RESUMO
Despite numerous beneficial therapeutic effects namely antioxidant and anti-inflammatory activity, Vitamin E has limited clinical applications due to its low water solubility. Throughout the present work, α-tocopherol's new PEGylated derivatives alongside with polyethylene glycol 300 (α-1TPGT300), 400 (α-TPGT400), and 1000 (α-TPGT1000) were synthesized. A 1,2,3-triazole ring was utilized as a linker for the attachment of alpha tocopherol to the PEGs through a click reaction. The purified derivatives were characterized by the means of 1H NMR, 13C NMR, mass spectroscopy, UV-vis and FT-IR methods. Synthesized derivatives' capacity to produce self-assembly nanoparticles was evaluated employing the critical micelle concentration (CMC) values. The stability of the micelles was studied by size analysis. In vitro cytotoxicity of the products was investigated using MTT assay against MCF-7 breast cancer cells. The IC50 value for TPGT1000 after 24 h treatment was 15.0 ± 1.8 µM, whereas no significant cytotoxicity effect was observed following the treatment of MCF-7 cells by TPGT300, 400. The present study showed that polymeric micelle TPGT1000 possessed better physicochemical and biological properties including relatively lower CMC value, higher stability in FBS environment in addition to higher cytotoxicity against MCF-7 breast cancer cells compared to the lower molecular weight PEGylated derivatives. These results confirmed that increasing PEG chain length left a positive effect on the polymeric micelle properties and also improved the cytotoxicity effect of new PEGylated vitamin E derivatives.
Assuntos
Nanocápsulas/química , Polietilenoglicóis/química , alfa-Tocoferol/síntese química , Sobrevivência Celular/efeitos dos fármacos , Química Click , Composição de Medicamentos , Humanos , Células MCF-7 , Micelas , Nanocápsulas/efeitos adversos , Tamanho da Partícula , Solubilidade , Triazóis/química , Vitamina E/químicaRESUMO
Daidzein is a common isoflavone, having multiple biological effects such as anti-inflammation, anti-allergy, and anti-aging. α-Tocopherol is the tocopherol isoform with the highest vitamin E activity including anti-allergic activity and anti-cancer activity. Hesperetin is a flavone, which shows potent anti-inflammatory effects. These compounds have shortcomings, i.e., water-insolubility and poor absorption after oral administration. The glycosylation of bioactive compounds can enhance their water-solubility, physicochemical stability, intestinal absorption, and biological half-life, and improve their bio- and pharmacological properties. They were transformed by cultured Nicotiana tabacum cells to 7-ß-glucoside and 7-ß-gentiobioside of daidzein, and 3'- and 7-ß-glucosides, 3',7-ß-diglucoside, and 7-ß-gentiobioside of hesperetin. Daidzein and α-tocopherol were glycosylated by galactosylation with ß-glucosidase to give 4'- and 7-ß-galactosides of daidzein, which were new compounds, and α-tocopherol 6-ß-galactoside. These nine glycosides showed higher anti-allergic activity, i.e., inhibitory activity toward histamine release from rat peritoneal mast cells, than their respective aglycones. In addition, these glycosides showed higher tyrosinase inhibitory activity than the corresponding aglycones. Glycosylation of daidzein, α-tocopherol, and hesperetin greatly improved their biological activities.
