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1.
J Oleo Sci ; 69(7): 693-701, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32612019

RESUMO

Fatty acid sugar esters are non-ionic surfactant active agents with excellent performance and many uses. This work is devoted to the synthesis of sugar esters by the esterification reaction of sugar with mixed carboxylicpalmitic anhydrides using resin Amberlyst-15 as heterogeneous acid catalyst. These anhydrides should be stable and react as acylating agents. Influence of different reaction parameters, such as the molar ratio (sucrose/anhydride), the type of solvent and the reaction time on the yield of the esterification reaction were studied. The esterification reaction of sucrose with mixed palmitic benzoic anhydride leads to a mixture of sucrose esters of palmitic acid with a good percentage of conversion. The mixed anhydride was both reactive and selective for the preparation of fatty acid ester.


Assuntos
Benzoatos/química , Ácidos Carboxílicos/química , Técnicas de Química Sintética/métodos , Ésteres/síntese química , Ácidos Graxos/síntese química , Ácido Palmítico/química , Sacarose/síntese química , Acilação , Catálise , Esterificação , Solventes , Estirenos , Tensoativos/síntese química , Fatores de Tempo
2.
J Med Chem ; 63(9): 4824-4836, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32302132

RESUMO

Mammary-tissue-restricted cytochrome P450 4Z1 (CYP4Z1) has garnered interest for its potential role in breast cancer progression. CYP4Z1-dependent metabolism of arachidonic acid preferentially generates 14,15-epoxyeicosatrienoic acid (14,15-EET), a metabolite known to influence cellular proliferation, migration, and angiogenesis. In this study, we developed time-dependent inhibitors of CYP4Z1 designed as fatty acid mimetics linked to the bioactivatable pharmacophore, 1-aminobenzotriazole (ABT). The most potent analogue, 8-[(1H-benzotriazol-1-yl)amino]octanoic acid (7), showed a 60-fold lower shifted-half-maximal inhibitory concentration (IC50) for CYP4Z1 compared to ABT, efficient mechanism-based inactivation of the enzyme evidenced by a KI = 2.2 µM and a kinact = 0.15 min-1, and a partition ratio of 14. Furthermore, 7 exhibited low off-target inhibition of other CYP isozymes. Finally, low micromolar concentrations of 7 inhibited 14,15-EET production in T47D breast cancer cells transfected with CYP4Z1. This first-generation, selective mechanism-based inhibitor (MBI) will be a useful molecular tool to probe the biochemical role of CYP4Z1 and its association with breast cancer.


Assuntos
Inibidores das Enzimas do Citocromo P-450/farmacologia , Família 4 do Citocromo P450/antagonistas & inibidores , Ácidos Graxos/farmacologia , Triazóis/farmacologia , Ácido Araquidônico/metabolismo , Linhagem Celular Tumoral , Inibidores das Enzimas do Citocromo P-450/síntese química , Inibidores das Enzimas do Citocromo P-450/metabolismo , Desenho de Fármacos , Ácidos Graxos/síntese química , Ácidos Graxos/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Oxirredução , Triazóis/síntese química , Triazóis/metabolismo
3.
Eur J Med Chem ; 185: 111810, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31678743

RESUMO

Ciprofloxacin (CP) has a confirmed cytotoxic action on some cancerous cells, but in high, non-pharmacological concentrations. Considering features of natural fatty acids, such as biocompatibility, biodegradability and their increased cellular uptake by cancer cells, it seems that combining them with a drug could improve its bioavailability, and thus cytotoxicity. Therefore, the aim of this study was coupling of CP with saturated and unsaturated fatty acids, and evaluation of their cytotoxicity, apoptosis-inducing effects and inhibition of IL-6 release in human primary (SW480) and metastatic (SW620) colon cancer, metastatic prostate cancer (PC3) and normal (HaCaT) cell lines. The PC3 cell line was the most sensitive to the presence of the obtained conjugates. The value of IC50 for oleic acid conjugate (4) was 7.7 µM, and it was 12 times lower than for CP alone (101.4 µM). The studied derivatives induced late apoptosis in all cancer cell lines, but not in normal cells. The most potent apoptosis inducer was conjugate 4, that resulted in the highest percentage of PC3 cells in late apoptosis (81.5% ±â€¯3.9), followed by elaidic acid amide 5 (75% ±â€¯4.8). The strongest pro-apoptic effects on SW480 cells were demonstrated by conjugates of DHA (8) and sorbic (2) acids, whereas in SW620 cell lines, compounds 2 and 5 appeared to be the most effective. To establish the mechanism of cytotoxic action of derivatives 2, 4, 5, the level of interleukin-6 (IL-6) was measured. The compounds with the highest cytotoxic potential significantly decreased the release of IL-6 by cancer cells. Additionally, all conjugates were evaluated for their in vitro antimicrobial activity. Short chain amides - crotonic (1) and sorbic (2) - were the most active against Staphyloccoci. The second-mentioned amide has shown both strong antistaphylococcal and antitumor properties.


