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1.
Int J Biol Macromol ; 171: 89-99, 2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33412202

RESUMO

In this study we describe the crystal structures of the apoform, the binary and the ternary complexes of a double bond reductase from Malus domestica L. (MdDBR) and explore a range of potential substrates. The overall fold of MdDBR is similar to that of the medium chain reductase/dehydrogenase/zinc-dependent alcohol dehydrogenase-like family. Structural comparison of MdDBR with Arabidopsis thaliana DBR (AtDBR), Nicotiana tabacum DBR (NtDBR) and Rubus idaeus DBR (RiDBR) allowed the identification of key amino acids involved in cofactor and ligands binding and shed light on how these residues may guide the orientation of the substrates. The enzyme kinetic for the substrate trans-4-phenylbuten-2-one has been analyzed, and MdDBR activity towards a variety of substrates was tested. This enzyme has been reported to be involved in the phenylpropanoid pathway where it would catalyze the NADPH-dependent reduction of the α, ß-unsaturated double bond of carbonyl metabolites. Our study provides new data towards the identification of MdDBR natural substrate and the biosynthetic pathway where it belongs. Furthermore, the originally proposed involvement in dihydrochalcone biosynthesis in apple must be questioned.


Assuntos
Apoproteínas/química , Butanonas/química , Malus/química , NADP/química , Oxirredutases/química , Proteínas de Plantas/química , Sequência de Aminoácidos , Apoproteínas/genética , Apoproteínas/metabolismo , Arabidopsis/química , Arabidopsis/enzimologia , Sítios de Ligação , Butanonas/metabolismo , Clonagem Molecular , Cristalografia por Raios X , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Cinética , Malus/enzimologia , Modelos Moleculares , NADP/metabolismo , Oxirredutases/genética , Oxirredutases/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Rubus/química , Rubus/enzimologia , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Especificidade por Substrato , Termodinâmica , Tabaco/química , Tabaco/enzimologia
2.
J Med Microbiol ; 69(5): 670-675, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32186482

RESUMO

Introduction. Biocide-induced cross-resistance to antimicrobials in bacteria has been described and is a concern for regulators. We have recently reported on a new protocol to predict the propensity of biocide to induce phenotypic resistance in bacteria.Aim. To measure bacterial propensity to develop antimicrobial resistance following exposure to a new cosmetic preservative developed by L'Oréal R and I.Methodology. Well-established antimicrobials including triclosan (TRI) and benzalkonium chloride (BZC) and a new molecule hydroxyethoxy phenyl butanone (HEPB) were investigated for their antimicrobial efficacy, effect on bacterial growth, and their potential to induce resistance to chemotherapeutic antibiotics using a new predictive protocol.Results. The use of this predictive protocol with Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa showed that TRI and BZC significantly affected bacterial growth, MICs and minimum bactericidal concentrations (MBCs). There was no change in antibiotic susceptibility profile following exposure to BZC, but E. coli became intermediate resistant to tobramycin following treatment with TRI (0.00002 % w/v). HEPB did not change the antimicrobial susceptibility profile in P. aeruginosa and S. aureus but E. coli became susceptible to gentamicin. TRI exposure resulted in bacterial susceptibility profile alteration consistent with the literature and confirmed the use of TRI as a positive control in such a test.Conclusion. Data produced on the propensity of a molecule to induce bacterial resistance is useful and appropriate when launching a new preservative.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Butanonas/farmacologia , Farmacorresistência Bacteriana , Conservantes Farmacêuticos/farmacologia , Butanonas/química , Interações Medicamentosas , Humanos , Testes de Sensibilidade Microbiana/métodos , Testes de Sensibilidade Microbiana/normas , Conservantes Farmacêuticos/química , Reprodutibilidade dos Testes
3.
Nat Commun ; 11(1): 1450, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-32193370

RESUMO

Olfactory and metabolic dysfunctions are intertwined phenomena associated with obesity and neurodegenerative diseases; yet how mechanistically olfaction regulates metabolic homeostasis remains unclear. Specificity of olfactory perception integrates diverse environmental odors and olfactory neurons expressing different receptors. Here, we report that specific but not all olfactory neurons actively regulate fat metabolism without affecting eating behaviors in Caenorhabditis elegans, and identified specific odors that reduce fat mobilization via inhibiting these neurons. Optogenetic activation or inhibition of the responsible olfactory neural circuit promotes the loss or gain of fat storage, respectively. Furthermore, we discovered that FLP-1 neuropeptide released from this olfactory neural circuit signals through peripheral NPR-4/neuropeptide receptor, SGK-1/serum- and glucocorticoid-inducible kinase, and specific isoforms of DAF-16/FOXO transcription factor to regulate fat storage. Our work reveals molecular mechanisms underlying olfactory regulation of fat metabolism, and suggests the association between olfactory perception specificity of each individual and his/her susceptibility to the development of obesity.


