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1.
Eur J Med Chem ; 185: 111783, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31732257

RESUMO

Over the past decade, many drug discovery endeavors have been invested in targeting the serine proteases prolyl oligopeptidase (POP) for the treatment of Alzheimer's and Parkinson's disease and, more recently, epithelial cancers. Our research group has focused on the discovery of reversible covalent inhibitors, namely nitriles, to target the catalytic serine residue in this enzyme. While there have been many inhibitors discovered containing a nitrile to covalently bind to the catalytic serine, we have been investigating others, particularly boronic acids and boronic esters, the latter of which have been largely unexplored as covalent warheads. Herein we report a series of computationally-designed POP boronic ester pro-drug inhibitors exhibiting nanomolar-potencies in vitro as their active boronic acid species. These easily-accessible (1-2 step syntheses) compounds could facilitate future biochemical and biological studies of this enzyme's role in neurodegenerative diseases and cancer progression.


Assuntos
Ácidos Borônicos/farmacologia , Descoberta de Drogas , Ésteres/farmacologia , Pró-Fármacos/farmacologia , Serina Endopeptidases/metabolismo , Ácidos Borônicos/síntese química , Ácidos Borônicos/química , Relação Dose-Resposta a Droga , Ésteres/síntese química , Ésteres/química , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-Atividade
2.
Molecules ; 24(19)2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591297

RESUMO

With raising prevalence of obesity, the regulation of human body fat is increasingly relevant. The modulation of fatty acid uptake by enterocytes represents a promising target for body weight maintenance. Recent results demonstrated that the trigeminal active compounds capsaicin, nonivamide, and trans-pellitorine dose-dependently reduce fatty acid uptake in differentiated Caco-2 cells as a model for the intestinal barrier. However, non-pungent alternatives have not been investigated and structural determinants for the modulation of intestinal fatty acid uptake have not been identified so far. Thus, based on the previous results, we synthesized 23 homovanillic acid esters in addition to the naturally occurring capsiate and screened them for their potential to reduce intestinal fatty acid uptake using the fluorescent fatty acid analog Bodipy-C12 in differentiated Caco­2 cells as an enterocyte model. Whereas pre-incubation with 100 µM capsiate did not change fatty acid uptake by Caco-2 enterocytes, a maximum inhibition of -47% was reached using 100 µM 1­methylpentyl-2-(4-hydroxy-3-methoxy-phenyl)acetate. Structural analysis of the 24 structural analogues tested in the present study revealed that a branched fatty acid side chain, independent of the chain length, is one of the most important structural motifs associated with inhibition of fatty acid uptake in Caco-2 enterocytes. The results of the present study may serve as an important basis for designing potent dietary inhibitors of fatty acid uptake.


Assuntos
Ésteres/química , Ésteres/farmacologia , Ácidos Graxos/metabolismo , Ácido Homovanílico/química , Transporte Biológico/efeitos dos fármacos , Células CACO-2 , Capsaicina/análogos & derivados , Capsaicina/síntese química , Capsaicina/química , Diferenciação Celular , Enterócitos/metabolismo , Ésteres/síntese química , Ácido Homovanílico/metabolismo , Humanos
3.
J Colloid Interface Sci ; 556: 616-627, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31494392

RESUMO

HYPOTHESIS: The development of functional and nutritional surfactants for the food industry remains a subject of great interest. Herein, therefore, we report on the design and synthesis of novel trisaccharide (raffinose) monoester-based surfactants in the expectation that they would display functional properties superior to certain disaccharide-based, commercially-deployed emulsifiers and thus have potential for industrial applications. EXPERIMENTS: The title esters were prepared by enzymatic methods and their properties as surfactants evaluated through determination of their HLB values, water solubilities, CMCs, foamabilities and foaming stabilities as well as through investigation of their impacts on the stability of oil-in-water emulsions over a range of storage times and under certain other conditions. FINDINGS: The emulsifying properties of 6-O-acylraffinose esters are dictated, in large part, by the length of the associated alkyl chains. The results of storage and environmental stress experiments revealed that the increasing length of alkyl chains enhances the stability of the derived emulsions. All the raffinose ester-stabilized oil-in-water emulsions displayed stratification effects under strongly acidic conditions (pH ≤ 4) or at high ionic strength (≥300 mM) while possessing reasonable resistance to variations in temperature. As such, a number of the raffinose monoesters showed greater stability to environmental stress than their commercially-deployed and sucrose-based counterparts. The structure-property profiles established through the present study provide a definitive guide for the development of raffinose esters as novel emulsifiers, particularly in the food industry.


