Estrutura Molecular , Oxirredução , Estereoisomerismo
2.
Surgery ; 169(1): 34-42, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32718802

RESUMO

BACKGROUND: Patients with advanced differentiated thyroid cancer develop resistance to lenvatinib treatment from metabolic dysregulation. Heat shock protein 90 is a molecular chaperone that plays an important role in glycolysis and metabolic pathway regulation. We hypothesize that lenvatinib-resistant differentiated thyroid cancer cells will have an increased dependency on glycolysis and that a novel C-terminal heat shock protein 90 inhibitor (KU757) can effectively treat lenvatinib-resistant cells by targeting glycolysis. METHODS: Inhibitory concentration 50 values of thyroid cancer cells were determined by CellTiter-Glo assay (Promega Corp, Madison, WI). Glycolysis was measured through Seahorse experiments. Reverse transcription-polymerase chain reaction and Western blot evaluated glycolytic pathway genes/proteins. Exosomes were isolated/validated by nanoparticle tracking analysis and Western blot. Differentially expressed long non-coding ribonucleic acids in exosomes and cells were evaluated using quantitative polymerase chain reaction. RESULTS: Extracellular acidification rate demonstrated >2-fold upregulation of glycolysis in lenvatinib-resistant cells versus parent cells and was downregulated after KU757 treatment. Lenvatinib-resistant cells showed increased expression of the glycolytic genes lactic acid dehydrogenase, pyruvate kinase M1/2, and hexokinase 2. KU757 treatment resulted in downregulation of these genes and proteins. Several long non-coding ribonucleic acids associated with glycolysis were significantly upregulated in WRO-lenvatinib-resistant cells and exosomes and downregulated after KU757 treatment. CONCLUSION: Lenvatinib resistance leads to increased glycolysis, and KU757 effectively treats lenvatinib-resistant cells and overcomes this increased glycolysis by targeting key glycolytic genes, proteins, and long non-coding ribonucleic acids.


Assuntos
Adenocarcinoma Folicular/tratamento farmacológico , Aminocumarinas/farmacologia , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adenocarcinoma Folicular/patologia , Aminocumarinas/uso terapêutico , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Glicólise/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Concentração Inibidora 50 , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Células Epiteliais da Tireoide , Neoplasias da Glândula Tireoide/patologia
3.
Int J Mol Sci ; 21(17)2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32859042

RESUMO

In this study, the synthesis and structure of 4-aminocoumarin derivatives of resorcin[4]arene were investigated. Spectroscopic analysis and quantum mechanical calculations showed that this molecule undertakes a crown-in conformation in chloroform. The conformations of the aminocoumarin derivative of resorcin[4]arene were compared with a hydroxycoumarin derivative of resorcin[4]arene, and the effect of the substituent on the conformational selectivity of the coumarin derivatives of resorcin[4]arene was demonstrated. Both UV-VIS and fluorescence spectroscopy for the coumarin derivative of resorcin[4]arene (3) were performed, and a strong fluorescence quenching of derivative 3 compared to 4-aminocoumarin was observed.


Assuntos
Aminocumarinas/química , Clorofórmio/química , Resorcinóis/síntese química , Teoria da Densidade Funcional , Ligação de Hidrogênio , Conformação Molecular , Estrutura Molecular , Pontos Quânticos , Resorcinóis/química , Espectrometria de Fluorescência
4.
Int J Antimicrob Agents ; 56(1): 106002, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32361027

RESUMO

Burkholderia pseudomallei causes melioidosis, a potentially lethal disease that can establish both chronic and acute infections in humans. It is inherently recalcitrant to many antibiotics, there is a paucity of effective treatment options and there is no vaccine. In the present study, the efficacies of selected aminocoumarin compounds, DNA gyrase inhibitors that were discovered in the 1950s but are not in clinical use for the treatment of melioidosis were investigated. Clorobiocin and coumermycin were shown to be particularly effective in treating B. pseudomallei infection in vivo. A novel formulation with dl-tryptophan or l-tyrosine was shown to further enhance aminocoumarin potency in vivo. It was demonstrated that coumermycin has superior pharmacokinetic properties compared with novobiocin, and the coumermycin in l-tyrosine formulation can be used as an effective treatment for acute respiratory melioidosis in a murine model. Repurposing of existing approved antibiotics offers new resources in a challenging era of drug development and antimicrobial resistance.