Assuntos
Comportamento Alimentar/fisiologia , Metabolismo dos Lipídeos/fisiologia , Sistemas Neurossecretores/metabolismo , Obesidade/metabolismo , Percepção Olfatória/fisiologia , Animais , Animais Geneticamente Modificados , Butanonas/química , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Humanos , Neurônios/metabolismo , Neuropeptídeos/metabolismo , Odorantes , Optogenética , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Neuropeptídeos/metabolismo
4.
Drug Dev Ind Pharm ; 46(2): 173-178, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31931645

RESUMO

In this paper, a novel low-temperature 3 D printing technique is introduced and characterized through a parametric printability study to fabricate poly-lactic-co-glycolic acid (PLGA) constructs using methyl ethyl ketone (MEK) as a solvent. The effects of varying concentrations of PLGA in MEK solvent, lactic to glycolic ratio of PLGA, the molecular weight of PLGA, and the scaling of PLGA constructs on the printability are investigated. PLGA concentrations of higher than 80% w/v, lactic to glycolic ratio more than 75%, molecular weight more than 100 kDa, and printing through nozzles smaller than 0.96 mm internal diameter are recommended for 3 D printing of PLGA constructs with high shape fidelity. Ultimately, a vacuum drying solvent removal process is implemented, and Proton Nuclear Magnetic Resonance (1H-NMR) spectroscopy is used to confirm complete removal of the solvent from PLGA constructs. The results of this study can be used for the development of drug-eluting implants.


Assuntos
Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Impressão Tridimensional , Solventes/química , Butanonas/química , Espectroscopia de Ressonância Magnética/métodos , Peso Molecular , Preparações Farmacêuticas/química , Temperatura
6.
Food Chem Toxicol ; 134 Suppl 2: 110948, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31756354

RESUMO

The existing information supports the use of this material as described in this safety assessment. 4-(p-Hydroxyphenyl)-2-butanone was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that 4-(p-hydroxyphenyl)-2-butanone is not genotoxic. Data on 4-(p-hydroxyphenyl)-2-butanone provide a calculated MOE >100 for the repeated dose toxicity endpoint. The developmental and reproductive toxicity and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class I material, and the exposure to 4-(p-hydroxyphenyl)-2-butanone is below the TTC (0.03 mg/kg/day and 1.4 mg/day, respectively). Data from 4-(p-hydroxyphenyl)-2-butanone show that there are no safety concerns for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; 4-(p-hydroxyphenyl)-2-butanone is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; 4-(p-hydroxyphenyl)-2-butanone was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.


Assuntos
Butanonas/toxicidade , Odorantes , Animais , Butanonas/química , Qualidade de Produtos para o Consumidor , Avaliação Pré-Clínica de Medicamentos , Determinação de Ponto Final , Humanos , Testes de Mutagenicidade , Nível de Efeito Adverso não Observado , Medição de Risco , Salmonella typhimurium/efeitos dos fármacos
7.
Molecules ; 24(19)2019 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-31590450

