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1.
J Agric Food Chem ; 67(45): 12402-12407, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31663732

RESUMO

The hydrolysis of chlorantraniliprole (3-bromo-N-[4-chloro-2-methyl-6-(methylcarbamoyl)phenyl]-1-(3-chloro-2-pyridine-2-yl)-1H-pyrazole-5-carboxamide; CAP) was investigated over the pH range of 6-10, reflective of California rice field conditions, with variable additions of Cu2+, Zn2+, Mn2+, or Ni2+. Dissipation accelerated as pH increased with half-lives ranging from 26.9 to 2.2 days with slight inhibition in rice field water. The addition of divalent metals was not observed to catalyze the hydrolysis of CAP at pH 6, indicating that the insecticide is likely to remain recalcitrant to hydrolysis in neutral or acidic surface waters. However, Mn2+ and Ni2+ were observed to inhibit hydrolysis at pH 8 and 9. Attenuated total reflectance Fourier transform infrared analysis supports the conclusion that divalent metals may withdraw electron density from the amide nitrogen via interaction with the amide oxygen, though additional quantum chemical modeling is necessary to provide further mechanistic insights. Overall, the hydrolysis of CAP in California rice fields and their surrounding surface waters will be dominated by pH and inhibited by dissolved metal species.


Assuntos
Hidróxidos/química , Inseticidas/química , Metais/química , Oryza/crescimento & desenvolvimento , Poluição Química da Água/análise , ortoaminobenzoatos/química , California , Concentração de Íons de Hidrogênio , Hidrólise
2.
J Phys Chem Lett ; 10(20): 5997-6002, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31545052

RESUMO

The classical method for evaluating the waveguide ability only focuses on the optical loss coefficient. However, for the micro- or submicroscale, an organic waveguide is demonstrated by the present study whose scale effect should not be neglected. We found that the optical loss coefficient increased remarkably when decreasing the sectional size of the microfibers. Furthermore, simulations based on Finite-Difference Time-Domain also demonstrated the size-dependent effect of the waveguide. Both the experimental and simulating results showed that the optical loss coefficient converges to a certain value, which means that the scale effect can be neglected as the sectional size is large enough. On the basis of the present study, we suggest that the scale-dependent effect on the sectional size of the waveguide should be investigated by evaluating the waveguide ability by the optical loss coefficient.


Assuntos
Cumarínicos/efeitos da radiação , ortoaminobenzoatos/efeitos da radiação , Cumarínicos/química , Cristalização , Fluorescência , Luz , Manufaturas/efeitos da radiação , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática , Difração de Raios X , ortoaminobenzoatos/química
3.
Molecules ; 24(14)2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31323797

RESUMO

The dissipation behaviors of acetamiprid and chlorantraniliprole in kimchi cabbages were studied under open-field conditions. A simple and rapid analytical method was developed using ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). The multiple reaction monitoring (MRM) conditions of two pesticides were optimized to quantify and identify the pesticide residues. Sample preparation was performed by the QuEChERS (quick, easy, cheap, effective, rugged, and safe) method. Average recovery rates at the different spiked levels (0.05 and 0.25 mg/kg) were in the range of 103.6-113.9% (acetamiprid) and 80.8-91.2% (chlorantraniliprole), and the relative standard deviations were ≤4.3% for all. The dissipation kinetics were assessed using first-order equations after spraying acetamiprid and chlorantraniliprole individually on kimchi cabbages. The biological half-lives in field 1 and 2 were 5.2 and 6.3 days (acetamiprid) and 10.0 and 15.2 days (chlorantraniliprole), respectively. Based on the dissipation equations, the pre-harvest residue limits (PHRLs) corresponding to each day before harvest were suggested as the guidelines to meet the MRL on harvest day. It was also predicted that the terminal residues observed after multiple sprayings (three and seven days) would be below the MRL when harvested, in compliance with the established pre-harvest intervals.