Assuntos
Antialérgicos/síntese química , Cosméticos/síntese química , Glicosídeos/síntese química , Hesperidina/síntese química , Isoflavonas/síntese química , alfa-Tocoferol/síntese química , Animais , Antialérgicos/metabolismo , Biocatálise , Técnicas de Cultura de Células , Cosméticos/metabolismo , Alimento Funcional/análise , Glicosídeos/metabolismo , Glicosilação , Hesperidina/metabolismo , Humanos , Isoflavonas/metabolismo , Masculino , Mastócitos/citologia , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Células Vegetais/metabolismo , Cultura Primária de Células , Ratos , Ratos Wistar , Solubilidade , Nicotiana/citologia , Nicotiana/metabolismo , alfa-Tocoferol/metabolismoRESUMO
Natural antioxidants and vitamins have potential to protect biological systems from peroxidative damage induced by peroxyl radicals, α-tocopherol (Vitamin E, lipid soluble) and ascorbic acid (vitamin C, water soluble), well known natural antioxidant molecules. In the present study we described the synthesis and biological evaluation of hybrid of these two natural antioxidants with each other via ammonium di-ethylether linker, Toc-As in gene delivery. Two control cationic lipids N14-As and Toc-NOH are designed in such a way that one is with ascorbic acid moiety and no tocopherol moiety; another is with tocopherol moiety and no ascorbic acid moiety respectively. All the three cationic lipids can form self-assembled aggregates. The antioxidant efficiencies of the three lipids were compared with free ascorbic acid. The cationic lipids (Toc-As, N14-As and Toc-NOH) were formulated individually with a well-known fusogenic co-lipid DOPE and characterization studies such as DNA binding, heparin displacement, size, charge, circular dichroism were performed. The biological characterization studies such as cell viability assay and in vitro transfection studies were carried out with the above formulations in HepG2, Neuro-2a, CHO andHEK-293T cell lines. The three formulations showed their transfection efficiencies with highest in Toc-As, moderate inN14-As and least in Toc-NOH. Interestingly, the transfection efficiency observed with the antioxidant based conjugated lipid Toc-As is found to be approximately two and half fold higher than the commercially available lipofectamine 2000 at 4:1 charge ratio in Hep G2 cell lines. In the other cell lines studied the efficiency of Toc-As is found to be either higher or similarly active compared to lipofectamine 2000. The physicochemical characterization results show that Toc-As lipid is showing maximum antioxidant potency, strong binding with pDNA, least size and optimal zeta potential. It is also found to be least toxic in all the cell lines studied especially in Neuro-2a cell lines when compared to other two lipids. In summary, the designed antioxidant lipid can be exploited as a delivering system for treating ROS related diseases such as malignancy, brain stroke, etc.
Assuntos
Ácido Ascórbico/farmacologia , DNA/química , Sequestradores de Radicais Livres/farmacologia , Lipossomos/farmacologia , Tensoativos/farmacologia , alfa-Tocoferol/farmacologia , Animais , Ácido Ascórbico/síntese química , Ácido Ascórbico/química , Ácido Ascórbico/toxicidade , Células CHO , Linhagem Celular Tumoral , Cricetulus , DNA/genética , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/toxicidade , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Lipossomos/síntese química , Lipossomos/química , Lipossomos/toxicidade , Camundongos , Tensoativos/síntese química , Tensoativos/química , Tensoativos/toxicidade , Transfecção/métodos , alfa-Tocoferol/síntese química , alfa-Tocoferol/química , alfa-Tocoferol/toxicidadeRESUMO
Amphiphilic polymer of α-tocopherol succinate modified glycol chitosan (TS-GC) was successfully constructed by conjugating α-tocopherol succinate to the skeleton of glycol chitosan and characterized by Fourier-transform infrared (FT-IR) and proton nuclear magnetic resonance (¹H-NMR). In aqueous milieu, the conjugates self-assembled to micelles with the critical aggregation concentration of 7.2 × 10−3 mg/mL. Transmission electron microscope (TEM) observation and dynamic light scattering (DLS) measurements were carried out to determine the physicochemical properties of the micelles. The results revealed that paclitaxel (PTX)-loaded TS-GC micelles were spherical in shape. Moreover, the PTX-loaded micelles showed increased particle sizes (35 nm vs. 142 nm) and a little reduced zeta potential (+19 mV vs. +16 mV) compared with blank micelles. The X-ray diffraction (XRD) spectra demonstrated that PTX existed inside the micelles in amorphous or molecular state. In vitro and in vivo tests showed that the PTX-loaded TS-GC micelles had advantages over the Cremophor EL-based formulation in terms of low toxicity level and increased dose, which suggested the potential of the polymer as carriers for PTX to improve their delivery properties.
Assuntos
Quitosana/química , Sistemas de Liberação de Medicamentos , Micelas , Paclitaxel/administração & dosagem , Polímeros/química , Animais , Antineoplásicos/farmacologia , Quitosana/síntese química , Feminino , Glicerol/análogos & derivados , Glicerol/farmacologia , Humanos , Injeções Intravenosas , Células MCF-7 , Masculino , Camundongos , Tamanho da Partícula , Polímeros/síntese química , Espectroscopia de Prótons por Ressonância Magnética , Coelhos , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática , Difração de Raios X , alfa-Tocoferol/análogos & derivados , alfa-Tocoferol/síntese química , alfa-Tocoferol/químicaRESUMO
The present study was conducted to prepare co-surfactant free, olive-oil based alpha tocopherol nanoemulsions, using a food grade non-ionic surfactant. Response surface methodology (RSM) was used to determine the effects of independent variables (ultrasonic homogenization time, olive oil concentrations and surfactant contents) on different physico-chemical characteristics of O/W nanoemulsions. This study was carried out using a central composite design. The coefficients of determination were greater than 0.900 for all response variables and there were significant effects of independent variables on all responses. The optimum levels of independent variables for the preparation of nanoemulsions were 3min. ultrasonic homogenization time, 4% olive oil content and 2.08% surfactant concentration. The physico-chemical responses at these levels were 151.68nm particle size, 7.17% p-anisidine and 88.64% antioxidant activity. These results will help in design of nanoemulsions with optimum independent variables.