Assuntos
Antineoplásicos/farmacologia , Ciprofloxacino/farmacologia , Ácidos Graxos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ciprofloxacino/síntese química , Ciprofloxacino/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ácidos Graxos/síntese química , Ácidos Graxos/química , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
4.
Molecules ; 24(23)2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31775342

RESUMO

Schiff base liquid crystals, known as [4-(hexyloxy)phenylimino)methyl]phenyl palmitate (IA), [4-(hexyloxy)phenylimino)methyl]phenyl oleate (IIA) and [4-(hexyloxy)phenylimino)methyl]phenyl linoleate (IIIA), were synthesized from palmitic, oleic, and linoleic natural fatty acids. The prepared compounds have been investigated for their thermal and optical behavior as well as phase formation using differential scanning calorimetry (DSC) and polarized optical microscopy (POM). Molecular structures of all studied compounds were confirmed via elemental analysis, FT-IR, 1H NMR, and 13C NMR. Smectic phase is the observed mesophase for all compounds; however, their type and range depend upon the terminal alkanoate chains attached to the phenyl ring. Computational calculations, Density functional theory (DFT), energy difference of the frontier molecular orbital (FMOs), as well as the thermodynamic parameters of different molecular configurations isomers were discussed. It was found that the mesophase behavior and the geometrical characteristics were affected by the degree of unsaturation of fatty terminal chains. Furthermore, the geometrical structure of the CH=N linkage plays an important role in the thermal stability and optical transition temperature.


Assuntos
Ésteres/química , Ácidos Graxos/química , Cristais Líquidos/química , Bases de Schiff/química , Varredura Diferencial de Calorimetria , Ésteres/síntese química , Ácidos Graxos/síntese química , Espectroscopia de Ressonância Magnética , Conformação Molecular , Estrutura Molecular , Óptica e Fotônica/métodos , Bases de Schiff/síntese química , Espectroscopia de Infravermelho com Transformada de Fourier , Termodinâmica , Temperatura de Transição
5.
Lipids ; 54(11-12): 715-723, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31658495

RESUMO

Growing health awareness has resulted in the increased use of dietary supplements derived from plants and marine sources, leaving consumers unsure of their best options. There were three objectives of the present study. The first was to design and evaluate an efficient derivatization procedure. The second was to perform a comparative analysis of liquid oils and their corresponding capsules of hemp, chia, and flax seeds. The final objective was to determine the fatty acid (FA) composition of six fish oil products and compare it to the one provided on the label. For the FA profiling, we implemented two efficient, one-step, sustainable methods with high percentage recovery for the synthesis of FA methyl esters (FAME), which use base catalysis and microwave-assisted heating. Our results found no difference in nutritional value between liquid oils and capsules of the seed supplements, with flaxseed and chia offering a higher, beneficial n-3:n-6 ratio compared to hemp oil. Four of the fish oils analyzed contained significantly less eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) than their reported label, and the other two not only agreed with the manufacturers' declaration but were able to fulfill the daily adequate intake (AI) with fewer capsules.