Assuntos
Brassica/química , Cromatografia Líquida de Alta Pressão , Neonicotinoides/análise , Resíduos de Praguicidas/análise , Espectrometria de Massas em Tandem , ortoaminobenzoatos/análise , Contaminação de Alimentos/análise , Limite de Detecção , Estrutura Molecular , Resíduos de Praguicidas/química , ortoaminobenzoatos/química
4.
J Agric Food Chem ; 67(29): 8130-8137, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31287295

RESUMO

Chlorantraniliprole (3-bromo-N-[4-chloro-2-methyl-6-(methylcarbamoyl)phenyl]-1-(3-chloro-2-pyridine-2-yl)-1H-pyrazole-5-carboxamide; CAP) was granted supplemental registration for use in rice cultivation in California through December, 2018. Previous work investigated the partitioning of CAP in California rice field soils; however, its degradation in soils under conditions relevant to California rice culture has not been investigated. The degradation of CAP in soils from two California rice fields was examined under aerobic and anaerobic conditions with varying salinity via microcosm experiments. Results indicate that soil properties governing bioavailability may have a greater influence on degradation than flooding practices or field salinization over a typical growing season. Differences between native and autoclaved soils (t1/2 = 59.0-100.2 and 78.5-171.7 days) suggest that biological processes were primarily responsible for CAP degradation; however, future work should be done to confirm specific biotic processes as well as to elucidate abiotic processes, such as degradation via manganese oxides and formation of nonextractable residues, which may contribute to its dissipation.


Assuntos
Inseticidas/química , Oryza/crescimento & desenvolvimento , Poluentes do Solo/química , Solo/química , ortoaminobenzoatos/química , Agricultura , California , Inundações , Cinética
5.
Arch Pharm (Weinheim) ; 352(7): e1800314, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31210387

RESUMO

Fumarate diester 3 was synthesized upon reacting anthranilic acid with diethylacetylenedicarboxylate. Compound 3 was reacted with different nucleophiles in mild reaction conditions. Selected reaction routes that afforded products 6, 9, 10, 11, and 12 were explained. The estimated mechanism for the reaction of 3 with ethylenediamine to afford 9 was proved by X-ray single-crystal and retro-synthetic reaction. Acetyl anthranilic acid was utilized with zinc and copper to afford the organometallic compounds 14a and 14b, respectively. Three single crystals were afforded for 3, 9 and the organocopper complex 14b. Target compounds were screened for their inhibitory potential against urease enzyme. Most compounds were more potent than thiourea as standard inhibitor, considering that oxopiperazine 9 exhibited double the activity: IC50 = 8.16 ± 0.65 µM (thiourea IC50 = 20.04 ± 0.33 µM). Docking studies were in agreement with the in vitro enzyme assay.


Assuntos
Alquinos/farmacologia , Inibidores Enzimáticos/farmacologia , Compostos Organometálicos/farmacologia , Urease/antagonistas & inibidores , ortoaminobenzoatos/farmacologia , Alquinos/química , Canavalia/enzimologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Modelos Moleculares , Estrutura Molecular , Compostos de Nitrogênio , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Relação Estrutura-Atividade , Urease/metabolismo , ortoaminobenzoatos/química
6.
J Microbiol Biotechnol ; 29(6): 839-844, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31154751

RESUMO

Anthranilate derivatives have been used as flavoring and fragrant agents for a long time. Recently, these compounds are gaining attention due to new biological functions including antinociceptive and analgesic activities. Three anthranilate derivatives, N-methylanthranilate, methyl anthranilate, and methyl N-methylanthranilate were synthesized using metabolically engineered stains of Escherichia coli. NMT encoding N-methyltransferase from Ruta graveolens, AMAT encoding anthraniloyl-coenzyme A (CoA):methanol acyltransferase from Vitis labrusca, and pqsA encoding anthranilate coenzyme A ligase from Pseudomonas aeruginosa were cloned and E. coli strains harboring these genes were used to synthesize the three desired compounds. E. coli mutants (metJ, trpD, tyrR mutants), which provide more anthranilate and/or S-adenosyl methionine, were used to increase the production of the synthesized compounds. MS/MS analysis was used to determine the structure of the products. Approximately, 185.3 µM N-methylanthranilate and 95.2 µM methyl N-methylanthranilate were synthesized. This is the first report about the synthesis of anthranilate derivatives in E. coli.