RESUMO

UV-curable inks, coatings, and adhesives are being increasingly used in food packaging systems. When exposed to UV energy, UV-photoinitiators (PI's) present in the formulations produce free radicals which catalyze polymerization of monomers and pre-polymers into resins. In addition to photopolymerization, other free radical reactions occur in these systems resulting in the formation of chemically varied photolytic decomposition products, many of which are low molecular weight chemical species with high migration potential. This research conducted model experiments in which 24 commonly used PI's were exposed to UV-energy at the typical upper limit of commercial UV-printing press conditions. UV-irradiated PI's were analyzed by gas chromatography-mass spectrometry (GC-MS) and electrospray-mass spectrometry (ESI-MS) in order to identify photolytic decomposition products. Subsequently, migration studies of 258 UV-cure food packaging samples were conducted using GC-MS; PI's and photolytic decomposition products were found in nearly all samples analyzed. One hundred-thirteen photolytic decomposition products were identified. Eighteen intact PI's and 21 photolytic decomposition products were observed as migrants from the 258 samples analyzed, and these were evaluated for frequency of occurrence and migratory concentration range. The most commonly observed PI's were 2-hydroxy-2-methylpropiophenone and benzophenone. The most commonly observed photolytic decomposition products were 2,4,6-trimethylbenzaldehyde and 1-phenyl-2-butanone. This compilation of PI photolytic decomposition data and associated migration data will aid industry in identifying and tracing non-intentionally added substances (NIAS) in food packaging materials.


Assuntos
Benzaldeídos/isolamento & purificação , Butanonas/isolamento & purificação , Contaminação de Alimentos/análise , Embalagem de Alimentos , Benzaldeídos/metabolismo , Benzofenonas/química , Butanonas/química , Cromatografia Gasosa-Espectrometria de Massas , Estrutura Molecular , Fotólise , Propiofenonas/química , Espectrometria de Massas por Ionização por Electrospray , Raios Ultravioleta
8.
J Org Chem ; 84(11): 6982-6991, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31066559

RESUMO

Polyhydroxylated compounds are building blocks for the synthesis of carbohydrates and other natural products. Their synthesis is mainly achieved by different synthetic versions of aldol-coupling reactions, catalyzed either by organocatalysts, enzymes, or metal-organic catalysts. We have investigated the formation of 1,4-substituted 2,3-dihydroxybutan-1-one derivatives from para- and meta-substituted phenylacetaldehydes by three distinctly different strategies. The first involved a direct aldol reaction with hydroxyacetone, dihydroxyacetone, or 2-hydroxyacetophenone, catalyzed by the cinchona derivative cinchonine. The second was reductive cross-coupling with methyl- or phenylglyoxal promoted by SmI2, resulting in either 5-substituted 3,4-dihydroxypentan-2-ones or 1,4 bis-phenyl-substituted butanones, respectively. Finally, in the third case, aldolase catalysis was employed for synthesis of the corresponding 1,3,4-trihydroxylated pentan-2-one derivatives. The organocatalytic route with cinchonine generated distereomerically enriched syn-products (de = 60-99%), with moderate enantiomeric excesses (ee = 43-56%) but did not produce aldols with either hydroxyacetone or dihydroxyacetone as donor ketones. The SmI2-promoted reductive cross-coupling generated product mixtures with diastereomeric and enantiomeric ratios close to unity. This route allowed for the production of both 1-methyl- and 1-phenyl-substituted 2,3-dihydroxybutanones at yields between 40-60%. Finally, the biocatalytic approach resulted in enantiopure syn-(3 R,4 S) 1,3,4-trihydroxypentan-2-ones.


Assuntos
Butanonas/síntese química , Butanonas/metabolismo , Cinchona/química , Frutose-Bifosfato Aldolase/metabolismo , Pentanonas/síntese química , Pentanonas/metabolismo , Butanonas/química , Catálise , Estrutura Molecular , Pentanonas/química , Estereoisomerismo
9.
J Environ Sci (China) ; 79: 1-10, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30784434

RESUMO

Methacrolein (MACR) and methyl vinyl ketone (MVK) are two major intermediate products from the photochemical oxidation of isoprene, the most important biogenic volatile organic compound. In addition, MACR and MVK have primary emissions. Investigating the sources and evolution of MACR and MVK could provide helpful information for the oxidative capacity of the atmosphere. In this study, hourly measurements of isoprene, MACR, and MVK were conducted at a receptor site in the Pearl River Delta region (PRD), i.e., the Heshan site (HS), from 22 October to 20 November, 2014. The average mixing ratios of isoprene, MACR and MVK were 151 ±â€¯17, 91 ±â€¯6 and 79 ±â€¯6 pptv, respectively. The daily variations and the ratios of MVK/MACR during daytime and nighttime suggested that other sources besides isoprene photooxidation influenced the MACR and MVK abundances at the HS. Positive matrix factorization was utilized to resolve the sources of MACR and MVK. Five sources were identified and quantified, including biogenic emissions, biomass burning, secondary formation, diesel, and gasoline vehicular emissions. Among them, secondary formation made the greatest contribution to observed MACR and MVK with average contributions of ~45% and ~70%, respectively. Through the yields of secondary products from the oxidation of MACR and MVK by the OH radical and the concentrations of MACR and MVK, it was found that methylglyoxal and formaldehyde were the main oxidation products of MACR and MVK at the HS site. Overall, this study evaluated the roles of primary emissions on ambient levels of MACR and MVK and advanced the understanding of photochemical oxidation of MACR and MVK in the PRD.