Assuntos
Nanotecnologia/métodos , Azeite de Oliva/síntese química , Ondas Ultrassônicas , Água/química , alfa-Tocoferol/síntese química , Emulsões , Azeite de Oliva/metabolismo , Tamanho da Partícula , Tensoativos/síntese química , Tensoativos/metabolismo , Água/metabolismo , alfa-Tocoferol/metabolismoRESUMO
α-tocopherol succinate (α-TOS), γ-tocotrienol (GT3) and δ-tocotrienol (DT3) have drawn large attention due to their efficacy as radioprotective agents. α-TOS has been shown to act superior to α-tocopherol (α-TOH) in mice by reducing lethality following total body irradiation (TBI). Because α-TOS has been shown to act superior to α-tocopherol (α-TOH) in mice by reducing lethality following total body irradiation (TBI), we hypothesized succinate may be contribute to the radioprotection of α-TOS. To study the contributions of succinate and to identify stronger radioprotective agents, we synthesized α-, γ- and δ-TOS. Then, we evaluated their radioprotective effects and researched further mechanism of δ-TOS on hematological recovery post-irradiation. Our results demonstrated that the chemical group of succinate enhanced the effects of α-, γ- and δ-TOS upon radioprotection and granulocyte colony-stimulating factor (G-CSF) induction, and found δ-TOS a higher radioprotective efficacy at a lower dosage. We further found that treatment with δ-TOS ameliorated radiation-induced pancytopenia, augmenting cellular recovery in bone marrow and the colony forming ability of bone marrow cells in sublethal irradiated mice, thus promoting hematopoietic stem and progenitor cell recovery following irradiation exposure. δ-TOS appears to be an attractive radiation countermeasure without known toxicity, but further exploratory efficacy studies are still required.
Assuntos
Radioisótopos de Cobalto/química , Fator Estimulador de Colônias de Granulócitos/farmacologia , Hematopoese/efeitos dos fármacos , Protetores contra Radiação/farmacologia , alfa-Tocoferol/análogos & derivados , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Células da Medula Óssea/efeitos da radiação , Ensaio de Unidades Formadoras de Colônias , Relação Dose-Resposta à Radiação , Hematopoese/efeitos da radiação , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/efeitos da radiação , Masculino , Dose Máxima Tolerável , Camundongos Endogâmicos C57BL , alfa-Tocoferol/síntese química , alfa-Tocoferol/química , alfa-Tocoferol/farmacologiaAssuntos
Antioxidantes/farmacologia , Melaninas/metabolismo , Pigmentação da Pele/efeitos dos fármacos , Pele/efeitos dos fármacos , alfa-Tocoferol/farmacologia , Animais , Antioxidantes/síntese química , Linhagem Celular Tumoral , Ensaios Enzimáticos , Camundongos , Monofenol Mono-Oxigenase/metabolismo , Polietilenoglicóis/química , Pele/metabolismo , alfa-Tocoferol/análogos & derivados , alfa-Tocoferol/síntese químicaRESUMO
α-Tocopheryl succinate (α-TOS) is a well-known mitochondrially targeted anticancer compound, however, it is highly hydrophobic and toxic. In order to improve its activity and reduce its toxicity, new surfactant-free biologically active nanoparticles (NP) were synthesized. A methacrylic derivative of α-TOS (MTOS) was prepared and incorporated in amphiphilic pseudoblock copolymers when copolymerized with N-vinylpyrrolidone (VP) by free radical polymerization (poly(VP-co-MTOS)). The selected poly(VP-co-MTOS) copolymers formed surfactant-free NP by nanoprecipitation with sizes between 96 and 220 nm and narrow size distribution, and the in vitro biological activity was tested. In order to understand the structure-activity relationship three other methacrylic monomers were synthesized and characterized: MVE did not have the succinate group, SPHY did not have the chromanol ring, and MPHY did not have both the succinate group and the chromanol ring. The corresponding families of copolymers (poly(VP-co-MVE), poly(VP-co-SPHY), and poly(VP-co-MPHY)) were synthesized and characterized, and their biological activity was compared to poly(VP-co-MTOS). Both poly(VP-co-MTOS) and poly(VP-co-MVE) presented triple