RESUMO
Caffeic acid phenethyl ester (CAPE) is a phenolic natural product with a wide range of biological activities, including anticancer activity; however, the ester group of CAPE is metabolically labile. The corresponding amide, CAPA, has improved metabolic stability but limited anticancer activity relative to CAPE. We report the synthesis using flow and on-water Wittig reaction approaches of five previously reported and five novel CAPA analogues. All of these analogues lack the reactive catechol functionality of CAPA and CAPE. Cytotoxicity studies of CAPE, CAPA, and these CAPA analogues in HeLa and BE(2)-C cells were carried out. Surprisingly, we found that CAPA is cytotoxic against the neuroblastoma BE(2)-C cell line (IC50 = 12 µM), in contrast to the weak activity of CAPA against HeLa cells (IC50 = 112 µM), and the literature reports of the absence of activity for CAPA against a variety of other cancer cell lines. One novel CAPA analogue, 3f, was identified as having cytotoxic activity similar to CAPE in HeLa cells (IC50 = 63 µM for 3f vs. 32 µM for CAPE), albeit with lower activity against BE(2)-C cells (IC50 = 91 µM) than CAPA. A different CAPA analogue, 3g, was found to have similar effects against BE(2)-C cells (IC50 = 92 µM). These results show that CAPA is uniquely active against neuroblastoma cells and that specific CAPA analogues that are predicted to be more metabolically stable than CAPE can reproduce CAPA's activity against neuroblastoma cells and CAPE's activity against HeLa cells.
Assuntos
Antineoplásicos , Ácidos Cafeicos , Álcool Feniletílico , Humanos , Ácidos Cafeicos/farmacologia , Ácidos Cafeicos/química , Ácidos Cafeicos/síntese química , Células HeLa , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/farmacologia , Álcool Feniletílico/química , Álcool Feniletílico/síntese química , Água/química , Linhagem Celular Tumoral , Amidas/farmacologia , Amidas/química , Sobrevivência Celular/efeitos dos fármacosRESUMO
2-phenylethanol (2-PE), an aromatic alcohol with a rose fragrance, is the second most widely used flavoring substance in the world. It is widely used in the cosmetic, food, and pharmaceutical industries. This paper introduces the chemical synthesis methods of 2-PE and the synthetic pathways in plants and microorganisms, summarizes the strategies to improve the microbial synthesis of 2-PE, reviews the research progress in de novo synthesis of 2-PE in microorganisms, and makes an outlook on the research prospects, aiming to provide a theoretical basis for the industrial production of 2-PE.
Assuntos
Álcool Feniletílico , Álcool Feniletílico/metabolismo , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/síntese química , Microbiologia Industrial , Aromatizantes/síntese química , Aromatizantes/metabolismo , Bactérias/metabolismo , Plantas/metabolismoRESUMO
Engineering of biological pathways with man-made materials provides inspiring blueprints for sustainable drug production. (R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethanol [(R)-3,5-BTPE], as an important artificial chiral intermediate for complicated pharmaceutical drugs and biologically active molecules, is often synthesized through a hydrogenation reaction of 3,5-bis(trifluoromethyl)acetophenone (3,5-BTAP), in which enantioselectivity and sufficient active hydrogen are the key to restricting the reaction. In this work, a biohybrid photocatalytic hydrogenation system based on an artificial cross-linked enzymes (CLEs)-TiO2-Cp*Rh(bpy) photoenzyme is developed through a bottom-up engineering strategy. Here, TiO2 nanotubes in the presence of Cp*Rh(bpy) are used to transform NADP+ to NADPH during the formation of chiral alcohol intermediates from the catalytic reduction of a ketone substrate by alcohol dehydrogenase CLEs. Hydrogen and electrons, provided by water and photocatalytic systems, respectively, are transferred to reduce NADP+ to NADPH via [Cp*Rh(bpy)(H2O)]2+. With the resulting NADPH, [(R)-3,5-BTPE] is synthesized using our efficient CLEs obtained from the cell lysate by nonstandard amino acid modification. Through this biohybrid photocatalytic system, the photoenzyme-catalyzed combined reductive synthesis of [(R)-3,5-BTPE] has a yield of 41.2% after reaction for 24 h and a very high enantiomeric excess value (>99.99%). In the case of reuse, this biohybrid system retained nearly 95% of its initial catalytic activity for synthesizing the above chiral alcohol. The excellent reusability of the CLEs and TiO2 nanotubes hybrid catalytic materials highlights the environmental friendliness of (R)-3,5-BTPE production.