Assuntos
Escherichia coli/genética , Escherichia coli/metabolismo , ortoaminobenzoatos/metabolismo , Vias Biossintéticas , Coenzima A Ligases/genética , Coenzima A Ligases/metabolismo , Coenzima A-Transferases/genética , Coenzima A-Transferases/metabolismo , Escherichia coli/enzimologia , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Engenharia Metabólica , Metiltransferases/genética , Metiltransferases/metabolismo , Mutação , Pseudomonas aeruginosa/enzimologia , Pseudomonas aeruginosa/genética , Proteínas Recombinantes/metabolismo , Ruta/enzimologia , Ruta/genética , Vitis/enzimologia , Vitis/genética , ortoaminobenzoatos/química
7.
Eur J Med Chem ; 173: 185-202, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31003060

RESUMO

A series of novel 2-aminobenzamide derivatives decorated with thioquinazolinone were designed and synthesized as histone deacetylase (HDAC) inhibitors. These derivatives were evaluated for their antiproliferative activities against several human cancer cell lines including A375, Hela, A549, HCT116 and SMMC7721. It's significantly indicated that some inhibitors exhibited potent antiproliferative activities towards all the studied cancer cell lines. Compounds 7a, 4i, 4o, and 4p exhibited higher antiproliferative activities towards three cancer cell lines: A375, A549 and SMMC7721 compared to CS055, MS275, and CI994. Compound 4p showed more than 4000-fold the isoform selectivity for HDAC1 and more than 250-fold selectivity for HDAC2 compared with HDAC6. The molecular docking analysis reasonably explained the HDAC inhibitory activity and isoform selectivity. In addition, compounds 7a, 4i, 4o, and 4p showed potent inhibitory activities in migration assay and colony formation analysis, and also promoted cell apoptosis. Moreover, compounds 7a, 4i, and 4o inhibited the growth of SMMC7721 cells at S phase of the cell cycle. The immunofluorometric analysis indicated that compounds 7a, 4i, 4o, and 4p could increase the acetylation status of H3K9. Furthermore, in vivo anticancer efficacy of compound 4p was assessed in the A549 xenograft models, and 4p demonstrated potent antitumor activity (TGI = 62.5%). This study provided an effective strategy for further development of tumor-targeting therapy.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Quinazolinonas/farmacologia , ortoaminobenzoatos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Quinazolinonas/química , Relação Estrutura-Atividade , ortoaminobenzoatos/síntese química , ortoaminobenzoatos/química
8.
Mater Sci Eng C Mater Biol Appl ; 100: 315-322, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30948067

RESUMO

Herein appropriateness of nonfunctionalized mesoporous silica nanoparticles SBA-15 and functionalized with (3-chloropropyl)triethoxysilane (→ SBA-15~Cl) and (3-aminopropyl)triethoxysilane (→ SBA-15~NH2) on delivery of physically adsorbed Ph3Sn(CH2)6OH (Sn6) is evaluated. Fluorescent nanomaterial, bearing isatoic moiety, loaded with Sn6 (→ SBA-15~NF|Sn6) was used for cellular uptake study. The fluorescent nanomaterial is efficiently acquired and distributed into the cytoplasm of the cells even after 2 h of cultivation. According to the attained data, all SBA-15 materials loaded with Sn6 diminished cellular viability in dose dependent manner while carriers alone (SBA-15, SBA-15~Cl, SBA-15~NH2) did not show cytotoxicity against B16 cells. According to the MC50 values structural modification of SBA-15 did not improve the efficacy of tested drug. While progressive apoptosis was detected upon the treatment with SBA-15|Sn6, exposure of cells to SBA-15~NH2|Sn6 revealed extinguished apoptosis in time, accompanied with lower caspase activity. This effect is probably due to triggered autophagic process under the treatment with the SBA-15~NH2|Sn6, thus opposed to apoptosis. Presented results suggested that functionalization of SBA-15 was not beneficial for the efficacy of loaded drug, thus, all of them are almost equally efficient considering loaded Sn6 content. Importantly, functionalization of SBA-15 does have an influence on the mode of action and differentiation inducing properties.