Assuntos
Ésteres/síntese química , Ácidos Graxos/síntese química , Óleos de Peixe/análise , Hidróxidos/química , Micro-Ondas , Compostos de Potássio/química , Sementes/química , Catálise , Suplementos Nutricionais/análise , Ésteres/química , Ácidos Graxos/química , Estrutura Molecular
6.
Eur J Med Chem ; 182: 111636, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31466017

RESUMO

Developing novel antimicrobial agents is a top priority in fighting against bacterial resistance. Thus, a series of new monomer and dimer peptides were designed and synthesized by conjugating fatty acids at the N-terminus of partial d-amino acid substitution analogues of anoplin and dimerization. The new peptides exhibited more efficient killing of gram-negative and gram-positive bacteria, including methicillin-resistant Staphylococcus aureus compared with the parent peptide anoplin, and the dimer peptides were superior to the monomer peptides. It was important that the new peptides displayed low impact on bacterial resistance development. In addition, the antimicrobial activities were not significantly influenced by a physiological salt environment. They also presented high stability in the presence of protease or serum. Almost all of the new peptides had better selectivity towards anionic bacterial membranes over zwitterionic mammalian cell membranes. Moreover, the new peptides displayed synergistic or additive effects when used together with the antibiotics rifampicin and polymyxin B. These results showed that the new peptides could also prevent the formation of bacterial biofilms. Furthermore, outer/inner membrane permeabilization and cytoplasmic membrane depolarization experiments revealed that the new peptides had strong membrane permeabilization and depolarization. Confocal laser scanning microscopy, flow cytometry analysis and scanning electron microscopy further demonstrated that the new peptides could damage the integrity of the bacterial membrane. Finally, a DNA-binding affinity assay showed that the new peptides could bind to bacterial DNA. In summary, the conjugation of fatty acids at the N-terminus of peptides and dimerization are promising strategies for obtaining potent antimicrobial agents.


Assuntos
Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Desenho de Fármacos , Ácidos Graxos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Animais , Antibacterianos/síntese química , Antibacterianos/química , Peptídeos Catiônicos Antimicrobianos/síntese química , Peptídeos Catiônicos Antimicrobianos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ácidos Graxos/síntese química , Ácidos Graxos/química , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Células RAW 264.7 , Relação Estrutura-Atividade
7.
Mar Drugs ; 17(7)2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31336763

RESUMO

Diverse non-methylene-interrupted (NMI) fatty acids (FAs) with odd-chain lengths have been recognized in triacylglycerols and polar lipids from the ovaries of the limpet Cellana toreuma, however their biological properties remain unclear. In this study, two previously unreported odd-chain NMI FAs, (12Z)-12,16-heptadecadienoic (1) and (14Z)-14,18-nonadecadienoic (2) acids, from the ovary lipids of C. toreuma were identified by a combination of equivalent chain length (ECL) values of their methyl esters and capillary gas chromatography-mass spectrometry (GC-MS) of their 3-pyridylcarbinol derivatives. On the basis of the experimental results, both 1 and 2 were synthesized to prove their structural assignments and to test their biological activity. The ECL values and electron impact-mass (EI-MS) spectra of naturally occurring 1 and 2 were in agreement with those of the synthesized 1 and 2. In an in vitro assay, both 1 and 2 activated protein phosphatase, Mg2+/Mn2+-dependent 1A (PPM1A) up to 100 µM in a dose-dependent manner.


Assuntos
Produtos Biológicos/farmacologia , Ativadores de Enzimas/farmacologia , Ácidos Graxos/farmacologia , Gastrópodes/química , Proteína Fosfatase 2C/metabolismo , Animais , Produtos Biológicos/síntese química , Ativadores de Enzimas/síntese química , Ensaios Enzimáticos , Ácidos Graxos/síntese química , Feminino , Células HL-60 , Humanos , Estrutura Molecular , Ovário/metabolismo , Proteínas Recombinantes/metabolismo
8.
J Nat Prod ; 82(7): 1908-1916, 2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31241928

RESUMO

The total synthesis of putative penasulfate A was effectively achieved by a convergent strategy with a longest linear sequence of 14 steps and overall yield of 8.6%. The highlights of our strategy involved an E-selective olefin cross-metathesis, Suzuki cross-coupling, and a copper(I)-catalyzed coupling reaction.