Assuntos
Álcool Desidrogenase/química , Nanotubos/química , Álcool Feniletílico/análogos & derivados , Titânio/química , Proteínas de Bactérias/química , Catálise/efeitos da radiação , Complexos de Coordenação/química , Complexos de Coordenação/efeitos da radiação , Hidrogenação , Lactobacillus/enzimologia , Luz , NADP/síntese química , Nanotubos/efeitos da radiação , Álcool Feniletílico/síntese química , Ródio/química , Ródio/efeitos da radiação , Estereoisomerismo , Titânio/efeitos da radiação , Água/químicaRESUMO
We synthesized phenylboronic acid pinacol ester (PBPE)-conjugated hyaluronic acid (HA) via thiobis(ethylamine) (TbEA) linkage (abbreviated as HAsPBPE conjugates) to fabricate the radiosensitive delivery of caffeic acid phenetyl ester (CAPE) and for application in radioprotection. PBPE was primarily conjugated with TbEA and then PBPE-TbEA conjugates were conjugated again with hyaluronic acid using carbodiimide chemistry. CAPE-incorporated nanoparticles of HAsPBPE were fabricated by the nanoprecipitation method and then the organic solvent was removed by dialysis. CAPE-incorporated HAsPBPE nanoparticles have a small particle size of about 80 or 100 nm and they have a spherical shape. When CAPE-incorporated HAsPBPE nanoparticles were irradiated, nanoparticles became swelled or disintegrated and their morphologies were changed. Furthermore, the CAPE release rate from HAsPBPE nanoparticles were increased according to the radiation dose, indicating that CAPE-incorporated HAsPBPE nanoparticles have radio-sensitivity. CAPE and CAPE-incorporated HAsPBPE nanoparticles appropriately prevented radiation-induced cell death and suppressed intracellular accumulation of reactive oxygen species (ROS). CAPE and CAPE-incorporated HAsPBPE nanoparticles efficiently improved survivability of mice from radiation-induced death and reduced apoptotic cell death. We suggest that HAsPBPE nanoparticles are promising candidates for the radio-sensitive delivery of CAPE.
Assuntos
Ácidos Borônicos/química , Ácidos Cafeicos/farmacologia , Glicóis/química , Ácido Hialurônico/química , Nanopartículas/química , Álcool Feniletílico/análogos & derivados , Proteção Radiológica , Animais , Ácidos Borônicos/síntese química , Ácidos Cafeicos/síntese química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Peróxido de Hidrogênio/toxicidade , Fígado/metabolismo , Camundongos Endogâmicos BALB C , Nanopartículas/ultraestrutura , Tamanho da Partícula , Álcool Feniletílico/síntese química , Álcool Feniletílico/farmacologia , Espectroscopia de Prótons por Ressonância Magnética , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
Caffeic acid ß-phenethyl ester (CAPE), an antioxidative bioactive catechol isolated from propolis, was semisynthesized from chlorogenic acid and related compounds in an extract of raw (unroasted) Robusta coffee (Coffea canephora) beans in 5 steps and a total yield of 31%. Oxidative degradation of the intermediates and target molecule was prevented by alkaline hydrolysis of the chlorogenic acids in the presence of sodium dithionite (Na2S2O4) and deprotection of the catecholic diacetate precursor by Candida antarctica lipase B-mediated transesterification as the final step.
Assuntos
Antioxidantes/síntese química , Ácidos Cafeicos/síntese química , Coffea/química , Álcool Feniletílico/análogos & derivados , Extratos Vegetais/síntese química , Própole/química , Esterificação , Álcool Feniletílico/síntese químicaRESUMO
To find a potent α-glucosidase inhibitor, 24 tyrosol derivatives with different substituents located at the meta, ortho, or para position of the phenyl group have been synthesised via the Mitsunobu reaction, characterised by 1H NMR, 13C NMR, ESI-MS and IR and evaluated for inhibition. The derivatives possessed varying degrees of in vitro inhibitory activity against α-glucosidase and a relationship between the structure and activity was subsequently established for all compounds. Two of these compounds with substituents at the para position showed significant inhibitory effects surpassing that of the control standard acarbose. Molecular docking studies performed to better understand the binding interactions between the enzyme and the two most active compounds showed substantial binding within the active site of α-glucosidase. Taken together, these results indicate that the position of the substituent plays a crucial role in this inhibition and may facilitate the development of new α-glucosidase inhibitors.