Assuntos
Compostos Orgânicos de Estanho/química , Dióxido de Silício/química , Anidridos/química , Animais , Corantes Fluorescentes/química , Camundongos , Nanopartículas/química , Nanopartículas/ultraestrutura , Porosidade , Propilaminas/química , Silanos/química , ortoaminobenzoatos/química
9.
Chem Commun (Camb) ; 55(37): 5371-5374, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-30994648

RESUMO

A new radiotracer, [18F]NA3BF3, capable of rapid, stable, and catalyst-free complexation of aldehydes in vivo is reported. [18F]NA3BF3 was shown to bind aldehydes in live subjects using locally administered aldehyde-presenting microparticles, and was then applied to mapping aldehydic load in a mouse model of sepsis. [18F]NA3BF3 may enable the direct investigation of the chemical biology of aldehydes in living subjects, and may open avenues for the adoption of endogenous aldehydic load as an imaging biomarker of inflammatory pathology.


Assuntos
Aldeídos/química , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Animais , Boranos/química , Radioisótopos de Flúor/química , Rim/diagnóstico por imagem , Lipopolissacarídeos/toxicidade , Fígado/diagnóstico por imagem , Camundongos , Camundongos Endogâmicos BALB C , Compostos Radiofarmacêuticos/síntese química , Sepse/diagnóstico , Sepse/diagnóstico por imagem , ortoaminobenzoatos/química
10.
J Environ Sci Health B ; 54(6): 475-488, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30931735

RESUMO

The behavior of chlorantraniliprole (CAP) and dinotefuran (DNF) insecticides was investigated in clay loam soil, a common type of the Egyptian soil. Effect of temperature, pH and particle size of the soil on the adsorption process was studied. Adsorption isotherm by bulk soil and its constituents; humic acid (HA), clay, silt and sand fractions was measured using batch equilibration technique. The results showed that the adsorption of the insecticides tested was significantly affected by the temperature and was a spontaneous interfacial process in the soil. Freundlich model accurately predicted the adsorption behavior of both insecticides. The interaction between soil and insecticides was endothermic and the highest adsorption for CAP and DNF was obtained at pH 9. However, the effect of pH on the adsorption of DNF was lower than that of CAP. Sorption of CAP and DNF on HA fraction was significantly greater than on clay fraction and bulk soil. In addition, the adsorption was significantly increased with particle size decrease. It could be inferred that the adsorption of CAP and DNF on clay loam soil was physical in nature and greatly influenced by the soil components, pH and temperature.


Assuntos
Guanidinas/química , Neonicotinoides/química , Nitrocompostos/química , ortoaminobenzoatos/química , Adsorção , Argila , Egito , Substâncias Húmicas , Concentração de Íons de Hidrogênio , Inseticidas/química , Tamanho da Partícula , Solo , Poluentes do Solo , Temperatura Ambiente , Termodinâmica
11.
Talanta ; 199: 290-295, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30952260

RESUMO

A chitosan membrane composed by 60% (w/w) chitosan and 40% (w/w) Aliquat®336 has been proposed as a new biopolymeric support for electromembrane extraction. The new support has been characterized by Scanning Electron Microscopy, resulting a 30-35 µm thickness. Amoxicillin, nicotinic acid, hippuric acid, salicylic acid, anthranilic acid, ketoprofen, naproxen and ibuprofen have been successfully extracted using the proposed support. Better enrichment factors were obtained for the acidic polar analytes than for the non-steroidal anti-inflammatory compounds (ranging from 118 for hippuric acid and 20 for ibuprofen). Electromembrane extraction was developed applying a DC voltage of 100 V, 1-octanol as supported liquid membrane and 20 min of extraction. The target analytes have also been satisfactorily extracted from human urine samples, providing high extraction efficiencies. The chitosan membrane is presented as a promising alternative for supporting liquid membrane compared to commonly used materials for this purpose.