Assuntos
Emulsificantes , Ácidos Graxos/química , Lipase/química , Rafinose/química , Emulsificantes/síntese química , Emulsificantes/química , Ésteres/síntese química , Ésteres/química , Estrutura Molecular
4.
Eur J Med Chem ; 182: 111655, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31494468

RESUMO

Stereo- and regioisomers of a series of N,N-bis(alkanol)amine aryl ester derivatives have been prepared and studied as multidrug resistance (MDR) modulators. The new compounds contain a 2-(methyl)propyl chain combined with a 3-, 5- or 7-methylenes long chain and carry different aromatic ester portions. Thus, these compounds have a methyl group on the 3-methylenes chain and represent branched homologues of previously studied derivatives. The introduction of the methyl group gives origin to a stereogenic center and consequently to (R) and (S) enantiomers. In the pirarubicin uptake assay on K562/DOX cell line these compounds showed good activity and efficacy and in many cases enantioselectivity was observed. Docking studies confirmed the influence of the stereocenter on the interaction in the P-gp pocket. The P-gp interaction mechanism and selectivity towards MRP1 and BCRP were also evaluated on MDCK transfected cells overexpressing the three transporters. Almost all these compounds inhibited both P-gp and BCRP, but only derivatives with specific structural characteristics showed MRP1 activity. Moreover, two compounds, (S)-3 and (R)-7, showed the ability to induce collateral sensitivity (CS) against MDR cells. Therefore, these two CS-promoting agents could be considered interesting leads for the development of selective cytotoxic agents for drug-resistant cells.


Assuntos
Aminas/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ésteres/farmacologia , Aminas/síntese química , Aminas/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cães , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ésteres/síntese química , Ésteres/química , Humanos , Células K562 , Células Madin Darby de Rim Canino/efeitos dos fármacos , Simulação de Acoplamento Molecular , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade
5.
Eur J Med Chem ; 182: 111597, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31422225

RESUMO

Fatty acid synthase (FASN) is a lipogenic enzyme that is selectively upregulated in malignant cells. There is growing consensus on the oncogenicity of FASN-driven lipogenesis and the potential of FASN as a druggable target in cancer. Here, we report the synthesis and FASN inhibitory activities of two novel galloyl esters of trans-stilbene EC1 and EC5. Inhibition of FASN was accompanied by a loss in AKT activation and profound apoptosis in several non-small cell lung cancer (NSCLC) cells at the growth inhibitory concentrations of EC1 and EC5. Both FASN and phospho-AKT levels were concurrently downregulated. However, addition of a lipid concentrate to the treated cells reinstated cell viability and reversed the loss of FASN and AKT protein levels, thus recapitulating the causal relationship between FASN inhibition and the loss in cell viability.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Ésteres/farmacologia , Ácido Graxo Sintase Tipo I/antagonistas & inibidores , Ácido Gálico/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Estilbenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ésteres/síntese química , Ésteres/química , Ácido Graxo Sintase Tipo I/metabolismo , Ácido Gálico/análogos & derivados , Ácido Gálico/química , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Estrutura Molecular , Estilbenos/síntese química , Estilbenos/química , Relação Estrutura-Atividade
6.
Amino Acids ; 51(9): 1377-1385, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31468209

RESUMO

This work presents the first study of the self-disproportionation of enantiomers via chromatography (SDEvC) of ß-aminophosphonic acid esters, several of which have been synthesized for the first time. Three types of structures were examined, N-acetylated, dipeptide construction with N-Cbz glycine, and a free amine. In the latter case, this is the first time that SDEvC has been reported for free amine amino acids. In all the three types of structures, significant SDE magnitudes (Δee's up to 55%) were exhibited underscoring the ubiquitous nature of the SDE phenomenon. Chemical models of homo- versus heterochiral intermolecular interactions are proposed to rationalize the SDE magnitude differences amongst these new ß-aminophosphonic acid derivatives. In addition, the incorporation of additional, competing binding modes to a molecule, was found to lead to a reduction of the SDE magnitude by shifting the intermolecular binding away from the stereogenic center and/or by leading to a convoluted binding system that disrupts the structured and relatively stable assemblies that give rise to the SDE.