Assuntos
Aminocumarinas/uso terapêutico , Burkholderia pseudomallei/efeitos dos fármacos , Melioidose/tratamento farmacológico , Novobiocina/análogos & derivados , Triptofano/uso terapêutico , Aminocumarinas/farmacocinética , Animais , Burkholderia pseudomallei/genética , Modelos Animais de Doenças , Farmacorresistência Bacteriana Múltipla/genética , Quimioterapia Combinada , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Mariposas/microbiologia , Novobiocina/farmacocinética , Novobiocina/uso terapêutico
5.
Bioorg Chem ; 99: 103818, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32276135

RESUMO

Targeted therapy is a new strategy for cancer treatment that targets chemical entities specific to cancer cells than normal ones. One of the features associated with malignancy is the elevated copper which plays an integral role in angiogenesis. Work is in progress in our lab to identify new copper chelators to target elevated copper under targeted therapy for the killing of cancer cells. Recently, a coumarin-based copper chelator, di(2-picolyl)amine-3(bromoacetyl)coumarin hybrid molecule (ligand-L) has been synthesized by us, and also studied its copper-dependent macromolecular damage response in copper overloaded lymphocytes. The present study investigates the anticancer activity of ligand-L and its mode of action in rat model of diethylnitrosamine (DEN) induced hepatocellular carcinoma. It has been found that liver tissue has a marked increase in copper levels in DEN induced hepatocellular carcinoma. Ex vivo results showed that ligand-L inhibited cell viability, induced reactive oxygen species (ROS) generation, DNA damage, loss of mitochondrial membrane potential and caspase-3 activation in isolated hepatocellular carcinoma cells (HCC). All these effects induced by ligand-L were abrogated by neocuproine and N-acetylcysteine (ROS scavenger). Further, ligand-L treatment of animals bearing hepatocellular carcinoma results in an increment in the cellular redox scavengers, lipid peroxidation and DNA breakage in malignant hepatocytes. In vivo studies using ligand-L also showed that ligand-L possesses anticancer properties as evidenced by improvement in liver marker enzymes and liver surface morphology, and reduced alpha-fetoprotein in the treated group compared to untreated cancer-induced group. Overall, this study suggests that copper-ligand-L interaction leads to ROS generation which caused DNA damage and apoptosis in malignant cells. This study provides enough support to establish ligand-L as a clinically relevant lead molecule for the treatment of different malignancies.


Assuntos
Aminocumarinas/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Cobre/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Aminocumarinas/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antioxidantes/síntese química , Antioxidantes/química , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cobre/química , Dano ao DNA , Dietilnitrosamina/administração & dosagem , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Injeções Intraperitoneais , Peroxidação de Lipídeos/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Estrutura Molecular , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/análise , Relação Estrutura-Atividade
6.
Med Chem ; 16(2): 229-243, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31309895