Assuntos
Biopolímeros/química , Quitosana , Técnicas Eletroquímicas , Amoxicilina/química , Amoxicilina/isolamento & purificação , Hipuratos/química , Hipuratos/isolamento & purificação , Humanos , Ibuprofeno/química , Ibuprofeno/isolamento & purificação , Cetoprofeno/química , Cetoprofeno/isolamento & purificação , Naproxeno/química , Naproxeno/isolamento & purificação , Niacina/química , Niacina/isolamento & purificação , Ácido Salicílico/química , Ácido Salicílico/isolamento & purificação , ortoaminobenzoatos/química , ortoaminobenzoatos/isolamento & purificação
12.
Eur J Med Chem ; 170: 141-156, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30878828

RESUMO

The transient receptor potential ankyrin 1 (TRPA1) channel is a non-selective cation channel, which detects noxious stimuli leading to pain, itch and cough. However, the mechanism(s) of channel modulation by many of the known, non-reactive modulators has not been fully elucidated. N-Cinnamoylanthranilic acid derivatives (CADs) contain structural elements from the TRPA1 modulators cinnamaldehyde and flufenamic acid, so it was hypothesized that specific modulators could be found amongst them and more could be learnt about modulation of TRPA1 with these compounds. A series of CADs was therefore screened for agonism and antagonism in HEK293 cells stably transfected with WT-human (h)TRPA1, or C621A, F909A or F944A mutant hTRPA1. Derivatives with electron-withdrawing and/or electron-donating substituents were found to possess different activities. CADs with inductive electron-withdrawing groups were agonists with desensitising effects, and CADs with electron-donating groups were either partial agonists or antagonists. Site-directed mutagenesis revealed that the CADs do not undergo conjugate addition reaction with TRPA1, and that F944 is a key residue involved in the non-covalent modulation of TRPA1 by CADs, as well as many other structurally distinct non-reactive TRPA1 ligands already reported.


Assuntos
Cinamatos/química , Cinamatos/farmacologia , Canal de Cátion TRPA1/agonistas , Canal de Cátion TRPA1/antagonistas & inibidores , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacologia , Animais , Sinalização do Cálcio/efeitos dos fármacos , Cinamatos/síntese química , Cobaias , Células HEK293 , Humanos , Masculino , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Canal de Cátion TRPA1/metabolismo , ortoaminobenzoatos/síntese química
13.
Nucleic Acids Res ; 47(8): 4136-4152, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-30892613

RESUMO

The UvrA2 dimer finds lesions in DNA and initiates nucleotide excision repair. Each UvrA monomer contains two essential ATPase sites: proximal (P) and distal (D). The manner whereby their activities enable UvrA2 damage sensing and response remains to be clarified. We report three key findings from the first pre-steady state kinetic analysis of each site. Absent DNA, a P2ATP-D2ADP species accumulates when the low-affinity proximal sites bind ATP and enable rapid ATP hydrolysis and phosphate release by the high-affinity distal sites, and ADP release limits catalytic turnover. Native DNA stimulates ATP hydrolysis by all four sites, causing UvrA2 to transition through a different species, P2ADP-D2ADP. Lesion-containing DNA changes the mechanism again, suppressing ATP hydrolysis by the proximal sites while distal sites cycle through hydrolysis and ADP release, to populate proximal ATP-bound species, P2ATP-Dempty and P2ATP-D2ATP. Thus, damaged and native DNA trigger distinct ATPase site activities, which could explain why UvrA2 forms stable complexes with UvrB on damaged DNA compared with weaker, more dynamic complexes on native DNA. Such specific coupling between the DNA substrate and the ATPase mechanism of each site provides new insights into how UvrA2 utilizes ATP for lesion search, recognition and repair.


Assuntos
Trifosfato de Adenosina/análogos & derivados , Proteínas de Bactérias/química , Reparo do DNA , DNA Bacteriano/química , Endodesoxirribonucleases/química , Proteínas de Escherichia coli/química , Geobacillus stearothermophilus/enzimologia , ortoaminobenzoatos/química , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Sequência de Aminoácidos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Clonagem Molecular , Dano ao DNA , DNA Bacteriano/genética , DNA Bacteriano/metabolismo , Endodesoxirribonucleases/genética , Endodesoxirribonucleases/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Geobacillus stearothermophilus/química , Geobacillus stearothermophilus/genética , Cinética , Modelos Moleculares , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Estrutura Secundária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Alinhamento de Sequência , Homologia Estrutural de Proteína , Especificidade por Substrato , Termodinâmica , Thermotoga maritima/química , Thermotoga maritima/enzimologia , Thermotoga maritima/genética , ortoaminobenzoatos/metabolismo
14.
J Ind Microbiol Biotechnol ; 46(3-4): 483-492, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30729343