Assuntos
Inibidores de Glicosídeo Hidrolases/farmacologia , Simulação de Acoplamento Molecular , Álcool Feniletílico/análogos & derivados , alfa-Glucosidases/metabolismo , Acarbose/química , Acarbose/farmacologia , Sítios de Ligação , Domínio Catalítico , Inibidores de Glicosídeo Hidrolases/química , Álcool Feniletílico/síntese química , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , Relação Estrutura-Atividade , Leveduras/enzimologia , alfa-Glucosidases/químicaRESUMO
Covering: 2005 up to 2020Olive bioactive secoiridoids are recognized as natural antioxidants with multiple beneficial effects on human health. Nevertheless, the study of their biological activity has also disclosed some critical aspects associated with their application. Firstly, only a few of them can be extracted in large amounts from their natural matrix, namely olive leaves, drupes, oil and olive mill wastewater. Secondly, their application as preventive agents and drugs is limited by their low membrane permeability. Thirdly, the study of their biological fate after administration is complicated by the absence of pure analytical standards. Accordingly, efficient synthetic methods to obtain natural and non-natural bioactive phenol derivatives have been developed. Among them, semi-synthetic protocols represent efficient and economical alternatives to total synthesis, combining efficient extraction protocols with efficient catalytic conversions to achieve reasonable amounts of active molecules. The aim of this review is to summarize the semi-synthetic protocols published in the last fifteen years, covering 2005 up to 2020, which can produce natural olive bioactive phenols scarcely available by extractive procedures, and new biophenol derivatives with enhanced biological activity. Moreover, the semi-synthetic protocols to produce olive bioactive phenol derivatives as analytical standards are also discussed. A critical analysis of the advantages offered by semi-synthesis compared to classical extraction methods or total synthesis protocols is also performed.
Assuntos
Iridoides/síntese química , Olea/química , Aldeídos/síntese química , Monoterpenos Ciclopentânicos/síntese química , Glucosídeos Iridoides/síntese química , Glucosídeos Iridoides/química , Azeite de Oliva/química , Fenóis/síntese química , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/síntese químicaRESUMO
Alzheimer's disease (AD) is an age-related neurodegenerative disorder with cognitive deficits, which is becoming markedly more common in the world. Currently, the exact cause of AD is still unclear, and no curative therapy is available for preventing or mitigating the disease progression. Caffeic acid phenethyl ester (CAPE), a natural phenolic compound derived from honeybee hive propolis, has been reported as a potential therapeutic agent against AD, while its application is limited due to the low water solubility and poor bioavailability. Here, caffeic acid phenethyl ester 4-O-glucoside (FA-97) is synthesized. We validate that FA-97 attenuates H2O2-induced apoptosis in SH-SY5Y and PC12 cells and suppresses H2O2-induced oxidative stress by inhibiting the ROS level, malondialdehyde (MDA) level, and protein carbonylation level, as well as induces cellular glutathione (GSH) and superoxide dismutase (SOD). Mechanistically, FA-97 promotes the nuclear translocation and transcriptional activity of Nrf2 associated with the upregulated expression of HO-1 and NQO-1. The prime importance of Nrf2 activation in the neuroprotective and antioxidant effects of FA-97 is verified by Nrf2 siRNA transfection. In addition, FA-97 prevents scopolamine- (SCOP-) induced learning and memory impairments in vivo via reducing neuronal apoptosis and protecting against cholinergic system dysfunction in the hippocampus and cortex. Moreover, the increased MDA level and low total antioxidant capacity in SCOP-treated mouse brains are reversed by FA-97, with the increased expression of HO-1, NQO-1, and nuclear Nrf2. In conclusion, FA-97 protects against oxidative stress-mediated neuronal cell apoptosis and SCOP-induced cognitive impairment by activating Nrf2/HO-1 signaling, which might be developed as a therapeutic drug for AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Ácidos Cafeicos/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/fisiologia , Fármacos Neuroprotetores/uso terapêutico , Álcool Feniletílico/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Ácidos Cafeicos/síntese química , Ácidos Cafeicos/metabolismo , Disfunção Cognitiva/induzido quimicamente , Modelos Animais de Doenças , Glucosídeos/síntese química , Heme Oxigenase-1/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Álcool Feniletílico/síntese química , Álcool Feniletílico/metabolismo , Álcool Feniletílico/uso terapêutico , RNA Interferente Pequeno/genética , Ratos , Escopolamina , Transdução de SinaisRESUMO
Forsythenethoside A (1) is a structurally unique macrocyclic phenylethanoid glycoside, which was isolated from Forsynthia suspensa and displayed considerable neuroprotective activities. Here, we report its first chemical synthesis via a longest linear sequence of 14 steps in 5% overall yield wherein intramolecular oxidative coupling was successfully employed to realize the pivotal macrocyclization. NMR analysis revealed the existence of an unexpected conformational interconversion of the congested macrocycles.
