Navegando por Palavras-chave "S-nitrosotióis"

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    Assessment of ocular surface toxicity after topical instillation of nitric oxide donors
    (Conselho Brasileiro de Oftalmologia, 2013-02-01) Cariello, Angelino Julio [UNIFESP]; Souza, Gabriela Freitas Pereira de; Lowen, Marcia Serva [UNIFESP]; Oliveira, Marcelo Ganzarolli de; Hofling-Lima, Ana Luisa [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Universidade Estadual de Campinas (UNICAMP)
    PURPOSE: To evaluate the ocular surface toxicity of two nitric oxide donors in ex vivo and in vivo animal models: S-nitrosoglutathione (GSNO) and S-nitroso-N-acetylcysteine (SNAC) in a hydroxypropyl methylcellulose (HPMC) matrix at final concentrations 1.0 and 10.0 mM. METHODS: Ex vivo GSNO and SNAC toxicities were clinically and histologically analyzed using freshly excised pig eyeballs. In vivo experiments were performed with 20 albino rabbits which were randomized into 4 groups (5 animals each): Groups 1 and 2 received instillations of 150 µL of aqueous HPMC solution containing GSNO 1.0 and 10.0 mM, respectively, in one of the eyes; Groups 3 and 4 received instillations of 150 µL of aqueous HPMC solution-containing SNAC 1.0 and 10.0 mM, respectively, in one of the eyes. The contralateral eyes in each group received aqueous HPMC as a control. All animals underwent clinical evaluation on a slit lamp and the eyes were scored according to a modified Draize eye test and were histologically analyzed. RESULTS: Pig eyeballs showed no signs of perforation, erosion, corneal opacity or other gross damage. These findings were confirmed by histological analysis. There was no difference between control and treated rabbit eyes according to the Draize eye test score in all groups (p>0.05). All formulations showed a mean score under 1 and were classified as non-irritating. There was no evidence of tissue toxicity in the histological analysis in all animals. CONCLUSION: Aqueous HPMC solutions containing GSNO and SNAC at concentrations up to 10.0 mM do not induce ocular irritation.
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    Nanopartículas poliméricas doadoras de óxido nítrico para aplicações tópicas
    (Universidade Federal de São Paulo, 2017-03-31) Pelegrino, Milena Trevisan [UNIFESP]; Seabra, Amedea Barozzi [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    Nitric oxide (NO) is a lipophilic uncharged free radical with small size. These features, help NO to diffuse in biological medium by crossing physiological barriers and communicating with cells. NO is involved in several important physiological processes in mammal cells, such as, vasodilation, macrophage toxicity, antitumoral activity and wound healing. In plant cells, NO is involved in seed germination, resistance to abiotic and biotic stress and leaf senescence. In biological medium, NO has a half-life of 1-5 s, then, therapeutical application of NO requires molecules capable of increasing its half-life. The S-nitrosothiols (RSNOs) are a class of NO donors formed by the nitrosation of thiol-containing molecules. In addition, the RSNOs are spontaneously decomposed and release the NO, what increases the NO half-life. There is a great interest in developing materials capable of carry and release the NO to apply in biomedical and agricultural fields. The nanotechnology and RSNOs combined are a strategy to delivery NO and achieve its therapeutical application. In this study, chitosan nanoparticles (CS NPs) and hidrogel of Pluronic F-127 (PL) containing RSNOs were synthesized and characterized to evaluated their potential in biomedical and agricultural applications. The CS NPs were synthesized through ionotropic gelation using sodium tripolyphosphate (TPP) as counter-ion, thus, the chitosan nanoparticles (CS NPs) obtained has size of ca. 100.0 ± 0.2 nm, measured by dynamic and static light scattering (DLS and SLS). The CS NPs has positive zeta potential of +19.6 ± 0.5 mV, moderate polydispersity of 0.27 ± 0.03, and the CS NPs also incorporated with high efficiency (greater than 98%) the RSNOs, S-nitroso-mercaptosuccinic acid (S-nitroso-MSA) and S-nitrosoglutathione (GSNO). Sequentially, the CS NPs were incorporated into PL hydrogel, in order to formulate a semisolid material in physiological temperature which is desired for a topical application. In addition, ex vivo experiments showed that NO released from CS NPs can permeate the human skin and increase the NO stores in epidermis. Regarding the safety of the CS NPs, cytotoxicity essays were performed. The CS NPs do not cause significant toxicity to healthy cell line (Melan-A) and, in contrast the CS NPs cause toxicity in tumoral cell lines (B16F10, K562, HepG2, Lucena-1). The application of NO donors in corn plants (Zea Mays) and sugarcane (Saccharum spp) helped to mitigate the abiotic stress effects of high salinity and NO donors encapsulated in CS NPs have shown more pronounced effects and a sustainable NO release in vivo. Taken all together, the CS NPs are an interesting vehicle for biomedical and agriculture applications, highlighting dermatological usage and resistance against abiotic stress.