RESUMO

Actinobacteria are a major source of novel bioactive natural products. A challenge in the screening of these microorganisms lies in finding the favorable growth conditions for secondary metabolite production and dereplication of known molecules. Here, we report that Streptomyces sp. MBT27 produces 4-quinazolinone alkaloids in response to elevated levels of glycerol, whereby quinazolinones A (1) and B (2) form a new sub-class of this interesting family of natural products. Global Natural Product Social molecular networking (GNPS) resulted in a quinazolinone-related network that included anthranilic acid (3), anthranilamide (4), 4(3H)-quinazolinone (5), and 2,2-dimethyl-1,2-dihydroquinazolin-4(3H)-one (6). Actinomycins D (7) and X2 (8) were also identified in the extracts of Streptomyces sp. MBT27. The induction of quinazolinone production by glycerol combined with biosynthetic insights provide evidence that glycerol is integrated into the chemical scaffold. The unprecedented 1,4-dioxepane ring, that is spiro-fused into the quinazolinone backbone, is most likely formed by intermolecular etherification of two units of glycerol. Our work underlines the importance of varying the growth conditions for the discovery of novel natural products and for understanding their biosynthesis.


Assuntos
Descoberta de Drogas , Quinazolinonas/química , Streptomyces/química , Produtos Biológicos/química , Fermentação , Espectroscopia de Ressonância Magnética , Estrutura Molecular , ortoaminobenzoatos/química
15.
J Chem Inf Model ; 59(2): 743-753, 2019 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-30758202

RESUMO

Cytochrome P450 102A1 from Bacillus megaterium (BM3) is a fatty acid hydroxylase that has one of the highest turnover rates of any mono-oxygenase. Recent studies have shown how mutants of BM3 can produce metabolites of known drug compounds similar to those observed in humans. Single-point mutations in the binding pocket change the regioselective metabolism of fenamic acids from aromatic hydroxylation to aliphatic hydroxylation. This study is concerned with the individual contribution from accessibility and reactivity for drug metabolism with a future goal to develop fast methods for prediction. For a BM3 M11 mutant as well as the M11 V87F and M11 V87I mutants, we studied the metabolism of the nonsteroidal anti-inflammatory drugs (NSAIDs) mefenamic acid, meclofenamic acid, tolfenamic acid, and diclofenac. Density functional theory (DFT; B3LYP and B3LYP-D3) calculations for all possible reactions were performed using a porphyrin model reacting with the four substrates. Molecular dynamics (MD) simulations were used to determine the potential sites of metabolism that are accessible. Finally, we combine reactivity and accessibility for each potential site to interpret the experimentally determined metabolism. Generally, the 3 and 5 positions (on the ring containing the acidic substituent) and the 2', 3', and 4' positions are most reactive, whereas 4, 5, 3', and 4' are most accessible. Combining reactivity and accessibility show that the 5, 3', and 4' positions are predicted to be most prone to be metabolized, in agreement with experimentally observed data. Reactivity seems to be the dominant factor in the CYP-mediated metabolism of these NSAIDs, which is consistent with previously published methods based solely on reactivity.


Assuntos
Bacillus megaterium/enzimologia , Sistema Enzimático do Citocromo P-450/metabolismo , Teoria da Densidade Funcional , Simulação de Dinâmica Molecular , Mutação , ortoaminobenzoatos/química , ortoaminobenzoatos/metabolismo , Bacillus megaterium/genética , Sítios de Ligação , Sistema Enzimático do Citocromo P-450/genética , Conformação Molecular , Estereoisomerismo , Especificidade por Substrato
16.
Science ; 363(6429): 875-880, 2019 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-30792303

RESUMO

Potassium (K+) channels have been evolutionarily tuned for activation by diverse biological stimuli, and pharmacological activation is thought to target these specific gating mechanisms. Here we report a class of negatively charged activators (NCAs) that bypass the specific mechanisms but act as master keys to open K+ channels gated at their selectivity filter (SF), including many two-pore domain K+ (K2P) channels, voltage-gated hERG (human ether-à-go-go-related gene) channels and calcium (Ca2+)-activated big-conductance potassium (BK)-type channels. Functional analysis, x-ray crystallography, and molecular dynamics simulations revealed that the NCAs bind to similar sites below the SF, increase pore and SF K+ occupancy, and open the filter gate. These results uncover an unrecognized polypharmacology among K+ channel activators and highlight a filter gating machinery that is conserved across different families of K+ channels with implications for rational drug design.