Assuntos
Glicosídeos/química , Glicosídeos/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/síntese química , Álcool Feniletílico/química , Álcool Feniletílico/síntese química , Técnicas de Química Sintética , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação MolecularRESUMO
Hydroxytyrosol and two other polyphenols of olive tree, hydroxytyrosol acetate and 3,4-dihydroxyphenylglycol, are known for a wide range of beneficial activities in human health and prevention from diseases. The inability to isolate high, pure amounts of these natural compounds and the difficult and laborious procedures for the synthesis of them led us to describe herein an efficient, easy, cheap, and scaling up synthetic procedure, from catechol, via microwave irradiation.
Assuntos
Técnicas de Química Sintética , Metoxi-Hidroxifenilglicol/análogos & derivados , Álcool Feniletílico/análogos & derivados , Técnicas de Química Sintética/métodos , Humanos , Metoxi-Hidroxifenilglicol/síntese química , Metoxi-Hidroxifenilglicol/química , Estrutura Molecular , Álcool Feniletílico/síntese química , Álcool Feniletílico/químicaRESUMO
Potential metabolites of bioactive compounds are important for their biological activities and as authentic standards for metabolic studies. The phenolic compounds contained in olive oil are an important part of the human diet, and therefore their potential metabolites are of utmost interest. We developed a convenient, scalable, one-pot chemoenzymatic method using the arylsulfotransferase from Desulfitobacterium hafniense for the sulfation of the natural olive oil phenols tyrosol, hydroxytyrosol, and of their monoacetylated derivatives. Respective monosulfated (tentative) metabolites were fully structurally characterized using LC-MS, NMR, and HRMS. In addition, Folin-Ciocalteu reduction, 1,1-diphenyl-2-picrylhydrazyl radical scavenging, and antilipoperoxidant activity in rat liver microsomes damaged by tert-butylhydroperoxide were measured and compared to the parent compounds. As expected, the sulfation diminished the radical scavenging properties of the prepared compounds. These compounds will serve as authentic standards of phase II metabolites.
Assuntos
Arilsulfotransferase/química , Proteínas de Bactérias/química , Sequestradores de Radicais Livres/química , Álcool Feniletílico/análogos & derivados , Acetilação , Biocatálise , Cromatografia Líquida de Alta Pressão , Desulfitobacterium/enzimologia , Sequestradores de Radicais Livres/síntese química , Espectrometria de Massas , Estrutura Molecular , Azeite de Oliva/química , Fenóis/química , Álcool Feniletílico/síntese química , Álcool Feniletílico/química , Sulfatos/químicaRESUMO
Hydroxytyrosol (HT) is a polyphenol of interest to the food, feed, supplements and pharmaceutical sectors. It is one of the strongest known natural antioxidants and has been shown to confer other benefits such as anti-inflammatory and anti-carcinogenic properties, and it has the potential to act as a cardio- and neuroprotectant. It is known to be one of the compounds responsible for the health benefits of the Mediterranean diet. In nature, HT is found in the olive plant (Olea europaea) as part of the secoiridoid compound oleuropein, in its leaves, fruit, oil and oil production waste products. HT can be extracted from these olive sources, but it can also be produced by chemical synthesis or through the use of microorganisms. This review looks at the production of HT using plant extraction, chemical synthesis and biotechnological approaches.