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    Síntese e estudo conformacional de algumas arilamidas derivadas de ésteres de l-cisteína, potenciais inibidores de HIV-1 protease
    (Universidade Federal de São Paulo, 2016-08-31) Espirito Santo, Stephanie Amarillis do [UNIFESP]; Reis, Adriana Karla Cardoso Amorim [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    AIDS is a disease that challenges public health on a global scale and which results in major problems due to its side effects, once patients submitted to antiretroviral therapies are bound to develop hypertension. In this context, this project aimed to synthesize new arylamides with structural similarity to the commercial antiretroviral Nelfinavir, which in further S-nitrosylation reaction studies, has potential to provide dual inhibition to HIV-1-PR and renin, vital compounds to the evolution of AIDS andhypertensionrespectively. The arylamides of interest were prepared by the coupling of substituted benzoic acids and L-cysteine derivatives via the coupling reagents DCC and COMU underclassical methods and assisted by microwaves, aiming the analysis of the reaction energy efficiency, in two different solvents (dichloromethane and dimethylcarbonate), in order to evaluate the replacement of a polluting solvent by a green one. The results of the coupling reactions showed that the solvent dichloromethane and the classical method proved to be efficient in termsof yield, although the solvent dimethylcarbonate and the methodology assisted by microwaves showed to have competitive performance and in fact might be used as a potential alternative route due to its environmentally friendly approach (green solvent and energy efficiency).Finally, it can be concluded that both coupling reagents COMU and DCC had similar average yield sand the arylamides of interest could be prepared efficiently by both reagents, either in dichloromethane or in dimethylcarbonate, usingirradiation and even classical methodologies. The theoretical calculations performed for the arylamides under study showed two stableand low-energy conformations, regardless ofthesubstituent, being the gauche conformation the most stable and with a contribution of population of approximately 60%, and the cis coformation with a populationof 40 %. The forces responsible for the stability of the gauche conformation are the electronic interactions which provides stability through intramolecular hydrogenbonds, and the Repulsive Field Effect which contributes to the hyperconjugative interactions between the p anti bonding orbital of the C = O Bond and the s bonding orbital of the C-Y bond.
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    Síntese e estudo da estabilidade conformacional de S-nitrosotiós derivados de AINEs (anti-inflamatórios não esteróidais)
    (Universidade Federal de São Paulo, 2014-09-30) Reginato, Marcelo Mota [UNIFESP]; Reis, Adriana Karla Cardoso Amorim [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    We synthesized and carried out a conformational study of the S-nitrosothiols 2-methyl-2-(nitrososulfanyl) propyl-phenylacetate-para-substituted 9R1, derivative of propanoic 2-(4-isobutylphenyl) acid (Ibuprofen) 9R2 and 2-methyl-2-(nitrososulfanyl) propyl 2-(4-isobutylphenyl) propanoate (Naproxen) 9R3 (S-Nitrosothiols 9R1, 9R2, and 9R3): Two synthetic routes have been proposed for the synthesis of S-Nitrosothiols 9R1, 9R2, and 9R3. In Route A we used brominated intermediates and dicyclohexylcarbodiimide (DCC) as coupling reagent for esterification. In Route B the esterification with an acyl chloride is the last step in the synthetic route. Both routes resulted in good yields of the final product (~ 50%), although only Route B led to the formation of the compounds of interest. S-Nitrosothiols 9R1, 9R2, and 9R3, together with their brominated intermediates were submitted to infrared spectroscopic analysis in solvents of low dielectric constant (CCl4, CH3Cl and CH3CN). For brominated intermediates we observed the presence of two bands in the carbonyl stretch region of the group indicating the existence of two conformations. S-Nitrosothiols 9R1, 9R2, and 9R3 showed only one band in the same region in most cases. We carried out the conformational search for the compounds under study and stable conformations geometries were theoretically optimized, B3LYP DFT / G 6311 + (2df, 2p). Results obtained in the infrared analysis were confronted with the theoretical data showing good agreement with experimental results in CCl4 for isolated molecules. Calculations made using the solvent effect by the method PCM do not indicate agreement with experimental data. The lowest energy conformations of S-Nitrosothiols 9R1, 9R2, and 9R3 and brominated intermediates are mainly stabilized by intra-molecular hydrogen bonds that promote greater stability of conformers. The geometrical analysis of the R-SNO group shows that these compounds are more stable in the trans conformation. Calculations of orbital interactions for the brominated intermediates using the method of Natural Bond Orbital (NBO) showed no electronic interactions capable of stabilizing their conformations. The NBO based calculations for the S-Nitrosothiols 9R1, 9R2, and 9R3 show that their conformers are stabilized by the following interactions: n_(O(OR)) 〖→ σ〗_(C-C(CO))^*, n_(O(OR))→σ_((CO))^*, n_(O(CO))→σ_((CO))^*, n_(O(CO))→〖 π〗_(C14-O15)^*, n_S→π_((NO))^*, e n_(O(NO))→σ_((S-N))^*. NBO results showed that the hyper-conjugative interaction n_(O(NO))→σ_((S-N))^* is very effective, weakening the σ bond resulting in increasing length of the S-N bond in R-SNO. The strong delocalization n_S→π_((NO))^*induces partial π character to the S-N bond. The weak link σ S-N indicates a strong delocalization of the electron pair of O(NO) due to interaction n_(O(NO))→σ_((S-N))^* . This interaction is responsible for the elongation of the S-N bond which increases the ability of the compound in releasing nitric oxide. The molecular mechanism of esterification using DCC was investigated by using electronic structure calculations on DFT-B3LYP / 6 311 + G (2df, 2p) level. We described two pathways for the esterification reaction: (i) concerted model (one step leads to the formation of products) and (ii) non-coordinated model (two steps followed by a [1-3] proton migration leads to the formation of products). Results were discussed in terms of energy, electronic parameters and calculated geometries of reactants under study (carboxylic acid, alcohol and DCC) and the reaction product (ester). The activation energy for the concerted model was lower (G‡ 27.8 kcal.mol-1) than for the non-coordinated model (G‡ 48.9 kcal.mol-1). This step was considered as a determinant of the reaction.