RESUMO

BACKGROUND: Urease enzyme catalyzes the hydrolysis of urea into ammonia and CO2, excess ammonia causes global warming and crop reduction. Ureases are also responsible for certain human diseases such as stomach cancer, peptic ulceration, pyelonephritis, and kidney stones. New urease inhibitors are developed to get rid of such problems. OBJECTIVE: This article describes the synthesis of a series of novel 1-aroyl-3-(2-oxo-2H-chromen-4- yl)thiourea derivatives (5a-j) as Jack bean urease inhibitors. METHODS: Freshly prepared aryl isothiocyanates were reacted with 4-aminocoumarin in the same pot in an anhydrous medium of acetone. The structures of the title thioureas (5a-j) were ascertained by their spectroscopic data. The inhibitory effects against jack bean urease were determined. RESULTS: It was found that compounds 5i and 5j showed excellent activity with IC50 values 0.0065 and 0.0293, µM respectively. Compound 5i bearing 4-methyl substituted phenyl ring plays a vital role in enzyme inhibitory activity. The kinetic mechanism analyzed by Lineweavere-Burk plots revealed that compound 5i inhibits the enzyme non-competitively. The Michaelis-Menten constant Km and inhibition constants Ki calculated from Lineweavere-Burk plots for compound 5i are 4.155mM and 0.00032µM, respectively. The antioxidant activity results displayed that compound 5j showed excellent radical scavenging activity. The cytotoxic effects determined against brine shrimp assay showed that all of the synthesized compounds are non-toxic to shrimp larvae. Molecular docking studies were performed against target protein (PDBID 4H9M) and it was determined that most of the synthesized compounds exhibited good binding affinity with the target protein. Molecular dynamics simulation (MDS) results revealed that compound 5i forms a stable complex with target protein showing little fluctuation. CONCLUSIONS: Based upon our investigations, it is proposed that 5i derivative may serve as a lead structure for devising more potent urease inhibitors.


Assuntos
Aminocumarinas/síntese química , Aminocumarinas/farmacologia , Canavalia/enzimologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Urease/antagonistas & inibidores , Aminocumarinas/química , Aminocumarinas/metabolismo , Animais , Artemia , Técnicas de Química Sintética , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Conformação Proteica , Urease/química , Urease/metabolismo
7.
J Bacteriol ; 201(23)2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31481544

RESUMO

The heat-stable nucleoid-structuring (H-NS) protein is a global transcriptional regulator implicated in coordinating the expression of over 200 genes in Escherichia coli, including many involved in adaptation to osmotic stress. We have applied superresolved microscopy to quantify the intracellular and spatial reorganization of H-NS in response to a rapid osmotic shift. We found that H-NS showed growth phase-dependent relocalization in response to hyperosmotic shock. In stationary phase, H-NS detached from a tightly compacted bacterial chromosome and was excluded from the nucleoid volume over an extended period of time. This behavior was absent during rapid growth but was induced by exposing the osmotically stressed culture to a DNA gyrase inhibitor, coumermycin. This chromosomal compaction/H-NS exclusion phenomenon occurred in the presence of either potassium or sodium ions and was independent of the presence of stress-responsive sigma factor σS and of the H-NS paralog StpA.IMPORTANCE The heat-stable nucleoid-structuring (H-NS) protein coordinates the expression of over 200 genes in E. coli, with a large number involved in both bacterial virulence and drug resistance. We report on the novel observation of a dynamic compaction of the bacterial chromosome in response to exposure to high levels of salt. This stress response results in the detachment of H-NS proteins and their subsequent expulsion to the periphery of the cells. We found that this behavior is related to mechanical properties of the bacterial chromosome, in particular, to how tightly twisted and coiled is the chromosomal DNA. This behavior might act as a biomechanical response to stress that coordinates the expression of genes involved in adapting bacteria to a salty environment.