action: reduced cell viability of cancer cells with little or no harm to normal cells (anticancer), reduced viability of proliferating endothelial cells with little or no harm to quiescent endothelial cells (antiangiogenic), and efficiently encapsulated hydrophobic molecules (nanocarrier). The anticancer and antiangiogenic activity of the synthesized copolymers is demonstrated as the active compound (vitamin E or α-tocopheryl succinate) do not need to be cleaved to trigger the biological action targeting ubiquinone binding sites of complex II. Poly(VP-co-SPHY) and poly(VP-co-MPHY) also formed surfactant-free NP that were also endocyted by the assayed cells; however, these NP did not selectively reduce cell viability of cancer cells. Therefore, the chromanol ring of the vitamin E analogues has an important role in the biological activity of the copolymers. Moreover, when succinate moiety is substituted and vitamin E is directly linked to the macromolecular chain through an ester bond, the biological activity is maintained.
Assuntos
Nanopartículas/química , Relação Estrutura-Atividade , Vitamina E/síntese química , alfa-Tocoferol/síntese química , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Células MCF-7 , Metacrilatos/síntese química , Metacrilatos/química , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Polímeros/síntese química , Polímeros/química , Tensoativos/química , Vitamina E/análogos & derivados , Vitamina E/química , Vitamina E/farmacologia , alfa-Tocoferol/análogos & derivados , alfa-Tocoferol/química , alfa-Tocoferol/farmacologiaRESUMO
The vitamin E analogues (2R,4'R,8'R)-nor-α-tocopherol (94 % de) and (2RS,4'R,8'R)-nor-α-tocopherol have been synthesized from (all R)-hexahydrofarnesol and phytol, respectively. According to in vitro experiments with murine macrophages nor-α-tocopherol is an anti-inflammatory compound more potent than α-tocopherol.
Assuntos
Antioxidantes/síntese química , Antioxidantes/farmacologia , alfa-Tocoferol/síntese química , alfa-Tocoferol/farmacologia , Animais , Antioxidantes/química , Linhagem Celular , Citocinas/metabolismo , Inflamação/genética , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Macrófagos/metabolismo , Camundongos , Modelos Moleculares , Conformação Molecular , Óxido Nítrico Sintase Tipo II/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Estereoisomerismo , alfa-Tocoferol/análogos & derivados , alfa-Tocoferol/químicaRESUMO
BACKGROUND/AIMS: Free radicals, in a colon, may damage DNA, make difficult DNA repair and change course of post-translational modifications of regulatory proteins, which promote tumor initiation and progression. Therefore risk of colon cancer is closely related to diet and other lifestyle factors. Dietary antioxidants, such as vitamin E, should reduce the levels of harmful oxidation products. However vitamin E is not soluble in water, which decreases its bioavailability. As O-glycosides of alpha-tocopherol are better soluble in water and penetrate to tissues easier than free alpha-tocopherol, the aim of our work was to investigate the rate of release the free tocopherol from its O-glycosides in colon cancer, in comparison to human healthy colon tissue. METHODOLOGY: The activities of enzymes catalysing hydrolysis of alpha-tocopheryl glucoside (1a) and mannoside (1b) as well as p-nitrophenyl beta-glucoside (2a) and mannoside (2b) in cancer and healthy human colon tissues, were determined according to the modified method described by Zwierz et al. RESULTS: The alpha-tocopherol and p-nitrophenol were significantly better released from the respective glucosides and mannosides in cancer tissue than in "healthy" human colon tissues, with p = 0.000947 for la, p = 0.033024 for 1b; p = 0.0028 for 2a, and p = 0.0033 for 2b, respectively. CONCLUSION: Alpha-tocopherol and p-nitrophenol are released from the O-glycosides of glucose and mannose in significantly higher amount in colon cancer than in healthy tissues. The alpha-tocopherol O-glycosides can be considered as prodrugs in prevention and treatment of the colon cancer.