Assuntos
Aminoácidos/química , Cromatografia/métodos , Fluoretos/química , Ácidos Fosfóricos/química , Acetilação , Dipeptídeos/química , Ésteres/síntese química , Ésteres/química , Ligação de Hidrogênio , Estereoisomerismo
7.
Chem Commun (Camb) ; 55(74): 11017-11020, 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31424070

RESUMO

Synthesis of adipic acid, a key monomer of nylon-66 and polyurethane, from biomass is highly attractive for establishing green and sustainable chemical processes. Here, we report that zirconia-supported rhenium oxide (ReOx/ZrO2) efficiently catalyses the deoxydehydration of cellulose-derived d-glucaric acid, offering adipic acid ester with a yield of 82% by combining with a Pd/C catalyst in subsequent reactions.


Assuntos
Adipatos/síntese química , Ésteres/síntese química , Rênio/química , Zircônio/química , Biomassa , Carbono/química , Catálise , Ácido Glucárico/química , Lactonas/química , Oxirredução , Paládio/química , Estereoisomerismo
8.
Carbohydr Polym ; 218: 126-135, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31221313

RESUMO

In this study, maltoheptaose (G7)-based sugar esters were synthesized from maltoheptaose and fatty acids (C10-C16) using a commercial lipase. With the exception of dimethyl sulfoxide (DMSO; 76.4%, w/v), G7 showed only limited solubility in organic solvents. Among the fatty acids, palmitic acid (PA) was the best substrate for G7-based ester formation. G7-PA ester was successfully synthesized as the monoester structure exclusively in 10% DMSO of t-butanol with a 22% conversion yield. NMR and enzymatic analyses of the purified monoester product revealed that the ester bond in the G7 was located at C-6 of the glucose at the reducing end. The G7-PA monoester showed the melting temperature at 56.3 °C that was 6.5 °C lower than that of the free PA and exhibited a different endothermic pattern from the free G7. The G7-PA monoester exhibited excellent emulsifier potential with more even droplet size distribution compared with the commercial sucrose esters for an oil-in-water emulsion system.


Assuntos
Hidrolases de Éster Carboxílico/química , Ésteres/química , Proteínas Fúngicas/química , Glucanos/química , Candida/enzimologia , Emulsificantes/síntese química , Emulsificantes/química , Emulsões , Esterificação , Ésteres/síntese química , Ácidos Graxos/química , Glucanos/síntese química , Solubilidade , Temperatura de Transição
9.
Appl Biochem Biotechnol ; 189(3): 933-959, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31152353

RESUMO

Yarrowia lipolytica lipase obtained by solid-state fermentation was characterized and applied in the synthesis of esters with commercial value in the food industry. The effect of different conditions on the hydrolysis activity of this biocatalyst was evaluated in the presence of metal ions, solvents, detergents, several pH and temperature parameters, and different substrates. Storage stability was also studied. The solid biocatalyst produced in soybean meal was used in synthesis reactions aiming to produce short-, medium-, and long-chain esters. Results showed that the best fermentation condition to produce the biocatalyst was using soybean oil (3% w/w), moisture content (55% w/v), and inoculum of 2.1 mgdry biomass/gsoybean meal at 28 °C for 14 h. High substrate conversion for ethyl octanoate, cetyl stearate, and stearyl palmitate synthesis was achieved in the presence of non-polar solvents in less than 6 h using a substrate molar ratio of 1:1 at 38 °C with 10-15% (w/v) of biocatalyst. This work showed the high potential of Y. lipolytica lipase to be used in the synthesis of different esters. Also, that it can be considered an attractive and economical process alternative to obtain high-added value products.