Assuntos
Acroleína/análogos & derivados , Poluentes Atmosféricos/análise , Butadienos/análise , Butanonas/análise , Hemiterpenos/análise , Acroleína/análise , Acroleína/química , Poluentes Atmosféricos/química , Biomassa , Butanonas/química , China , Monitoramento Ambiental , Formaldeído/química , Gasolina , Modelos Teóricos , Oxirredução , Aldeído Pirúvico/química , Emissões de Veículos
10.
Curr Med Chem ; 26(15): 2601-2608, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30009704

RESUMO

Attachment of different tails to the well-known carbonic anhydrase (CA) pharmacophores has led to the development of several new CA inhibitors (CAIs). A very good example of such "tails" is constituted by carbohydrates, which represent a wide range of chemotypes, leading thus to a high number of new CAIs. In the last years, several C-cinnamoyl glycosides containing different scaffolds have been prepared and investigated as carbonic anhydrase inhibitors, showing that some of them are very potent and selective CAIs. This article will review the latest developments in the synthesis and biological activity of these Cglycosides.


Assuntos
Butanonas/química , Inibidores da Anidrase Carbônica/química , Glicosídeos/química , Antituberculosos/síntese química , Antituberculosos/química , Bactérias/efeitos dos fármacos , Bactérias/enzimologia , Butanonas/síntese química , Inibidores da Anidrase Carbônica/síntese química , Anidrases Carbônicas/química , Domínio Catalítico , Glicosídeos/síntese química , Humanos , Estrutura Molecular
11.
Chemosphere ; 214: 1-9, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30248553

RESUMO

In-cloud processing of volatile organic compounds is one of the significant routes leading to secondary organic aerosol (SOA) in the lower troposphere. In this study, we demonstrate that two atmospherically relevant α,ß-unsaturated carbonyls, i.e., but-3-en-2-on (methyl vinyl ketone, MVK) and 2-methylopropenal (methacrolein, MACR), undergo sulfate radical-induced transformations in dilute aqueous systems under photochemical conditions to form organosulfates previously identified in ambient aerosols and SOA generated in smog chambers. The photooxidation was performed under sun irradiation in unbuffered aqueous solutions containing carbonyl precursors at a concentration of 0.2 mmol and peroxydisulfate as a source of sulfate radicals (SO4-) at a concentration of 0.95 mmol. UV-vis analysis of solutions showed the fast decay of unsaturated carbonyl precursors in the presence of sulfate radicals. The observation confirms the capacity of sulfate radicals to transform the organic compounds into SOA components in atmospheric waters. Detailed interpretation of high-resolution negative ion electrospray ionization tandem mass spectra allowed to assign molecular structures to multiple aqueous organosulfate products, including an abundant isoprene-derived organosulfate C4H8SO7 detected at m/z 199. The results highlight the solar aqueous-phase reactions as a potentially significant route for biogenic SOA production in clouds at locations where isoprene oxidation occurs. A recent modelling study suggests that such processes could likely contribute to 20-30 Tg year-1 production of SOA, referred to as aqSOA, which is a non-negligible addition to the still underestimated budget of atmospheric aerosol.