Assuntos
Cromossomos Bacterianos/efeitos dos fármacos , Proteínas de Escherichia coli/genética , Escherichia coli/efeitos dos fármacos , Proteínas de Fímbrias/genética , Regulação Bacteriana da Expressão Gênica , Pressão Osmótica , Cloreto de Potássio/farmacologia , Adaptação Fisiológica , Aminocumarinas/farmacologia , Cátions Monovalentes , Cromossomos Bacterianos/metabolismo , Cromossomos Bacterianos/ultraestrutura , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Escherichia coli/genética , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/ultraestrutura , Proteínas de Escherichia coli/metabolismo , Proteínas de Fímbrias/metabolismo , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Potássio/metabolismo , Transporte Proteico/efeitos dos fármacos , Fator sigma/genética , Fator sigma/metabolismo , Sódio/metabolismo , Inibidores da Topoisomerase II/farmacologia , Transcrição Genética
8.
Spectrochim Acta A Mol Biomol Spectrosc ; 223: 117330, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31280128

RESUMO

HSA is an important plasma protein responsible for transport of drug molecules. Coumarin derivatives play critical role as anticancer, antidiabetic and antiparkinson agents. In our lab we have synthesized coumarin-based pharmacophore, di(2-picolyl)amine-3(bromoacetyl) coumarin (ligand-L) endowed with anticancer activity. Anticancer agents binding mode of HSA provides valuable pharmacological information and is a structural guidance in synthesizing new drugs with greater efficacy. Thus, binding mechanism of ligand-L with HSA was explored using spectroscopic and molecular docking techniques. UV-Vis spectroscopy demonstrates hyperchromism in the absorbance spectra of HSA on addition of ligand-L suggesting interaction of ligand-L with HSA. Fluorescence spectroscopy indicates quenching in the fluorescence of HSA in the presence of ligand-L confirming the complex formation and this binding follows static mechanism. Steady state fluorescence spectroscopy revealed high binding affinity between ligand-L and HSA with a 1:1 stoichiometry. Thermodynamic parameters obtained by ITC suggest that the interaction between ligand-L and HSA is mainly driven by van der Waals forces and hydrogen bonds, and the negative value of ΔG is an indication of spontaneous binding process. Competitive binding and molecular docking experiments showed that the binding site of ligand-L mainly resides in sub-domain IIA of HSA. CD experiments revealed no significant conformational changes in the secondary structure of HSA on binding of ligand-L. We also found that esterase-like activity of HSA was not affected by ligand-L. In conclusion, this study demonstrates binding mechanism of ligand-L with HSA, and the binding did not induce conformational changes in HSA. This study is likely to provide better understanding of transport and delivery of ligand-L via HSA. Overall, it will provide insights into pharmacokinetic properties of ligand-L and designing new ligand-L based derivatives with greater efficacy.


Assuntos
Aminocumarinas/química , Cumarínicos/química , Modelos Moleculares , Albumina Sérica Humana/química , Análise Espectral , Sítios de Ligação , Calorimetria , Dicroísmo Circular , Esterases/metabolismo , Humanos , Cinética , Ligantes , Simulação de Acoplamento Molecular , Ligação Proteica , Carbonilação Proteica , Espectrometria de Fluorescência , Espectrofotometria Ultravioleta , Termodinâmica
9.
J Med Chem ; 62(8): 4225-4231, 2019 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-30920824

RESUMO

Coumermycin A1 is a natural aminocoumarin that inhibits bacterial DNA gyrase, a member of the GHKL proteins superfamily. We report here the first cocrystal structures of gyrase B bound to coumermycin A1, revealing that one coumermycin A1 molecule traps simultaneously two ATP-binding sites. The inhibited dimers from different species adopt distinct sequence-dependent conformations, alternative to the ATP-bound form. These structures provide a basis for the rational development of coumermycin A1 derivatives for antibiotherapy and biotechnology applications.