Assuntos
Arabinose/química , Ácidos Graxos/química , Ácidos Graxos/síntese química , Ácidos Pipecólicos/química , Ácidos Pipecólicos/síntese química , Alcenos/química , Catálise , Estrutura Molecular , Estereoisomerismo
9.
Molecules ; 24(11)2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31159242

RESUMO

3-Hydroxy fatty acids have attracted the interest of researchers, since some of them may interact with free fatty acid receptors more effectively than their non-hydroxylated counterparts and their determination in plasma provides diagnostic information regarding mitochondrial deficiency. We present here the development of a convenient and general methodology for the asymmetric synthesis of 3-hydroxy fatty acids. The enantioselective organocatalytic synthesis of terminal epoxides, starting from long chain aldehydes, is the key-step of our methodology, followed by ring opening with vinylmagnesium bromide. Ozonolysis and subsequent oxidation leads to the target products. MacMillan's third generation imidazolidinone organocatalyst has been employed for the epoxide formation, ensuring products in high enantiomeric purity. Furthermore, a route for the incorporation of deuterium on the carbon atom carrying the hydroxy group was developed allowing the synthesis of deuterated derivatives, which may be useful in biological studies and in mass spectrometry studies. In addition, the synthesis of fatty γ-lactones, corresponding to 4-hydroxy fatty acids, was also explored.


Assuntos
Ácidos Graxos/síntese química , Lactonas/síntese química , Catálise , Ácidos Graxos/química , Lactonas/química , Estrutura Molecular , Análise Espectral
10.
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
11.
Int J Mol Sci ; 20(5)2019 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-30832353

RESUMO

A biological evaluation of a library of extracts from entomopathogen strains showed that Pantoea sp. extract has significant antimicrobial and insecticidal activities. Three hydroxyacyl-phenylalanine derivatives were isolated from this strain. Their structures were elucidated by a comprehensive analysis of their NMR and MS spectroscopic data. The antimicrobial and insecticidal potencies of these compounds were evaluated, and compound 3 showed 67% mortality against Aedes aegypti larvae at a concentration of 100 ppm, and a minimum inhibitory concentration (MIC) of 16 µg/mL against methicillin-resistant Staphylococcus aureus. Subsequently, hydroxyacyl-phenylalanine analogues were synthesized to better understand the structure-activity relationships within this class of compounds. Bioassays highlighted the antimicrobial potential of analogues containing saturated medium-chain fatty acids (12 or 14 carbons), whereas an unsaturated long-chain fatty acid (16 carbons) imparted larvicidal activity. Finally, using a molecular networking-based approach, several close analogues of the isolated and newly synthesized lipoamino acids were discovered in the Pantoea sp. extract.


Assuntos
Anti-Infecciosos/química , Ácidos Graxos/química , Inseticidas/química , Pantoea/química , Aedes/efeitos dos fármacos , Animais , Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Ácidos Graxos/síntese química , Ácidos Graxos/farmacologia , Inseticidas/síntese química , Inseticidas/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Relação Estrutura-Atividade
12.
J Agric Food Chem ; 67(13): 3789-3795, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30874433

RESUMO

A novel synthetic route was designed, developed, and utilized to synthesize six high-purity 2-monochloropropanediol fatty acid esters (2-MCPD esters), a group of potential processing-induced food contaminants. A chlorine atom was introduced to C-2 of a diethyl malonate molecule, which was reduced by NaBH4 and followed by esterification using fatty acids. The reaction products were isolated and purified using silica gel columns to obtain three 2-MCPD monoesters and three diesters at about 50-54% and 56-59% yields, respectively. In addition, 2-MCPD monopalmitate and dipalmitate were examined for their acute oral toxicities in Swiss mice. The LD50 values of 2-MCPD mono- and dipalmitate were greater than 5000 mg/kg body weight (BW), along with detectable nephrotoxicity and testicular toxicity. The results of this study may promote future investigation of MCPD ester toxicology and detection.