Assuntos
Acroleína/análogos & derivados , Poluentes Atmosféricos/química , Butanonas/química , Água/química , Acroleína/química , Poluentes Atmosféricos/análise , Oxirredução , Água/análise
12.
Chem Pharm Bull (Tokyo) ; 66(7): 721-726, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29962455

RESUMO

Highly reactive α,ß-unsaturated carbonyl compounds, such as acrolein (ACR), crotonaldehyde (CA) and methyl vinyl ketone (MVK), are environmental pollutants present in high concentrations in cigarette smoke. We have previously found that these carbonyl compounds in cigarette smoke extract (CSE) react with intracellular glutathione (GSH) to produce the corresponding GSH-ACR, GSH-CA and GSH-MVK adducts via Michael addition reaction. These adducts are then further reduced to the corresponding alcohol forms by intracellular aldo-keto reductases in highly metastatic mouse melanoma (B16-BL6) cells and then excreted into the extracellular fluid. This time, we conducted a similar study using sheep erythrocytes and found analogous changes in the sheep erythrocytes after exposure to CSE as those with B16-BL6 cells. This indicates similarity of the detoxification pathways of the α,ß-unsaturated carbonyl compounds in sheep blood cells and B16-BL6 cells. Also, we found that the GSH-MVK adduct was reduced by aldose reductase in a cell-free solution to generate its alcohol form, and its reduction reaction was completely suppressed by pretreatment with epalrestat, an aldose reductase inhibitor, a member of the aldo-keto reductase family. In the presence of sheep blood cells, however, reduction of the GSH-MVK adduct was partially inhibited by epalrestat. This revealed that some member of the aldo-keto reductase superfamily other than aldose reductase is involved in reduction of the GSH-MVK adduct in sheep blood. These results suggest that blood cells, mainly erythrocytes are involved in reducing the inhalation toxicity of cigarette smoke via an aldo-keto reductase pathway other than that of aldose reductase.


Assuntos
Acroleína/metabolismo , Aldeídos/metabolismo , Butanonas/metabolismo , Fumar Cigarros/metabolismo , Eritrócitos/metabolismo , Fumaça/análise , Acroleína/química , Acroleína/farmacologia , Aldeídos/química , Aldeídos/farmacologia , Animais , Butanonas/química , Butanonas/farmacologia , Eritrócitos/efeitos dos fármacos , Ovinos , Produtos do Tabaco
13.
J Am Chem Soc ; 140(29): 9034-9037, 2018 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-29998737

RESUMO

DNA polymerase Î¸ (Pol Î¸) is a multifunctional enzyme. It is nonessential in normal cells, but its upregulation in cancer cells correlates with cellular resistance to oxidative damage and poor prognosis. Pol Î¸ possesses polymerase activity and poorly characterized lyase activity. We examined the Pol Î¸ lyase activity on various abasic sites and determined that the enzyme is inactivated upon attempted removal of the oxidized abasic site commonly associated with C4'-oxidation (pC4-AP). Covalent modification of Pol Î¸ by the DNA lesion enabled determination of the primary nucleophile (Lys2383) responsible for Schiff base formation in the lyase reaction. Unlike some other base excision repair polymerases, Pol Î¸ uses a single active site for polymerase and lyase activity. Mutation of Lys2383 significantly reduces both enzyme activities but not DNA binding. Demonstration that Lys2383 is required for polymerase and lyase activities indicates that this residue is an Achilles heel for Pol Î¸ and suggests a path forward for designing inhibitors of this attractive anticancer target.


Assuntos
Carbono-Oxigênio Liases/antagonistas & inibidores , Carbono-Oxigênio Liases/química , DNA Polimerase Dirigida por DNA/química , Inibidores da Síntese de Ácido Nucleico/química , Butanonas/química , Carbono-Oxigênio Liases/genética , Domínio Catalítico , DNA Polimerase Dirigida por DNA/genética , Humanos , Lisina/química , Mutação , Bases de Schiff/química
14.
Comput Biol Chem ; 75: 178-195, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29883916