Assuntos
Ésteres/síntese química , Fermentação , Indústria Alimentícia , Lipase/química , Lipase/metabolismo , Yarrowia/enzimologia , Biocatálise , Técnicas de Química Sintética , Estabilidade Enzimática , Enzimas Imobilizadas/química , Enzimas Imobilizadas/metabolismo , Esterificação , Ésteres/química , Concentração de Íons de Hidrogênio , Hidrólise , Solventes/química , Especificidade por Substrato , Temperatura , Yarrowia/metabolismo
10.
Carbohydr Polym ; 221: 37-47, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31227165

RESUMO

Bile salts tend to form micelles in aqueous media and can thereby contribute to drug solubilization; they also exhibit crystallization inhibition properties that can stabilize supersaturated drug solutions. Herein, we explore conjugation of bile salts with polysaccharides to create new, amphiphilic polysaccharide derivatives with intriguing properties, portending broad utility in various applications. We introduce efficient conjugation of cholesterol (as a model steroid), lithocholic acid, and deoxycholic acid by mild, modular olefin cross-metathesis reactions. These small molecules were first modified with an acrylate group from the A-ring hydroxyl, then reacted with cellulose derivatives bearing olefin-terminated metathesis "handles". Successful conjugation of bile acids has demonstrated chemoselective cross-metathesis with complex, polyfunctional structures, and large multi-ring systems. It also enabled an efficient, general pathway for polysaccharide-bile salt conjugates, which promise synergy for applications such as amorphous solid dispersion (ASD).


Assuntos
Celulose/química , Colesterol/análogos & derivados , Ácido Desoxicólico/análogos & derivados , Ésteres/química , Ácido Litocólico/análogos & derivados , Celulose/síntese química , Colesterol/síntese química , Ácido Desoxicólico/síntese química , Ésteres/síntese química , Ácido Litocólico/síntese química , Ácido Litocólico/química , Estudo de Prova de Conceito , Solubilidade
11.
ACS Appl Mater Interfaces ; 11(26): 22973-22978, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31252497

RESUMO

Misfolding and abnormal assembly of proteins cause many intractable diseases. The modulation of the assembly process of these proteins could contribute to understanding and controlling amyloid protein aggregation. Previous works focused mainly on the inhibition of the assembly process. To broaden the interaction modality of modulators with proteins for developing new modulators, in this work, we designed and synthesized two reactive poly ( p-phenylene vinylene) polymers, respectively, functionalized with N-hydroxysuccinimide ester (PPV-NHS) and pentafluorophenol ester (PPV-PFP), which exhibited the prevention or co-assembly effect on the aggregation process of islet amyloid polypeptide (IAPP). Cell assays demonstrated that both of the two polymers could effectively eliminate the cytotoxicity of IAPP. Moreover, PPV-NHS also could irreversibly disrupt preformed IAPP fibrils. We envision that PPV-NHS and PPV-PFP might offer a new design method for the modulation of protein assembly.


Assuntos
Polipeptídeo Amiloide das Ilhotas Pancreáticas/química , Polímeros/química , Agregação Patológica de Proteínas/tratamento farmacológico , Sequência de Aminoácidos/genética , Ésteres/síntese química , Ésteres/química , Ésteres/farmacologia , Fluorbenzenos/síntese química , Fluorbenzenos/química , Fluorbenzenos/farmacologia , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/síntese química , Polipeptídeo Amiloide das Ilhotas Pancreáticas/farmacologia , Fenóis/síntese química , Fenóis/química , Fenóis/farmacologia , Polímeros/síntese química , Polímeros/farmacologia , Agregação Patológica de Proteínas/genética , Succinimidas/síntese química , Succinimidas/química , Succinimidas/farmacologia
12.
Bioprocess Biosyst Eng ; 42(8): 1385-1389, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31069512

RESUMO

Deep eutectic solvents (DESs) have gained increased attention as alternative reaction media for biocatalysis in recent years. There are many investigations on biotransformations in a variety of DESs, but the purification of bioproducts from DES reaction mixtures has not yet been sufficiently addressed. The present study demonstrates a product recovery strategy from a DES reaction medium composed of (-)-menthol and dodecanoic acid. Since the DES is not formed by equimolar amounts of the substrates, but the eutectic point occurs at a 3:1 molar ratio, product isolation is an important task for effective biocatalytic process development, even if the limiting substrate is converted completely. Both DES compounds acted as substrates and reaction solvent in the lipase-catalyzed esterification to synthesize (-)-menthyl dodecanoate. The product (-)-menthyl dodecanoate ester was separated from the DES reaction mixture by a vacuum distillation step and a second esterification reaction can be performed with the recovered (-)-menthol.