Assuntos
Antioxidantes/isolamento & purificação , Biotecnologia/métodos , Álcool Feniletílico/análogos & derivados , Tecnologia Farmacêutica/métodos , Antioxidantes/síntese química , Antioxidantes/metabolismo , Olea/química , Álcool Feniletílico/síntese química , Álcool Feniletílico/isolamento & purificação , Álcool Feniletílico/metabolismoRESUMO
Unexpected inhibitory effects against eeAChE could be found for a newly synthesized class of caffeic acid phenethyl ester (CAPE) derivatives. Thus, phenethyl-(E)-3-(3,5-dimethoxy-4-phenethoxyphenyl)-acrylate (Kiâ¯=â¯1.97⯱â¯0.38⯵M, Ki´â¯=â¯2.44⯱â¯0.07⯵M) and 4-(2-(((E)-3-(3,4-bis(benzyloxy)phenyl)acryloyl)oxy)ethyl)-1,2-phenylene (2E,2'E)-bis(3-(3,4-bis(benzyloxy)phenyl)acrylate) (Kiâ¯=â¯0.72⯱â¯0.31⯵M, Ki´â¯=â¯1.80⯱â¯0.21⯵M) showed very good inhibition of eeAChE, while being non cytotoxic for malignant human cancer cells and non-malignant mouse fibroblasts. Also, they are weak inhibitors for BChE (from equine serum).
Assuntos
Ácidos Cafeicos/farmacologia , Inibidores da Colinesterase/farmacologia , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/farmacologia , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Butirilcolinesterase/metabolismo , Ácidos Cafeicos/síntese química , Ácidos Cafeicos/química , Ácidos Cafeicos/toxicidade , Domínio Catalítico , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/toxicidade , Electrophorus , Cavalos , Humanos , Camundongos , Simulação de Acoplamento Molecular , Células NIH 3T3 , Álcool Feniletílico/síntese química , Álcool Feniletílico/toxicidadeRESUMO
Inhibitors of the enzyme xanthine oxidase (XO) with radical scavenging properties hold promise as novel agents against reperfusion injuries after ischemic events. By suppressing the formation of damaging reactive oxygen species (ROS) by XO or scavenging ROS from other sources, these compounds may prevent a buildup of ROS in the aftermath of a heart attack or stroke. To combine these two properties in a single molecule, we synthesized and characterized the non-purine XO inhibitor caffeic acid phenethylester (CAPE) and 19 derivatives using a convenient microwave-assisted Knoevenagel condensation protocol. Varying systematically the number and positions of the hydroxyl groups at the two phenyl rings, we derived structure-activity relationships based on experimentally determined XO inhibition data. Molecular docking suggested that critical enzyme/inhibitor interactions involved π-π interactions between the phenolic inhibitor ring and Tyr914, hydrogen bonds between inhibitor hydroxyl groups and Glu802, and hydrophobic interactions between the CAPE phenyl ring and non-polar residues located at the entrance of the binding site. To effectively scavenge the stable radical DPPH, two hydroxyl groups in 1,2- or 1,4-position at the phenyl ring were required. Among all compounds tested, E-phenyl 3-(3,4-dihydroxyphenyl)acrylate, a CAPE analog without the ethyl tether, showed the most promising properties.
Assuntos
Ácidos Cafeicos/farmacologia , Inibidores Enzimáticos/farmacologia , Sequestradores de Radicais Livres/farmacologia , Álcool Feniletílico/análogos & derivados , Xantina Oxidase/antagonistas & inibidores , Animais , Compostos de Bifenilo/antagonistas & inibidores , Ácidos Cafeicos/síntese química , Ácidos Cafeicos/química , Bovinos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/química , Modelos Moleculares , Estrutura Molecular , Álcool Feniletílico/síntese química , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , Picratos/antagonistas & inibidores , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Xantina Oxidase/metabolismoRESUMO
Fatty acid monoesters of hydroxytyrosol [2-(3,4-dihydroxyphenyl)ethanol] were synthesized in two steps from tyrosol (4-hydroxyphenylethanol) by successive Candida antarctica lipase B-catalyzed chemoselective acylation on the primary aliphatic hydroxy group over phenolic hydroxy group in tyrosol, and 2-iodoxybenzoic acid (IBX)-mediated hydroxylation adjacent to the remaining free phenolic hydroxy group. Examination of their suppression effects on nitric oxide production stimulated by lipopolysaccharides in RAW264.7 cells showed that hydroxytyrosol butyrate exhibited the highest inhibition (IC50 7.0 µM) among the tested compounds.