Assuntos
Clorofenóis/toxicidade , Ésteres/toxicidade , Ácidos Graxos/toxicidade , Animais , Clorofenóis/síntese química , Clorofenóis/química , Ésteres/síntese química , Ésteres/química , Ácidos Graxos/síntese química , Ácidos Graxos/química , Feminino , Contaminação de Alimentos/análise , Rim/efeitos dos fármacos , Masculino , Camundongos , Testículo/efeitos dos fármacos
13.
Langmuir ; 35(9): 3545-3552, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30712353

RESUMO

Dry eye syndrome (DES) is a prevalent disease in which the tear film homeostasis is compromised. One of the main causes of DES is thought to be an alteration in the composition of the outermost layer of the tear film, the tear film lipid layer (TFLL), resulting in an increased evaporation of water from the tear film and subsequent drying of the ocular surface. Recent studies have suggested that the specific TFLL lipids, namely, O-acyl-ω-hydroxy fatty acids (OAHFAs) and diesters (DiEs), may play a role in the development of DES. However, their specific connection to DES has remained largely unknown until now because of the lack of information on their biophysical properties and their role in the TFLL. Herein, we have addressed this issue by studying the biophysical properties and evaporation resistance of a library containing 10 synthetic analogues of TFLL OAHFAs and DiEs. Our results show how the variations of chain length and polar groups affect the phase behavior of these lipids at the tear film surface. In addition, the results revealed that the OAHFAs exhibiting a liquid-expanded to solid phase transition formed films with high evaporation resistance, whereas the DiEs were found to have no evaporation resistance. Altogether, our results shed new light on the role of the OAHFAs and DiEs in the TFLL and their connection to DES, suggesting that OAHFAs are likely a key lipid class in maintaining the TFLL evaporation resistance.


Assuntos
Ésteres/química , Ácidos Graxos/química , Lágrimas/química , Síndromes do Olho Seco/etiologia , Ésteres/síntese química , Ácidos Graxos/síntese química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Propriedades de Superfície
14.
Talanta ; 193: 29-36, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30368294

RESUMO

The recent growing interest in primary fatty acid amides (PFAMs) is due to the broad range of physiological effects they exhibit as bioindicator of pathological states. These bioactive lipids are usually in biological samples at the nanomolar level, making their detection and identification a challenging task. A method for quantitative analysis of seven main PFAMs (lauramide, myristamide, linoleamide, palmitamide, oleamide, stearamide and behenamide) in four human biofluids -namely, urine, plasma, saliva and sweat- is here reported. Two sample preparation procedures were compared to test their efficiency in each biofluid: solid-phase extraction (SPE) and protein precipitation. The latter was the best for plasma and urine, while the analysis of saliva and sweat required an SPE step for subsequent suited determination of PFAMs. Detection of the seven metabolites was performed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) in multiple reaction monitoring (MRM) mode. Quantitative analysis was supported on the use of stable isotopically labeled internal standards (SIL-ISs) in the calibration method, which required the synthesis of each IS from the precursor deuterated fatty acids. Detection limits for the target analytes were within 0.3-3 ng mL-1. The method was applied to a small cohort of male and female volunteers (n = 6) to estimate the relative concentration profiles in the different biofluids. The analytical features of the method supported its applicability in clinical studies aimed at elucidating the role of PFAMs metabolism.


Assuntos
Amidas/sangue , Amidas/urina , Ácidos Graxos/sangue , Ácidos Graxos/urina , Amidas/síntese química , Amidas/normas , Cromatografia Líquida/métodos , Deutério , Ácidos Graxos/síntese química , Ácidos Graxos/normas , Feminino , Humanos , Limite de Detecção , Masculino , Padrões de Referência , Reprodutibilidade dos Testes , Saliva/química , Suor/química , Espectrometria de Massas em Tandem/métodos
15.
Bioorg Chem ; 82: 378-384, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30428416

RESUMO

Capsaicinoids are reported to have a bunch of promising pharmacological activities, among them antibacterial effects against various strains of bacteria. In this study the effect on efflux pumps of mycobacteria was investigated. The importance of efflux pumps, and the inhibition of these, is rising due to their involvement in antibiotic resistance development. In order to draw structure and activity relationships we tested natural and synthetical capsaicinoids as well as synthetical capsinoids. In an accumulation assay these compounds were evaluated for their ability to accumulate ethidium bromide into mycobacterial cells, a well-known substrate for efflux pumps. Capsaicin and dihydrocapsaicin, the two most abundant capsaicinoids in Capsicum species, proved to be superior efflux pump inhibitors compared to the standard verapamil. A dilution series showed dose dependency of both compounds. The compound class of less pungent capsinoids qualified for further investigation as antibacterials against Mycobacterium smegmatis.