Assuntos
Biocatálise , Candida/enzimologia , Ésteres , Proteínas Fúngicas/química , Ácidos Láuricos/química , Lipase/química , Mentol/química , Esterificação , Ésteres/síntese química , Ésteres/química , Solventes/química
13.
Appl Biochem Biotechnol ; 189(3): 745-759, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31111376

RESUMO

The total or partial substitution of fossil raw materials by biobased materials from renewable resources is one of the great challenges of our society. In this context, the reaction under mild condition as enzyme-catalyzed esterification was applied to investigate the esterification of the biobased 10-undecenoic acid with 2-hydroxyethyl methacrylate (HEMA) to obtain a new diene ester monomer. The environmentally friendly enzymatic reaction presented up to 100% of conversion; moreover, the production of possible by-products was minimized controlling reaction time and amount of enzyme. Furthermore, the presence of chloroform was evaluated during the enzymatic reactions and despite high conversions with higher enzyme concentration, the solvent-free system showed fast kinetics even with 1.13 U/g substrates. In addition, the commercial immobilized lipases Novozym 435 and NS 88011 could be applied for up to 10 cycles keeping conversions about 90%. The scale-up of the reaction was possible and a purification procedure was applied in order to isolate the diene ester monomer 2-(10-undecenoyloxy)ethyl methacrylate, preserving its double bonds, which could allow a potential use of this product in the synthesis of new renewable polymers through techniques as metathesis, thiol-ene, or free-radical polymerization.


Assuntos
Ésteres/química , Ésteres/síntese química , Proteínas Fúngicas/metabolismo , Lipase/metabolismo , Ácidos Undecilênicos/química , Biocatálise , Técnicas de Química Sintética , Esterificação , Química Verde , Cinética , Metacrilatos/química
14.
Eur J Med Chem ; 176: 187-194, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31103899

RESUMO

Inhibitors of the flaviviral serine proteases, which are crucial for the replication of dengue and West-Nile virus, have attracted much attention over the last years. A dibasic 4-guanidinobenzoate was previously reported as inhibitor of the dengue protease with potency in the low-micromolar range. In the present study, this lead structure was modified with the intent to explore structure-activity relationships and obtain compounds with increased drug-likeness. Substitutions of the guanidine moieties, the aromatic rings, and the ester with other functionalities were evaluated. All changes were accompanied by a loss of inhibition, indicating that the 4-guanidinobenzoate scaffold is an essential element of this compound class. Further experiments indicate that the target recognition of the compounds involves the reversible formation of a covalent adduct.


Assuntos
Amidas/química , Antivirais/química , Carbamatos/química , Ésteres/química , Inibidores da Tripsina/química , Amidas/síntese química , Antivirais/síntese química , Carbamatos/síntese química , Vírus da Dengue/efeitos dos fármacos , Vírus da Dengue/enzimologia , Estabilidade de Medicamentos , Ésteres/síntese química , Estrutura Molecular , Relação Estrutura-Atividade , Trombina/antagonistas & inibidores , Inibidores da Tripsina/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Vírus do Nilo Ocidental/efeitos dos fármacos , Vírus do Nilo Ocidental/enzimologia
15.
Org Lett ; 21(9): 3299-3303, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-30993989

RESUMO

IrCl(cod)2]/dppe-catalyzed α-methylation of aryl esters using methanol as the C1 source was developed. This methylation process is useful in several fields including organic chemistry, biochemistry, and medicinal chemistry. Readily available methanol as methylation reagent was successfully adapted. The reaction processed high atom economy and efficient. By applying the reaction system, the synthesis method of naproxen was provided.


Assuntos
Complexos de Coordenação/química , Ésteres/síntese química , Irídio/química , Metanol/química , Catálise , Ligantes , Metilação , Estrutura Molecular , Oxirredução , Temperatura
16.
Artigo em Inglês | MEDLINE | ID: mdl-30945995

RESUMO

This paper reports the first results on depleting certain organochlorines from vegetable oils without the use of any solvent in order to mitigate monochloropropanediol diesters (MCDPE). The concept is based on separating the organochlorines from the bulk oil by using trapping agents (e.g. monoacylglycerols) that can be easily separated from the oil. The process starts by mixing and homogenizing crude vegetable oils with the trapping agent and subsequently separating the trapping agent from the oil bulk via crystallization. The proof-of-concept of the approach is demonstrated on a spiked sunflower model system, solvent extracted crude sunflower oil, industrially produced crude soybean and corn oils. The depletion of organochlorines in the crude oils and its beneficial effect on the MCPDE content in the heat treated samples is measured by LC-MS. The depletion efficacy of the monitored organochlorines was estimated to be in the 60-95 % range. Both the melting point and polarity of the trapping agents affected the depletion efficacy of the organochlorines. Trapping agents with higher melting point and polarity, such as monostearin were more effective in comparison to high melting point but less polar agents such as palm stearin or agents rich in polar but low melting point monolinolein/monoolein. The effect of organochlorine depletion on the subsequent MPCDE levels in heat treated oil was in the range of 60-90 % reduction depending on the type of the studied oil.