Assuntos
Ésteres/síntese química , Proteínas Fúngicas/metabolismo , Lipase/metabolismo , Lipopolissacarídeos/farmacologia , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Álcool Feniletílico/análogos & derivados , Acilação , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Ésteres/química , Ésteres/farmacologia , Hidroxilação , Concentração Inibidora 50 , Camundongos , Álcool Feniletílico/síntese química , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , Espectroscopia de Prótons por Ressonância Magnética , Células RAW 264.7 , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Several lipophilic ω-hydroxyalkylcarbonate hydroxytyrosol derivatives and also their corresponding dimeric derivatives have been synthesized, coupling the primary hydroxy group of this phenolic compound with several terminal diols of different chain lengths, by the use of a carbonate linker. The trypanocidal activity and cytotoxicity of these ω-hydroxyalkylcarbonate derivatives of hydroxytyrosol and known alkylcarbonate derivatives of hydroxytyrosol were assessed. Three of the hydroxytyrosol alkylcarbonate derivatives were active against Trypanosoma brucei: two with an alkyl chain of average size (0.2 and 0.5 µM) and another with a double bond in the alkyl chain (0.4 µM). These values suggest an increase in activity with respect to hydroxytyrosol (264-, 90-, and 116-fold, respectively). Furthermore, these compounds showed high selectivity indices against MRC-5, a nontumor human cell line (62, 71, and 39, respectively). Some other ω-hydroxyalkylcarbonate and alkylcarbonate derivatives of hydroxytyrosol were also active against T. brucei within a low micromolar range (about 1 µM).
Assuntos
Álcool Feniletílico/análogos & derivados , Tripanossomicidas/síntese química , Linhagem Celular , Humanos , Espectroscopia de Ressonância Magnética , Álcool Feniletílico/síntese química , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , Relação Estrutura-Atividade , Trypanosoma brucei brucei/efeitos dos fármacosRESUMO
Oxidative stress is one of the underlying mechanisms of the toxic effects exerted by mercury (Hg) on human health. Several antioxidant compounds, including the olive oil phenol hydroxytyrosol (HT), were investigated for their protective action. Recently, we have reported that 5-S-lipoylhydroxytyrosol (Lipo-HT) has shown increased antioxidant activities compared to HT and exerted potent protective effects against reactive oxygen species (ROS) generation and oxidative damage in human hepatocellular carcinoma HepG2 cell lines. In this study, the effects of Lipo-HT and HT on oxidative alterations of human erythrocytes induced by exposure to 40 µM HgCl2 were comparatively evaluated. When administered to the cells, Lipo-HT (5-20 µM) proved nontoxic and it decreased the Hg-induced generation of ROS, the hemolysis, and the depletion of intracellular GSH levels. At all tested concentrations, Lipo-HT exhibited higher ability to counteract Hg-induced cytotoxicity compared to HT. Model studies indicated the formation of a mercury complex at the SH group of Lipo-HT followed by a redox reaction that would spare intracellular GSH. Thus, the enhanced erythrocyte protective action of Lipo-HT from Hg-induced damage with respect to HT is likely due to an effective chelating and reducing ability toward mercury ions. These findings encourage the use of Lipo-HT in nutraceutical strategies to contrast heavy metal toxicity in humans.