RESUMO

The present paper deals with in silico evaluation of 32 virtually designed transition metal complexes of 2-butanone thiosemicarbazone and N,S,O containing donor hetero-ligands namely py, bpy, furan, thiophene, 2-picoline, 1,10-phenanthroline, piperazine and liquid ammonia. The complexes were designed with a view to assess their potential anticancer, antioxidant and antibacterial activity. The absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of the chosen ligands were calculated by admetSAR software. Metabolic sites of different ligands likely to undergo metabolism were predicted using Metaprint 2D. The proposed complexes were also evaluated for their drug-like quality based on Lipinski's, Veber, Ghose and leadlikeness filters. Druglikeness and toxicity potential were predicted by OSIRIS property explorer. The pharmacokinetic properties and bioactivity scores were calculated by Molinspiration tool. Bioactivity scores of the complexes were predicted for drug targets including enzymes, nuclear receptors, kinase inhibitors, G-protein coupled receptor ligands and ion channel modulators. Molecular docking of selected Fe(II) mixed-ligand complexes was performed using AutoDock version 4.2.6 and i-GEMDOCK version 2.1 with two target proteins namely Ribonucleotide reductase (RR) and Topoisomerase II (Topo II). The results were compared with three standard reference drugs viz. Doxorubicin HCl, Letrozole (anticancer) and Tetracycline (antibiotic). Multivariate data obtained were analyzed using principal component analysis (PCA) for visualization and projection as scatter and 3D plots. Positive results obtained for hetero-ligands using admetSAR version 1.0 indicated good absorption and transport kinetics of the hetero-ligand complexes through the human intestine and blood-brain barrier. The hetero-ligands were predicted to have no associated mutagenic effect(s) also. However, none of the hetero-ligands was predicted to be Caco-2 (human colon cancer cell line) permeable. Most of the hetero-ligands and the parent ligand (2-butanone thiosemicarbazone) were predicted to undergo Phase-I metabolism prior to excretion using MetaPrint2D software. Pharmacokinetic evaluation of the proposed complexes revealed that all complexes displayed drug-like character and were predicted to have no apparent toxic side-effects. All the proposed complexes showed moderate to good biological activity scores (-5.0 to 0.0). Mixed complexes with bpy, 2-picoline and 1,10-phenanthroline showed significant bioactivity scores (as enzyme inhibitors) in the range 0.02-0.13. Likewise, good docking scores were obtained for Fe (II) complexes with the same ligands. [FeL(2-pic)2] displayed the lowest binding energy (-6.47 kcal/mol) with respect to Topo II followed by [FeL(py)2] (-6.14 kcal/mol) as calculated by AutoDock version 4.2.6. With respect to binding with RR, [FeL(2--pic)2] again displayed the lowest binding energy (-7.21 kcal/mol) followed by [FeL(py)2] (-5.96 kcal/mol). On the basis of docking predictions and various other computational evaluations, four mixed-ligand complexes of Fe in +2 oxidation state with py, bpy, 2--picoline and 1,10-phenanthroline were synthesized with 2-butanone thiosemicarbazone. All the synthesized Fe complexes were characterized using various spectroscopic techniques and tested for their potential anticancer activity in vitro against human breast carcinoma cell line MDA-MB 231 and human lung carcinoma cell line A549 cell line using MTT assay. [FeL(2-pic)2], [FeL(bpy)], and [FeL(py)2] were found to exhibit significant antiproliferative activity with IC50 values in the range of 80-100 µM against breast and lung cancer cells. The synthesized Fe complexes also displayed mild antioxidant activities. The synthesized and studied Fe complexes have the potential for development into future anticancer agents if analyzed and modified further for improvement of their ADMET, solubility and permeability criteria set for potential drug-candidates.


Assuntos
Antineoplásicos/farmacologia , Técnicas de Química Combinatória , Desenho Assistido por Computador , Desenho de Fármacos , Compostos Organometálicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Butanonas/química , Butanonas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Solubilidade , Relação Estrutura-Atividade , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia , Elementos de Transição/química , Elementos de Transição/farmacologia
15.
Chem Commun (Camb) ; 54(47): 6000-6003, 2018 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-29796466
16.
Dent Mater ; 34(9): 1263-1270, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29801684

RESUMO

OBJECTIVES: This is a confirmatory study to evaluate the effect of photoinitiator type and concentration, matrix monomer chemical structure, and nanoparticle incorporation on the physical and mechanical properties of an experimental dentin bonding agent. MATERIALS AND METHODS: Different concentrations of camphorquinone-amine (CQ-A) system, butanedione (BD), and phenylpropanedione (PPD), as photoinitiator, BTDMA, as a comonomer containing carboxylic acid groups, and silica nanoparticles as reinforcing inorganic filler were incorporated into a methacrylate base experimental dental adhesive. The effect of these ingredients, as independent variables, on the shrinkage kinetics, flexural strength and modulus, and microshear bond strength of the adhesives were then investigated. The results were analyzed using one-way ANOVA and Tukey's post-hoc test at the significance level of 0.05. RESULTS: The results indicate that the efficiency of CQ-A initiator system is diminished in the presence of the acidic monomer BTDMA while the photopolymerization is efficiently progressed with BD as initiator. PPD shows the lowest efficiency in the photopolymerization of the adhesives. BTDMA as a monomer with the capability of interaction with tooth structure provides adhesive with improved microshear bond strength to dentin. Incorporation of silica nanoparticles at low concentrations enhances the flexural and microshear strength of the dentin bonding agent. SIGNIFICANCE: Understanding the structure-property relationship in dental adhesives may help the material selection in clinical dentistry. The study elucidates the relationship between monomer structure, initiator type, and nanofiller and physical and mechanical properties in dental adhesives.