Assuntos
Ésteres/síntese química , Hidrocarbonetos Clorados/isolamento & purificação , Óleos Vegetais/química , alfa-Cloridrina/síntese química , Ésteres/análise , Hidrocarbonetos Clorados/química , alfa-Cloridrina/química
17.
Eur J Med Chem ; 172: 71-94, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30947123

RESUMO

In this study, a new series of N,N-bis(alkanol)amine aryl ester heterodimers was synthesized and studied. The new compounds were designed based on the structures of our previous arylamine ester derivatives endowed with high P-gp-dependent multidrug resistance reversing activity on a multidrug-resistant leukemia cell line. All new compounds were active in the pirarubicin uptake assay on the doxorubicin-resistant erythroleukemia K562 cells (K562/DOX). Compounds bearing a linker made up of 10 methylenes showed unprecedented high reversal activities regardless of the combination of aromatic moieties. Docking results obtained by an in silico study supported the data obtained by the biological tests and a study devoted to establish the chemical stability in phosphate buffer solution (PBS) and human plasma showed that only a few compounds exhibited a significant degradation in the human plasma matrix. Ten selected non-hydrolysable derivatives were able to inhibit the P-gp-mediated rhodamine-123 efflux on K562/DOX cells, and the evaluation of their apparent permeability and ATP consumption on other cell lines suggested that the compounds can behave as unambiguous or not transported substrates. The activity of these the compounds on the transport proteins breast cancer resistance protein (BCRP) and multidrug resistance associated protein 1 (MRP1) was also analyzed. All tested derivatives displayed a moderate potency on the BCRP overexpressing cells; while only four molecules showed to be effective on MRP1 overexpressing cells, highlighting a clear structural requirement for selectivity. In conclusion, we have identified a new very powerful series of compounds which represent interesting leads for the development of new potent and efficacious P-gp-dependent MDR modulators.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Aminas/farmacologia , Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ésteres/farmacologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Aminas/síntese química , Aminas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Células CACO-2 , Dimerização , Relação Dose-Resposta a Droga , Ésteres/síntese química , Ésteres/química , Humanos , Células K562 , Modelos Moleculares , Estrutura Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
18.
Enzyme Microb Technol ; 126: 18-23, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31000160

RESUMO

A solvent-mediated method (SMM) was used to prepare supersaturated sugar solutions in hydrophobic and mixture of hydrophilic/hydrophobic ionic liquids (ILs), namely, [Bmim][Tf2N] and [Bmim][TfO]/[Bmim][Tf2N], respectively. In this method, sugars were first solubilized in a mixture of organic solvent and water (i.e. methanol:water, 1:1 v/v), and then added to [Bmim][Tf2N] and/or [Bmim][TfO]/[Bmim][Tf2N] mixture. Supersaturated sugar solution in ILs were obtained by removing organic solvents and water under vacuum evaporation. Sugar solubilities in ILs, especially in hydrophobic IL ([Bmim][Tf2N]) and in [Bmim][TfO]/[Bmim][Tf2N] mixture prepared by SMM were greater than in ILs prepared using water-mediated method (WMM), which suggested methanol aided sugar solvation in hydrophobic media. In addition, interactions between glucose molecules and between glucose and methanol, water, and IL were investigated by all-atom molecular dynamics (MD) simulation. The MD simulation results showed that initial water and water/methanol molecules around glucose were gradually replaced by IL anions. Notably, SMM resulted in stronger interaction between IL anions and glucose than WMM, which was attributed to greater solubility of sugar in ILs prepared by SMM. Resultantly, the productivity of lipase-catalyzed production of glucose laurate using supersaturated glucose solution in [Bmim][TfO]/[Bmim][Tf2N] mixture prepared by SMM was at least 1.76-fold greater than that obtained in IL mixture prepared by WMM.