Assuntos
Amidas/farmacologia , Antibacterianos/farmacologia , Ésteres/farmacologia , Ácidos Graxos/farmacologia , Guaiacol/análogos & derivados , Guaiacol/farmacologia , Amidas/síntese química , Amidas/química , Antibacterianos/síntese química , Antibacterianos/química , Proteínas de Bactérias/antagonistas & inibidores , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Ésteres/síntese química , Ésteres/química , Ácidos Graxos/síntese química , Ácidos Graxos/química , Guaiacol/síntese química , Proteínas de Membrana Transportadoras/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium smegmatis/efeitos dos fármacos , Relação Estrutura-Atividade
16.
Sci Rep ; 8(1): 15271, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30323241

RESUMO

A cocoa butter equivalent (CBE) was synthesized enzymatically from readily available edible fats with fatty acid and triacylglycerol compositions that closely resemble the fat present in chocolate, cocoa butter. A commercially available immobilized fungal lipase, Lipozyme RM IM, was used as the reaction catalyst. Reaction parameters were a temperature of 65 °C, water activity of 0.11, a 4 h reaction time, and a substrate mass ratio of a commercial enzymatically synthesized shea stearin (SS) to palm mid-fraction (PMF) of 6:4 (w/w). Fractionation was also used after reaction completion to further approach the triacylglycerol composition of cocoa butter by removing trisaturated and unsaturated triacylglycerols. The yield of the triglyceride 1-palmitoyl-2-oleoyl, 3-stearoyl-glycerol (POS) produced was 57.7% (w/w). The amounts of 1,3-dipalmitoyl-2-oleoyl-glycerol (POP), (POS) and 1,3-stearoyl-2-oleoyl-glycerol (SOS) in the final CBE were 11.2%, 36.3%, and 34.8%, respectively. In comparison, the amounts of POP, POS and SOS in the cocoa butter used in this study were 15.2%, 38.2%, and 27.8%, respectively. No significant differences (P > 0.05) in melting point and enthalpy of fusion between CB and the CBE were observed. In comparison, a non-interesterified blend of SS and PMF (60:40 w/w) showed significantly (P < 0.05) higher melting point and lower enthalpy of fusion compared to CB. The crystal polymorphic form V of CB (ß2-3L) was similar to that of CBE and SS/PMF (60:40 w/w). The solid fat content (SFC) vs. temperature profile of the CBE generally resembled that of CB, except that the CBE had significantly (P < 0.05) higher SFCs at 5, 10, 15, 20 and 25 °C compared to both CB and SS/PMF (60:40 w/w). Addition of 15% (w/w) CBE to CB did not cause any changes in physical properties (melting point, SFC and crystal polymorphic forms) of the CB. This study demonstrates the potential for synthesizing a CB-like CBE using a green, rapid, straightforward one step enzymatic conversion followed by fractionation from widely available edible fats.


Assuntos
Gorduras na Dieta/síntese química , Ácidos Graxos/síntese química , Lipase/química , Óleos Vegetais/síntese química , Cacau/química , Catálise , Enzimas Imobilizadas/química , Ácidos Graxos/química , Humanos , Óleos Vegetais/química , Triglicerídeos/síntese química , Triglicerídeos/química
17.
AAPS PharmSciTech ; 19(7): 3067-3075, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30094721

RESUMO

The purpose of this study was to prepare sustained release (SR) matrix tablets using a direct compression incorporated with a post-heating process. Allopurinol was selected due to the water-soluble property and Compritol 888 ATO® (also known as glyceryl behenate) was used as an SR matrix-forming agent. The API, SR material, microcrystalline cellulose, and magnesium stearate (lubricant) were mixed and prepared into a tablet by a direct compression method. The compressed tablets were stored in a dry oven at four temperatures (60, 70, 80, and 90°C) and for three time periods (15, 30, 45 min). The DSC and PXRD data indicated that the crystallinity of the API was not altered by the post-heating method. However, SEM images demonstrated that Compritol 888 ATO® was melted by the post-heating method, and that the melted Compritol 888 ATO® could form a strong matrix. This strong matrix led to the significant sustained release behavior of hydrophilic APIs. As little as 3 mg of Compritol 888 ATO® (0.65% of total tablet weight), when heated at 80°C for 15 min, showed sustained release over 10 h. The post-heating method exerted a significant influence on lipid-based matrix tablets and allowed a reduction in the amount of material required for a water-soluble drug. This will also provide a valuable insight into lipid-based SR tablets and will allow their application to higher quality products and easier processing procedures.