Assuntos
Adesivos Dentinários/química , Nanopartículas/química , Fotoiniciadores Dentários/química , Relação Estrutura-Atividade , Condicionamento Ácido do Dente , Aminas/química , Butanonas/química , Cânfora/análogos & derivados , Cânfora/química , Módulo de Elasticidade , Resistência à Flexão , Humanos , Técnicas In Vitro , Teste de Materiais , Polimerização , Resistência ao Cisalhamento , Dióxido de Silício/química
17.
Exp Mol Med ; 50(2): e446, 2018 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-29504608

RESUMO

Atopic dermatitis (AD) is a chronic inflammatory skin disease, and its prevalence is increasing. AD usually elicits skin barrier dysfunction, dry skin and itching. As the mechanisms of AD remain unknown, there is an urgent need to find effective therapies. Because of the diversity and complexity of marine environments, the discovery of drugs from marine organisms as novel therapeutic agents for human diseases has seen renewed interest. Dihydroaustrasulfone alcohol (WA-25), the synthetic precursor of austrasulfone, which is a natural product isolated from a Formosan soft coral, has been shown to possess many therapeutic effects in our previous studies. However, the detailed mechanisms and therapeutic effects of WA-25 on AD are incompletely understood. We performed in vitro and in vivo studies to examine the effects of WA-25 on AD. We showed that WA-25 blocks inflammation and oxidative stress. Simultaneously, we also found that WA-25 reduces the AD scores and AD-induced transepidermal water loss (TEWL), scratching behavior, and alloknesis. WA-25 is more effective in cases of AD than are the drugs that are currently used clinically. Importantly, we also found that when nucleophosmin (NPM) was inhibited or when its expression was reduced, the anti-inflammatory and anti-AD effects of WA-25 were blocked. These data suggest that NPM plays dual roles in inflammation and AD. Overall, these results suggest that WA-25 is a potential anti-inflammatory and AD therapeutic agent that is modulated by NPM.


Assuntos
Organismos Aquáticos , Produtos Biológicos/farmacologia , Butanonas/farmacologia , Dermatite Atópica/metabolismo , Proteínas Nucleares/metabolismo , Sulfonas/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Organismos Aquáticos/química , Produtos Biológicos/química , Butanonas/química , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/etiologia , Dermatite Atópica/patologia , Modelos Animais de Doenças , Humanos , Lipopolissacarídeos/efeitos adversos , Lipopolissacarídeos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Sulfonas/química
18.
Recent Pat Drug Deliv Formul ; 12(2): 130-149, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29485013

RESUMO

BACKGROUND: Nabumetone is biopharmaceutics classification system (BCS) class II drug, widely used in the treatment of osteoarthritis and rheumatoid arthritis. The most frequently reported adverse reactions for the drug involve disturbance in gastrointestinal tract, diarrhea, dyspepsia and abdominal pain. Microemulgel has advantages of microemulsion for improving solubility for hydrophobic drug. Patent literature had shown that the work for drug has been carried on spray chilling, enteric coated tablet, and topical formulation which gave an idea for present research work for the development of transdermal delivery. OBJECTIVE: The objective of the present research work was to optimize transdermal microemulgel delivery for Nabumetone for the treatment of arthritis. METHODS: Oil, surfactant and co-surfactant were selected based on solubility study of the drug. Gelling agents used were Carbopol 934 and HPMC K100M. Optimization was carried out using 32 factorial design. Characterization and evaluation were carried out for microemulsion and microemulsion based gel. RESULTS: Field emission-scanning electron microscopy (FE-SEM) study of the microemulsion revealed globules of 50-200 nm size. Zeta potential -9.50 mV indicated good stability of microemulsion. Globule size measured by dynamic light scattering (zetasizer) was 160nm. Design expert gave optimized batch as F7 which contain 0.2% w/w drug, 4.3% w/w liquid paraffin, 0.71% w/w tween 80, 0.35% w/w propylene glycol, 0.124% w/w Carbopol 934, 0.187% w/w HPMC K100M and 11.68% w/w water. In-vitro diffusion study for F7 batch showed 99.16±2.10 % drug release through egg membrane and 99.15±2.73% drug release in ex-vivo study. CONCLUSION: Nabumetone microemulgel exhibiting good in-vitro and ex-vivo controlled drug release was optimized.