Assuntos
Ésteres/síntese química , Ácidos Graxos/síntese química , Proteínas Fúngicas/metabolismo , Glucose/química , Líquidos Iônicos/química , Lipase/metabolismo , Catálise , Esterificação , Proteínas Fúngicas/química , Interações Hidrofóbicas e Hidrofílicas , Lipase/química , Simulação de Dinâmica Molecular , Solubilidade
19.
J Oleo Sci ; 68(4): 329-337, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30867390

RESUMO

Lipase-catalyzed production of palm esters was performed via alcoholysis of palm oil and oleyl alcohol in solvent and solvent-free systems using a 2 L stirred tank reactor (STR). Two immobilized lipases were tested and Lipozyme RM IM exhibited superior performance in both reaction systems. Reusability studies of the enzymes in a solvent-free system also demonstrated the high stability of Lipozyme RM IM as shown by its ability to yield more than 70% palm esters with up to 19 cycles of reusing the same enzymes. Modification of the enzyme washing process improved the stability of Lipozyme TL IM in a solvent system as demonstrated by maintaining 65% yield after 5 times of repeated enzyme use. The scale up process for both lipases was conducted in the presence of solvents by using the impeller tip speed approach. Lipozyme RM IM-catalyzed reaction in a 15 L STR produced 85.7% yield and there was a significant drop to 60.7% in the 300 L STR, whereas Lipozyme TL IM had a lower yield (65%) when the reaction volume was increased to 15 L. The low yields could be due to the accumulation of enzymes at the bottom of the vessel. Purification of palm esters via solvent-solvent extraction revealed that more than 90% of oleyl alcohol was extracted after the third extraction cycle at 150 rpm impeller speed with reduced palm esters: ethanol ratio (v/v) from 1:4 to 1:3.


Assuntos
Reatores Biológicos , Enzimas Imobilizadas/química , Ésteres/síntese química , Lipase/química , Óleo de Palmeira/química , Catálise , Etanol , Álcoois Graxos/química , Álcoois Graxos/isolamento & purificação , Extração Líquido-Líquido/métodos , Solventes
20.
PLoS One ; 14(3): e0214216, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30921370

RESUMO

The purpose of the research was to obtain new derivatives of natural triterpene lupeol and to evaluate their potential as active substances in the treatment of skin damage. Four new lupeol esters (propionate, succinate, isonicotinate and acetylsalicylate) and lupeol acetate were obtained using an eco-friendly synthesis method. In the esterification process, the commonly used hazardous reagents in this type of synthesis were replaced by safe ones. This unconventional, eco-friendly, method is particularly important because the compounds obtained are potentially active substances in skin care formulations. Even trace amounts of hazardous reagents can have a toxic effect on damaged or irritated tissues. The molecular structure of the esters were confirmed by 1H NMR, 13C NMR and IR spectroscopy methods. Their crystal structures were determined using XRD method. To complete the analysis of their characteristics, physicochemical properties (melting point, lipophilicity, water solubility) and biological activity of the lupeol derivatives were studied. Results of an irritant potential test, carried out on Reconstructed Human Epidermis (RHE), confirmed that the synthesized lupeol derivatives are not cytotoxic and they stimulate a process of human cell proliferation. The safety of use for tested compounds was determined in a cell viability test (cytotoxicity detection kit based on the measurement of lactate dehydrogenase activity) for keratinocytes and fibroblasts. The results obtained showed that the modification of lupeol structure improve its bioavailability and activity. All of the esters penetrate the stratum corneum and the upper layers of the dermis better than the maternal lupeol. Lupeol isonicotinate, acetate and propionate were the most effective compounds in a stimulation of the human skin cell proliferation process. This combination resulted in an increase in the concentration of cells of more than 30% in comparison to control samples. The results indicate that the chemical modification of lupeol allows to obtain promising active substances for treatment of skin damage, including thermal, chemical and radiation burns.


Assuntos
Queimaduras/tratamento farmacológico , Derme/lesões , Epiderme/lesões , Fibroblastos/metabolismo , Queratinócitos/metabolismo , Triterpenos Pentacíclicos , Queimaduras/metabolismo , Queimaduras/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Derme/metabolismo , Derme/patologia , Epiderme/metabolismo , Epiderme/patologia , Ésteres/síntese química , Ésteres/química , Ésteres/farmacologia , Fibroblastos/patologia , Humanos , Queratinócitos/patologia , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/farmacologia
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