Assuntos
Aminocumarinas/química , DNA Girase/química , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Aminocumarinas/metabolismo , Sítios de Ligação , DNA Girase/metabolismo , Dimerização , Escherichia coli/enzimologia , Ligação de Hidrogênio , Simulação de Dinâmica Molecular , Estrutura Quaternária de Proteína , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , Thermus thermophilus/enzimologia
10.
ACS Chem Biol ; 14(3): 397-404, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30715847

RESUMO

Nitric oxide (NO) is a pleiotropic signaling molecule involved in the regulation of diverse physiological and pathophysiological mechanisms in cardiovascular, nervous, and immunological systems. To understand the biological functions of NO in detail, comprehensive characterization of proteins found in high-NO concentration environments is crucial. Herein, we describe the design of NO-responsive protein labeling reagents based on N-alkoxyacyl- o-phenylenediamine as an optimal reactive scaffold. The designed molecules can label proteins in murine macrophage cells in response to endogenously produced NO. The combination of NO-responsive protein labeling and liquid chromatography-tandem mass spectrometry technology allowed the characterization of the proteome under NO-generated conditions. Moreover, we demonstrated that our reagent was able to selectively mark and be used to fluorescently visualize NO-producing cells in a mixed cell culture system.


Assuntos
Corantes Fluorescentes/síntese química , Óxido Nítrico/química , Fenilenodiaminas/síntese química , Proteoma/análise , Aminocumarinas/química , Animais , Microambiente Celular , Corantes Fluorescentes/metabolismo , Humanos , Camundongos , Fenilenodiaminas/metabolismo , Proteômica
11.
J Mol Graph Model ; 84: 215-235, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30031951

RESUMO

Hsp90 contains two Nucleotide Binding Sites (NBS): one each in its N-terminal domain (NTD) and C-terminal domain (CTD), respectively. Previously we used computational techniques to locate a nucleotide-binding site in the CTD. Nucleotide binding at this site stabilized the structurally labile region within this domain, thus providing a rationale for increased resistance to thermal denaturation and proteolysis. A scan for ligand-binding sites in CTD revealed four potential sites with the requisite volume to accommodate aminocoumarins and -derived inhibitors. Only one of these reproducibly formed docked complexes with inhibitors and showed excellent interactions with residues lining the site. Fortuitously, it was identical to the aforementioned nucleotide-binding site thus providing an explanation for the reported direct competition between inhibitors and nucleotides. Further studies with carefully chosen inhibitors and some inactive analogues provided an explanation for the known Structure-Activity Relationships (SAR) of aminocoumarin and -derived inhibitors. We also performed similar studies of the NTD to discern the reason(s) for its inability to bind aminocoumarins, given the family resemblance to prokaryotic Top-IV and Gyr-B. Our studies permitted the identification of the putative inhibitor binding site in the CTD, an explanation for increased resistance to thermal denaturation and proteolysis upon inhibitor binding as well as direct competition with ATP.


Assuntos
Aminocumarinas/química , Sítios de Ligação , Proteínas de Choque Térmico HSP90/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Domínios e Motivos de Interação entre Proteínas , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Aminocumarinas/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Ligação de Hidrogênio , Ligantes , Ligação Proteica , Relação Quantitativa Estrutura-Atividade
12.
Bioorg Chem ; 79: 277-284, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29783098

RESUMO

DPP-IV "a moonlighting protein" has immerged as promising pathway to control Type 2 diabetes as well as found to play key role in earlier stages of cancer. Here we have reported design, synthesis and applications of aminocoumarin derivatives as DPP-IV inhibitors. Compounds have been synthesized and studied for their DPP-IV inhibition activity. Three compounds have shown moderate inhibition at 100 µM concentration. All compounds were also screened for their anticancer activity against A549 (Lung cancer cell line), MCF-7 (Breast cancer cell line) using MTT assay. One of the compounds has shown very good anticancer activity with IC50 value 24 ±â€¯0.1 nM against A549 cell line.


Assuntos
Aminocumarinas/farmacologia , Antineoplásicos/farmacologia , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Desenho de Fármacos , Aminocumarinas/síntese química , Aminocumarinas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Estrutura Molecular , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
13.
Chem Commun (Camb) ; 54(55): 7589-7592, 2018 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-29796477

RESUMO

A synthetic three-fluorophore system with two enzymatically cleavable linkers has been developed for the simultaneous detection of two proteases in a mixture. The probe was designed to afford single excitation/triple emission ratiometric detection through a fluorescence change during the cleavage of a peptide linker. The developed assays were verified for trypsin and chymotrypsin as the model enzymes.