Assuntos
Alopurinol/síntese química , Ácidos Graxos/síntese química , Temperatura Alta , Alopurinol/metabolismo , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/metabolismo , Excipientes/síntese química , Ácidos Graxos/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Solubilidade , Comprimidos , Temperatura
19.
J Lipid Res ; 59(8): 1510-1518, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29907595

RESUMO

The (O-acyl)-ω-hydroxy FAs (OAHFAs) comprise an unusual lipid subclass present in the skin, vernix caseosa, and meibomian gland secretions. Although they are structurally related to the general class of FA esters of hydroxy FAs (FAHFAs), the ultra-long chain (30-34 carbons) and the putative ω-substitution of the backbone hydroxy FA suggest that OAHFAs have unique biochemistry. Complete structural elucidation of OAHFAs has been challenging because of their low abundance within complex lipid matrices. Furthermore, because these compounds occur as a mixture of closely related isomers, insufficient spectroscopic data have been obtained to guide structure confirmation by total synthesis. Here, we describe the full molecular structure of ultra-long chain OAHFAs extracted from human meibum by exploiting the gas-phase purification of lipids through multi-stage MS and novel multidimensional ion activation methods. The analysis elucidated sites of unsaturation, the stereochemical configuration of carbon-carbon double bonds, and ester linkage regiochemistry. Such isomer-resolved MS guided the first total synthesis of an ultra-long chain OAHFA, which, in turn, confirmed the structure of the most abundant OAHFA found in human meibum, OAHFA 50:2. The availability of a synthetic OAHFA opens new territory for future investigations into the unique biophysical and biochemical properties of these lipids.


Assuntos
Ácidos Graxos/química , Ácidos Graxos/síntese química , Espectrometria de Massas , Técnicas de Química Sintética , Ésteres/química , Humanos , Glândulas Tarsais/química , Estereoisomerismo
20.
Bioorg Med Chem ; 26(9): 2599-2609, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29673717

RESUMO

Glucagon-like peptide-1 is a potent hypoglycemic hormone with beneficial properties for the treatment of diabetes. However, its half-life is short because the rapid metabolic degradation. This study aims to prolong the half-life of glucagon-like peptide-1 through conjugation with the fatty acid side chain which helps the conjugates to interact with the albumin. Firstly, we chose two optimized polypeptide chains which have tremendous hypoglycemic effect named Cys17-Gly8-GLP-1(7-36)-NH2 and Cys37-Gly8-GLP-1(7-37)-NH2, and various fatty acid chains were modified. All conjugates preserved relatively strong GLP-1R activation and I-6 behaved best in glucose-lowering ability. The prolonged antidiabetic effects of I-6 were further confirmed by hypoglycemic efficacy test in vivo. Meanwhile, once daily injection of I-6 to diabetic mice achieved long-term beneficial effects on glucose tolerance, body weight and blood chemistry. It is concluded that I-6 is a promising agent for further investigation of its potential to treat obese patients with diabetes.


Assuntos
Ácidos Graxos/farmacologia , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Hipoglicemiantes/farmacologia , Lipopeptídeos/farmacologia , Adipócitos/metabolismo , Adiponectina/metabolismo , Animais , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Estabilidade de Medicamentos , Ácidos Graxos/síntese química , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Peptídeo 1 Semelhante ao Glucagon/síntese química , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Células HEK293 , Meia-Vida , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Leptina/metabolismo , Lipopeptídeos/síntese química , Lipopeptídeos/química , Lipopeptídeos/metabolismo , Liraglutida/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Pâncreas/metabolismo , Ratos Sprague-Dawley , Albumina Sérica Humana/metabolismo
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