Assuntos
Antioxidantes/metabolismo , Colo/metabolismo , Neoplasias do Colo/metabolismo , Glicosídeos/metabolismo , alfa-Tocoferol/metabolismo , Antioxidantes/síntese química , Cromatografia Líquida de Alta Pressão , Glicosídeos/síntese química , Humanos , Manosidases/síntese química , Manosidases/metabolismo , Estrutura Molecular , Nitrofenóis/síntese química , Nitrofenóis/metabolismo , alfa-Tocoferol/síntese químicaRESUMO
PURPOSE: Among derivatives of alpha-vitamin E, alpha-vitamin E succinate (VES), has attracted much attention due to its potent anti-prostate cancer activity in vitro and in vivo. However, the in vivo antitumor activity of VES might be compromised if administrated orally due to the VES hydrolysis by esterases in the gastrointestinal tract. EXPERIMENTAL DESIGN: New nonhydrolyzable VES ether analogues were synthesized and their growth inhibition was screened by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide growth assay. Among them, RRR-alpha-tocopheryloxybutyl sulfonic acid (VEBSA) was further characterized by terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling apoptosis assay, soft agar assay, and in vivo tumor formation. RESULTS: VEBSA has potent antitumor ability, albeit to a lesser extent than VES, in in vitro cultured prostate cancer LNCaP and PC3 cells. Like VES, VEBSA induced apoptosis, repressed androgen receptor protein expression, and enhanced vitamin D receptor expression, suggesting that VEBSA can go through mechanisms similar to those used by VES to inhibit the growth of prostate cancer cells in vitro. However, 6 weeks of oral consumption of VEBSA, but not of VES, reduced the tumor burden in the xenografted prostate tumors in nude mice. Furthermore, oral intake of VEBSA for 20 weeks inhibited prostate tumor growth and progression more efficiently compared with VES in the prostate cancer tumor model of TRAMP mice. CONCLUSION: Oral consumption of VEBSA allows a greater anticancer activity compared with VES. Chemoprevention prefers the oral consumption of agents; the advantage of VEBSA over VES to be administrated orally will allow VEBSA to serve as an agent for both preventive and therapeutic purposes for prostate cancer.
Assuntos
Neoplasias da Próstata/tratamento farmacológico , Vitamina E/análogos & derivados , Administração Oral , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Camundongos , Camundongos Nus , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Receptores de Calcitriol/metabolismo , Ácidos Sulfônicos/síntese química , Ácidos Sulfônicos/uso terapêutico , Vitamina E/administração & dosagem , Vitamina E/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , alfa-Tocoferol/análogos & derivados , alfa-Tocoferol/síntese química , alfa-Tocoferol/uso terapêuticoRESUMO
Synthesis, physicochemical, and biological characterization of a series of alpha-tocopherol mimetics with NO-releasing capacity are reported. The selected NO-donor moieties were nitrooxy and furoxan. All products were tested for their in vitro NO-releasing capacities, vasodilating properties and mammal cytotoxic activities. The lipophilic-hydrophilic balance of all products was also evaluated. A new hybrid furoxan, phenol derivative 17, possesses adequate profile of the studied properties.
Assuntos
Antioxidantes/farmacologia , Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico/metabolismo , Oxidiazóis/síntese química , Vasodilatadores/farmacologia , alfa-Tocoferol/síntese química , Animais , Antioxidantes/síntese química , Antioxidantes/química , Aorta Torácica/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Camundongos , Estrutura Molecular , Doadores de Óxido Nítrico/síntese química , Doadores de Óxido Nítrico/química , Oxidiazóis/química , Oxidiazóis/farmacologia , Ratos , Ratos Endogâmicos WKY , Vasodilatação/efeitos dos fármacos , Vasodilatadores/síntese química , Vasodilatadores/química , Difração de Raios X , alfa-Tocoferol/química , alfa-Tocoferol/farmacologiaRESUMO
The synthesis of a series of Tocopherol long chain Fatty Alcohols (TFA) and their biological activities on the modulation of microglial activation are described. Specifically, the 2-(12-hydroxy-dodecyl)-2,5,7,8-tetramethyl-chroman-6-ol, the TFA bearing 12 carbon atoms on the side chain (n=12), shows the most potent inhibition of secretion on nitric oxide (NO) and tumour necrosis factor-alpha (TNF-alpha) by lipopolysaccharide (LPS)-activated microglia.