Assuntos
Aminocumarinas/química , Quimotripsina/análise , Fluoresceínas/química , Corantes Fluorescentes/química , Rodaminas/química , Tripsina/análise , Aminocumarinas/síntese química , Aminocumarinas/efeitos da radiação , Estabilidade de Medicamentos , Ensaios Enzimáticos , Fluoresceínas/síntese química , Fluoresceínas/efeitos da radiação , Fluorescência , Transferência Ressonante de Energia de Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/efeitos da radiação , Hidrólise , Lisina/análogos & derivados , Lisina/química , Fenilalanina/análogos & derivados , Fenilalanina/química , Rodaminas/síntese química , Rodaminas/efeitos da radiação
14.
Comb Chem High Throughput Screen ; 21(5): 344-348, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29792140

RESUMO

AIM AND OBJECTIVE: The importance of Chromeno[4,3-b]pyridines in bioactive compounds, highlighted the ongoing research on developing novel methods for the construction of this heterocyclic scaffold. Regarding the advantageous features of multi-component reactions in organic synthesis, we will try to synthesize pyridocoumarins through this method. MATERIALS AND METHODS: Chromeno[4,3-b]pyridines were conveniently prepared from a threecomponent condensation reaction between 4-hydroxy coumarin, ammonia and ethyl 2,4-dioxo-4- arylbutanoates in refluxing n-propanol. The synthesized compounds were characterized by NMR, IR and Mass spectroscopy. RESULTS: The reaction proceeded through an in situ formed 4-amino coumarin, affording eight new target compounds in good yields. CONCLUSION: This method introduce a novel approach to ethyl 4-aryl-5-oxo-5H-chromeno[4,3- b]pyridine-2-carboxylate derivatives and allow organic chemists to prepare 4-aminocoumarin in reaction medium.


Assuntos
Benzopiranos/síntese química , Piridinas/síntese química , Aminocumarinas/síntese química , Amônia/química , Ácido Butírico/química , Estrutura Molecular , Solventes/química , Temperatura
15.
Molecules ; 22(8)2017 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-28805688

RESUMO

The water sensing properties of two efficient two-component fluorescent "turn-on" chemo-sensors based on the 7-dialkylaminocoumarin oxime acid-base equilibrium were investigated. Interestingly, although simple frontier orbital analysis predicts an intramolecular photoinduced electron transfer quenching pathway in conjugated oximates, TD-DFT (Time-dependent density functional theory) quantum chemical calculations support non-radiative dark S1 excited state deactivation as a fluorescence quenching mechanism. Due to the acid-base sensing mechanism and sensitive "turn-on" fluorescent response, both studied coumarin aldoxime chemosensors exhibit rapid response to low-level water content in polar aprotic solvents, with detection limits comparable to chemodosimeters or chemosensors based on interpolymer π-stacking aggregation.


Assuntos
Aminocumarinas/química , Corantes Fluorescentes/química , Solventes/química , Água/análise , Dimerização , Transporte de Elétrons , Cromatografia Gasosa-Espectrometria de Massas/métodos , Limite de Detecção , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Oximas/química , Prótons , Teoria Quântica , Espectrometria de Fluorescência/métodos
16.
Electron. j. biotechnol ; 19(6): 43-48, Nov. 2016. ilus
Artigo em Inglês | LILACS | ID: biblio-840312