Assuntos
Clorobenzenos/farmacologia , Canal de Potássio ERG1/agonistas , Canal de Potássio ERG1/química , Ativação do Canal Iônico/efeitos dos fármacos , Canais de Potássio Ativados por Cálcio de Condutância Alta/agonistas , Canais de Potássio Ativados por Cálcio de Condutância Alta/química , Tetra-Hidronaftalenos/farmacologia , Tetrazóis/farmacologia , Tioureia/análogos & derivados , ortoaminobenzoatos/farmacologia , Animais , Células CHO , Clorobenzenos/química , Cricetulus , Cristalografia por Raios X , Desenho de Drogas , Células HEK293 , Humanos , Simulação de Dinâmica Molecular , Domínios Proteicos , Tetra-Hidronaftalenos/química , Tetrazóis/química , Tioureia/química , Tioureia/farmacologia , Xenopus , ortoaminobenzoatos/química
17.
Phytochemistry ; 160: 85-91, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30802801

RESUMO

Three undescribed natural products, the anthranilic acid derivatives laccanthrilic acids A, B, and C, as well as the known (3S)-1,2,3,4-tetrahydro-3-ß-carboline-3-carboxylic acid were isolated from fruiting bodies of Laccaria laccata. The structures were established by 1D and 2D NMR spectroscopy, HR-(+)-ESIMS and chemical synthesis. The absolute configuration of laccanthrilic acids A and B was determined by GC-MS after hydrolytic cleavage and derivatisation of the resulting glutamic acid with methanol and Mosher's reagent and subsequent comparison with authentic synthetic samples of known absolute configuration. The absolute configuration of laccanthrilic acid C was determined by comparison of the CD spectra of laccanthrilic acids B and C with each other. Metabolic profiling of related species showed that the compounds are common in the genus Laccaria. Laccanthrilic acid B exhibited moderate nematicidal effects against Caenorhabditis elegans, which might explain to some degree the beneficial role of these fungi for the growth and survival of their host plants.


Assuntos
Antinematódeos/química , Antinematódeos/farmacologia , Laccaria/química , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacologia , Animais , Caenorhabditis elegans/efeitos dos fármacos , Carpóforos/química
18.
J Steroid Biochem Mol Biol ; 188: 59-70, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30615932

RESUMO

Androgen receptor (AR) antagonists are used for hormone therapy of prostate cancer (PCa). However resistance to the treatment occurs eventually. One possible reason is the occurrence of AR mutations that prevent inhibition of AR-mediated transactivation by antagonists. To offer in future more options to inhibit AR signaling, novel chemical lead structures for new AR antagonists would be beneficial. Here we analyzed structure-activity relationships of a battery of 36 non-steroidal structural variants of methyl anthranilate including 23 synthesized compounds. We identified structural requirements that lead to more potent AR antagonists. Specific compounds inhibit the transactivation of wild-type AR as well as AR mutants that render treatment resistance to hydroxyflutamide, bicalutamide and the second-generation AR antagonist enzalutamide. This suggests a distinct mode of inhibiting the AR compared to the clinically used compounds. Competition assays suggest binding of these compounds to the AR ligand binding domain and inhibit PCa cell proliferation. Moreover, active compounds induce cellular senescence despite inhibition of AR-mediated transactivation indicating a transactivation-independent AR-pathway. In line with this, fluorescence resonance after photobleaching (FRAP) - assays reveal higher mobility of the AR in the cell nuclei. Mechanistically, fluorescence resonance energy transfer (FRET) - assays indicate that the amino-carboxy (N/C)-interaction of the AR is not affected, which is in contrast to known AR-antagonists. This suggests a mechanistically novel mode of AR-antagonism. Together, these findings indicate the identification of a novel chemical platform as a new lead structure that extends the diversity of known AR antagonists and possesses a distinct mode of antagonizing AR-function.