Assuntos
Hemólise/efeitos dos fármacos , Cloreto de Mercúrio/toxicidade , Azeite de Oliva/química , Álcool Feniletílico/análogos & derivados , Substâncias Protetoras/farmacologia , Catecóis/síntese química , Catecóis/química , Catecóis/farmacologia , Cromatografia Líquida de Alta Pressão , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Glutationa/metabolismo , Células Hep G2 , Humanos , Espectrometria de Massas , Estresse Oxidativo/efeitos dos fármacos , Álcool Feniletílico/síntese química , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , Substâncias Protetoras/síntese química , Substâncias Protetoras/química , Espécies Reativas de Oxigênio/metabolismo , EspectrofotometriaRESUMO
Myeloid differentiation protein 2 (MD2) is an essential molecule which recognizes lipopolysaccharide (LPS), leading to initiation of inflammation through the activation of Toll-like receptor 4 (TLR4) signaling. Caffeic acid phenethyl ester (CAPE) from propolis of honeybee hives could interfere interactions between LPS and the TLR4/MD2 complex, and thereby has promising anti-inflammatory properties. In this study, we designed and synthesized 48 CAPE derivatives and evaluated their anti-inflammatory activities in mouse primary peritoneal macrophages (MPMs) activated by LPS. The most active compound, 10s, was found to bind with MD2 with high affinity, which prevented formation of the LPS/MD2/TLR4 complex. The binding mode of 10s revealed that the major interactions with MD2 were established via two key hydrogen bonds and hydrophobic interactions. Furthermore, 10s showed remarkable protective effects against LPS-caused ALI (acute lung injury) in vivo. Taken together, this work provides new lead structures and candidates as MD2 inhibitors for the development of anti-inflammatory drugs.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios não Esteroides/farmacologia , Ácidos Cafeicos/farmacologia , Descoberta de Drogas , Antígeno 96 de Linfócito/antagonistas & inibidores , Álcool Feniletílico/análogos & derivados , Lesão Pulmonar Aguda/metabolismo , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Ácidos Cafeicos/síntese química , Ácidos Cafeicos/química , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Antígeno 96 de Linfócito/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Álcool Feniletílico/síntese química , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , Relação Estrutura-AtividadeRESUMO
Glioblastoma multiforme (GBM) is an aggressive brain tumor that correlates with short patient survival and for which therapeutic options are limited. Polyphenolic compounds, including caffeic acid phenethyl ester (CAPE, 1a), have been investigated for their anticancer properties in several types of cancer. To further explore these properties in brain cancer cells, a series of caffeic and ferulic acid esters bearing additional oxygens moieties (OH or OCH3) were designed and synthesized. (CAPE, 1a), but not ferulic acid phenethyl ester (FAPE, 1b), displayed substantial cytotoxicity against two glioma cell lines. Some but not all selected compounds derived from both (CAPE, 1a) and (FAPE, 1b) also displayed cytotoxicity. All CAPE-derived compounds were able to significantly inhibit 5-lipoxygenase (5-LO), however FAPE-derived compounds were largely ineffective 5-LO inhibitors. Molecular docking revealed new hydrogen bonds and π-π interactions between the enzyme and some of the investigated compounds. Overall, this work highlights the relevance of exploring polyphenolic compounds in cancer models and provides additional leads in the development of novel therapeutic strategies in gliomas.
Assuntos
Ácidos Cafeicos/síntese química , Ácidos Cafeicos/farmacologia , Ácidos Cumáricos/síntese química , Ácidos Cumáricos/farmacologia , Leucotrienos/biossíntese , Álcool Feniletílico/análogos & derivados , Araquidonato 5-Lipoxigenase/metabolismo , Ácidos Cafeicos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ácidos Cumáricos/química , Células HEK293 , Humanos , Imageamento Tridimensional , Ligantes , Inibidores de Lipoxigenase/farmacologia , Simulação de Acoplamento Molecular , Álcool Feniletílico/síntese química , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , TermodinâmicaRESUMO
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used medications in inflammatory illnesses. However, the gastrointestinal bleeding and toxicity associated with NSAIDs long term use prompted the quest towards investigations for new anti-inflammatory agents. Natural and natural-derived molecules proved its anti-inflammatory efficacy in vitro as well as in vivo. Given this background, the scope of this research involves structural changes of the natural polyphenol (tyrosol) generating two new salicylate derivatives and testing their biological properties, focusing on anti-inflammatory effects assessed in vitro and in vivo assays. The first molecular modification was the introduction of a carboxylic acid group adjacent to the phenol group present in this compound, which creates a new salicylate-like tyrosol. In addition, the acetylation of phenol group in this molecule produced an acetylsalicylate derivative, which may be regarded as aspirin-like natural polyphenol. Interestingly, tyrosol and its novel derivatives attenuated the edema in acute inflammatory response on carrageenan- induced local inflammation in mice. In addition, our results demonstrated that tyrosol and its novel derivatives were able to reduce the chemotaxis of neutrophil assessed in vitro model by chemo attractant (fMLP). Furthermore, only derivative 2 was able to reduce this effect in the acute inflammatory model. In (DPPH)- scavenging activity, tyrosol derivatives demonstrated a minor antioxidant activity, which may suggest that radical scavenging is not a major pathway involved in the anti-inflammatory effects of these derivatives. Salicylate-like tyrosol derivatives are of particular interest for future studies.