RESUMO

Background: Synthesized aminocoumarins are heterocyclic compounds possessing potential for the treatment of insulin-dependent diabetes mellitus with unexplored anti-glycative action. Results: In this study 4-aminocoumarin derivatives (4-ACDs) were evaluated in vitro for antiglycation (AG) activities by using the human serum albumin (HSA)/glucose system, for 8 weeks of incubation. The glycation and conformational alteration of HSA in the presence of the tested compounds were evaluated by Congo red assay, fluorescence and circular dichroism spectroscopy. The antioxidant (AO) capacity were also tested by four different assays including: DPPH (2,2'-diphenyl-1-picrylhydrazyl radical), ABTS (2,2-azinobis (3-ethylbenzothiazoline-6-sulphonate) diammonium salt), FRAP (ferric reducing antioxidant power) and β-carotene-linoleic acid assay. The tested compounds showed AG and AO effects. The intensity of the accomplished AO potential is related to the type of the used assay. Significant alterations in the secondary (monitored by CD spectropolarimetry) and tertiary structure (assessed by spectrofluorimetry) of HSA upon glycation were mitigated by the 4-ACDs, suggesting their suppressive role in the late stage (post-Amadori) of the HSA glycation. Conclusions: By the analogues, in vitro ascertained AO and AG properties of 4-ACD may be recognized as rationale for their protective role against oxidative changes of proteins, thereby precluding diabetic complications in humans.


Assuntos
Aminocumarinas/farmacologia , Antioxidantes/farmacologia , Glicosilação/efeitos dos fármacos , Aminocumarinas/química , Antioxidantes/química , Diabetes Mellitus Tipo 1 , Técnicas In Vitro , Análise Espectral/métodos
17.
Anal Chem ; 88(20): 10237-10244, 2016 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-27647382

RESUMO

Vicinal dithiol-containing proteins (VDPs) play a significant role in maintaining the cellular redox homeostasis and are implicated in many diseases. To provide new chemical tools for VDPs imaging, we report here a ratiometric fluorescent probe CAsH2 for VDPs using 7-diethylaminiocoumarin as the fluorescent reporter and cyclic 1,3,2-dithiarsenolane as the specific ligand. CAsH2 shows peculiar dual fluorescence emission from the excited intramolecular charge transfer (ICT) and twisted intramolecular charge transfer (TICT) states in aqueous media. However, upon selective binding of protein vicinal dithiols to the trivalent arsenical of CAsH2, the probe was brought from the polar water media into the hydrophobic protein domain, causing the excited state ICT to TICT conversion to be restricted; as a result, an increase from the ICT emission band and a decrease from the TICT emission band were observed simultaneously. The designed probe shows high selectivity toward VDPs over other proteins and biological thiols. Preliminary experiments show that CAsH2 can be used for the ratiometric imaging of endogenous VDPs in living cells. So far as we know, this is a rare example of the ratiometric fluorescent probe designed via modulating the ICT-TICT conversion process, which provides a new way to construct various protein-specific ratiometric fluorescent probes.


Assuntos
Aminocumarinas/química , Arsenicais/química , Corantes Fluorescentes/química , Proteínas/análise , Compostos de Sulfidrila/análise , Aminocumarinas/metabolismo , Aminocumarinas/efeitos da radiação , Animais , Arsenicais/metabolismo , Arsenicais/efeitos da radiação , Linhagem Celular Tumoral , Fluorescência , Corantes Fluorescentes/metabolismo , Corantes Fluorescentes/efeitos da radiação , Humanos , Luz , Camundongos , Microscopia Confocal , Microscopia de Fluorescência , Mitocôndrias/metabolismo , Proteínas/metabolismo , Compostos de Sulfidrila/metabolismo
18.
Cell Biochem Biophys ; 74(3): 353-63, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27376828