Assuntos
Artrite/tratamento farmacológico , Butanonas/administração & dosagem , Butanonas/uso terapêutico , Administração Cutânea , Animais , Butanonas/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Emulsões , Géis/administração & dosagem , Géis/química , Nabumetona , Óvulo/metabolismo , Tamanho da Partícula , Ratos , Absorção Cutânea , Propriedades de Superfície , Tensoativos/administração & dosagem , Tensoativos/química
19.
Life Sci ; 194: 205-212, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29225109

RESUMO

AIM: The cardioprotective role of raspberry ketone (RK) against isoproterenol (ISO)-induced myocardial infarction (MI) in rats was assessed. MATERIALS AND METHODS: Rats were randomly divided into Group I - Vehicle control; Group II - Toxic control ISO (85mg/kg, s.c.); Group III, IV and V - RK (50, 100 and 200mg/kg, respectively) with ISO; Group VI- RK (200mg/kg) alone; Group VII - Propranolol (10mg/kg) with ISO; and Group VIII - Propranolol (10mg/kg) alone. After twenty-four hours of the last dose, animals were sacrificed and creatine kinase-MB, lactate dehydrogenase, total cholesterol, triglycerides, high-density-lipoprotein, low-density-lipoprotein, very-low-density-lipoprotein, malondialdehyde, reduced glutathione, superoxide dismutase, catalase, Na+, K+-ATPase, nitric oxide, histopathological and immunohistochemical analysis (tumor necrosis factor-α and inducible nitric oxide synthase) were performed. KEY FINDINGS: Treatment with ISO significantly deviated the biochemical parameters from the normal levels, which were considerably restored by RK at 100 and 200mg/kg doses. 50mg/kg dose, however, did not demonstrate any significant cardioprotective action. The histopathological and immunohistochemical analysis further substantiated these findings. SIGNIFICANCE: Our study showed a dose-dependent reduction in oxidative stress, inflammation and dyslipidemia by RK in ISO-intoxicated rats, which signifies that RK from the European red raspberry plant might be a valuable entity for the management of MI.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Butanonas/uso terapêutico , Cardiotônicos/uso terapêutico , Infarto do Miocárdio/prevenção & controle , Animais , Butanonas/química , Isoproterenol , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/patologia , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , PPAR alfa/agonistas , Ratos , Ratos Wistar , Rubus/química
20.
Chimia (Aarau) ; 72(12): 866-869, 2018 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-30648952

RESUMO

We recently developed a flavopeptide immobilized on polystyrene resin, Fl-Pep-PS, that could realize the first N5-unmodified neutral flavin (Fl)-catalyzed aerobic oxygenation reactions under non-enzymatic conditions. Although a key active species is assumed to be the corresponding 4a-hydroperoxyflavin (Fl4aOOH) from the unprecedented activity and unique chemoselectivity, further circumstantial support would be helpful to be sure since spectroscopic evidence is difficult to obtain due to the compound's insolubility. In this article, we report that the aerobic Baeyer-Villiger oxidation of a fused cyclobutanone, (±)-cis-bicyclo[3.2.0]hept-2-en-6-one (1), can be promoted with Fl-Pep-PS in a FMO-like chemoselectivity and regiodivergent manner via Fl-related catalytic intermediates, which delivers strong evidence of the involvement of Fl4aOOH as an active species in Fl-Pep-PS-catalyzed aerobic oxygenation reactions.


Assuntos
Peptídeos/química , Butanonas/química , Catálise , Modelos Moleculares , Estrutura Molecular , Oxirredução
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