Assuntos
Antagonistas de Receptores de Andrógenos/química , Antagonistas de Receptores de Andrógenos/farmacologia , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacologia , Animais , Células COS , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Halogenação , Humanos , Masculino , Mutação , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo
19.
Bioorg Med Chem ; 27(5): 769-776, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30679133

RESUMO

Anthranilic diamide insecticide could control lepidopteran pests by selectively binding and activating insect ryanodine receptors (RyRs), and the unique mode of action is different from other conventional insecticides. In order to discover new anthranilic diamide insecticide as ryanodine receptors activators, a series of 11 novel anthranilic diamides derivatives (Ia-k) were synthesized and confirmed by melting point, 1H NMR, 13C NMR and elemental analyses. The preliminary bioactivity revealed that most title compounds showed moderate to remarkable activities against oriental armyworm (Mythimna separata) and diamondback moth (Plutella xylostella). Especially, compounds Ia and If, which exhibited 100% larvicidal activity against oriental armyworm at 1.0 mg L-1, and comparable to that of chlorantraniliprole (100% at 1 mg L-1). If displayed 60% insecticidal activity against diamondback moth at 0.01 mg L-1, better than chlorantraniliprole (45% at 0.01 mg L-1). The preliminary structure activity relationships were discussed. In addition, the calcium imaging experiment indicated that the insect ryanodine receptor is the potential target of If.


Assuntos
Amidas/farmacologia , Agonistas dos Canais de Cálcio/farmacologia , Inseticidas/farmacologia , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , ortoaminobenzoatos/farmacologia , Amidas/síntese química , Amidas/química , Animais , Cálcio/metabolismo , Agonistas dos Canais de Cálcio/síntese química , Agonistas dos Canais de Cálcio/química , Inseticidas/síntese química , Inseticidas/química , Larva/efeitos dos fármacos , Estrutura Molecular , Mariposas/efeitos dos fármacos , Periplaneta/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/química , Sulfonas/farmacologia , ortoaminobenzoatos/síntese química , ortoaminobenzoatos/química
20.
Nanoscale ; 11(3): 1326-1334, 2019 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-30604816

RESUMO

The transformation of renewable natural resources is an appealing and sustainable protocol to minimize fossil fuel consumption. Here, a simple incipient wetness protocol is developed to prepare ultrasmall gold clusters, immobilized on TiO2 (particle size: 1.2-1.7 nm), using anthranilic acid as a stabilizing agent. The Au clusters can be reduced to metallic Au0 (Au/TH-150 and Au/TH-200) during 150 and 200 °C annealing in the presence of H2 gas, while the Au clusters are converted to Auδ+ species in air at 200 and 500 °C (Au/TA-200 and Au/TA-500), a conclusion supported by XPS and low-temperature (-150 °C) Operando-DRIFTS analysis. Au/TA-200 and Au/TA-500 showed inactivity in the base-free direct oxidation of glucose. For comparison, Au/TH-150 and Au/TH-200 exhibited salient catalytic performance (87-92% conversion and 95-97% selectivity for gluconic acid), revealing that glucose oxidation occurs preferentially on the Au0 species. The turnover frequency (TOF) of Au/TH-150 reaches 1908 molreacted glucose molAu-1 h-1, which is much higher than that of commercial Pd-Bi/C under alkaline conditions (TOF: 1298 molreacted glucose molPd-1 h-1, pH 9.5). The apparent activation energies are 37 (over Au/TH-150) and 47 kJ mol-1 (Au/TH-200), comparable to the unsupported Au colloids, indicating that the oxidation should occur at the Au surface rather than at the perimeter interface between the Au clusters and the supports.


Assuntos
Gluconatos/química , Glucose/química , Ouro/química , Nanoestruturas/química , Titânio/química , Catálise , Temperatura Baixa , Cinética , Oxirredução , Tamanho da Partícula , Termogravimetria , ortoaminobenzoatos/química
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