RESUMO

Heat shock protein (Hsp) 90 an emerging and attracting target in the anti-HIV drug discovery process due to the key role it plays in the pathogenicity of HIV-1 virus. In this research study, long-range all-atom molecular dynamics simulations were engaged for the bound and the unbound proteins to enhance the understanding of the molecular mechanisms of the Hsp90 dimerization and inhibition. Results evidently showed that coumermycin A1 (C-A1), a recently discovered Hsp90 inhibitor, binds at the dimer's active site of the Hsp90 protein and leads to a substantial parting between dimeric opposed residues, which include Arg591.B, Lys594.A, Ser663.A, Thr653.B, Ala665.A, Thr649.B, Leu646.B and Asn669.A. Significant differences in magnitudes were observed in radius of gyration, root-mean-square deviation and root-mean-square fluctuation, which confirms a reasonably more flexible state in the apo conformation associated with it dimerization. In contrast, the bound conformer of Hsp90 showed less flexibility. This visibly highpoints the inhibition process resulting from the binding of the ligand. These findings were further validated by principal component analysis. We believe that the detailed dynamic analyses of Hsp90 presented in this study, would give an imperative insight and better understanding to the function and mechanisms of inhibition. Furthermore, information obtained from the binding mode of the inhibitor would be of great assistance in the design of more potent inhibitors against the HIV target Hsp90.


Assuntos
Aminocumarinas/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Aminocumarinas/química , Sítios de Ligação , Dimerização , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Simulação de Dinâmica Molecular , Análise de Componente Principal , Ligação Proteica , Termodinâmica
19.
Chemistry ; 22(20): 6921-31, 2016 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-27037933

RESUMO

Development of heat shock protein 90 (Hsp90) C-terminal inhibitors has emerged as an exciting strategy for the treatment of cancer. Previous efforts have focused on modifications to the natural products novobiocin and coumermycin. Moreover, variations in both the sugar and amide moieties have been extensively studied, whereas replacements for the coumarin core have received less attention. Herein, 24 cores were synthesized with varying distances and angles between the sugar and amide moieties. Compounds that exhibited good anti-proliferative activity against multiple cancer cell lines and Hsp90 inhibitory activity, were those that placed the sugar and amide moieties between 7.7 and 12.1 Šapart along with angles of 180°.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/química , Novobiocina/análogos & derivados , Aminocumarinas/química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Cumarínicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Novobiocina/química , Relação Estrutura-Atividade
20.
Retrovirology ; 13: 28, 2016 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-27107820

RESUMO

BACKGROUND: HIV-1 capsid influences viral uncoating and nuclear import. Some capsid is detected in the nucleus but it is unclear if it has any function. We reported that the antibiotic Coumermycin-A1 (C-A1) inhibits HIV-1 integration and that a capsid mutation confers resistance to C-A1, suggesting that capsid might affect post-nuclear entry steps. RESULTS: Here we report that C-A1 inhibits HIV-1 integration in a capsid-dependent way. Using molecular docking, we identify an extended binding pocket delimited by two adjacent capsid monomers where C-A1 is predicted to bind. Isothermal titration calorimetry confirmed that C-A1 binds to hexameric capsid. Cyclosporine washout assays in Jurkat CD4+ T cells expressing engineered human TRIMCyp showed that C-A1 causes faster and greater escape from TRIMCyp restriction. Sub-cellular fractionation showed that small amounts of capsid accumulated in the nuclei of infected cells and C-A1 reduced the nuclear capsid. A105S and N74D capsid mutant viruses did not accumulate capsid in the nucleus, irrespective of C-A1 treatment. Depletion of Nup153, a nucleoporin located at the nuclear side of the nuclear pore that binds to HIV-1 capsid, made the virus less susceptible to TRIMCyp restriction, suggesting that Nup153 may help maintain some integrity of the viral core in the nucleus. Furthermore C-A1 increased binding of CPSF6, a nuclear protein, to capsid. CONCLUSIONS: Our results indicate that capsid is involved in post-nuclear entry steps preceding integration.


Assuntos
Proteína do Núcleo p24 do HIV/metabolismo , HIV-1/fisiologia , Internalização do Vírus , Aminocumarinas/metabolismo , Antivirais/metabolismo , Linhagem Celular , HIV-1/efeitos dos fármacos , Humanos
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