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1.
Inorg Chem ; 56(16): 10013-10020, 2017 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-28767237

RESUMO

A polystyrene-supported molybdenum peroxo material [Mo-Y(s)] was applied toward the oxidative degradation of the organophosphate neurotoxin O,S-diethylphenyl phosphonothioate (1) through ethanolysis. In addition to the operational advantages of the heterogeneous reactivity, oxidative ethanolysis with a 10-fold excess of hydrogen peroxide yields only P-S bond scission to produce diethylphenyl phosphonate and ethyl sulfate. This is the first report of a molybdenum solid support that promotes the degradation of sulfur-containing organophosphate with the turnover benefits of heterogeneous catalysis. The activation parameters of 1 ethanolysis by Mo-Y(s) (Ea = 57 ± 6 kJ/mol and ΔS⧧ = -124 ± 21 J/mol·K) and by the model compound oxodiperoxo(pyridine-2-carboxylato)molybdate(VI) bis(pyridine-2-carboxylic acid) monohydrate (3; Ea = 55 ± 5 kJ/mol and ΔS⧧ = -154 ± 15 J/mol·K) are almost identical for the oxidation of thioanisole by 3. This suggests that the rate-determining step for 1 ethanolysis is sulfur oxidation to form an intermediate phosphonothioate S-oxide, which subsequently undergoes nucleophilic attack by the ethanol solvent to form diethylphenyl phosphonate and ethyl sulfate. Evidence for the formation of this S-oxide intermediate and the postulated ethanolysis mechanism is provided.


Assuntos
Complexos de Coordenação/química , Etanol/química , Molibdênio/química , Neurotoxinas/química , Organotiofosfonatos/química , Catálise , Peróxido de Hidrogênio/química , Modelos Químicos , Oxirredução , Polímeros/química
2.
J Cell Mol Med ; 21(10): 2441-2451, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28387464

RESUMO

Hydrogen sulphide (H2 S) serves as a vital gastric mucosal defence under acid condition. Non-steroidal anti-inflammatory drugs (NSAIDs) are among widely prescribed medications with effects of antipyresis, analgesia and anti-inflammation. However, their inappropriate use causes gastric lesions and endogenous H2 S deficiency. In this work, we reported the roles of a novel pH-controlled H2 S donor (JK-1) in NSAID-related gastric lesions. We found that JK-1 could release H2 S under mild acidic pH and increase solution pH value. Intragastrical administration of aspirin (ASP), one of NSAIDs, to mice elicited significant gastric lesions, evidenced by mucosal festering and bleeding. It also led to infiltration of inflammatory cells and resultant releases of IL-6 and TNF-α, as well as oxidative injury including myeloperoxidase (MPO) induction and GSH depletion. In addition, the ASP administration statistically inhibited H2 S generation in gastric mucosa, while up-regulated cyclooxygenase (COX)-2 and cystathionine gamma lyase (CSE) expression. Importantly, these adverse effects of ASP were prevented by the intragastrical pre-administration of JK-1. However, JK-1 alone did not markedly alter the property of mouse stomachs. Furthermore, in vitro cellular experiments showed the exposure of gastric mucosal epithelial (GES-1) cells to HClO, imitating MPO-driven oxidative injury, decreased cell viability, increased apoptotic rate and damaged mitochondrial membrane potential, which were reversed by pre-treatment with JK-1. In conclusion, JK-1 was proved to be an acid-sensitive H2 S donor and could attenuate ASP-related gastric lesions through reconstruction of endogenous gastric defence. This work indicates the possible treatment of adverse effects of NSAIDs with pH-controlled H2 S donors in the future.


Assuntos
Aspirina/toxicidade , Mucosa Gástrica/efeitos dos fármacos , Sulfeto de Hidrogênio/metabolismo , Organotiofosfonatos/farmacologia , Substâncias Protetoras/farmacologia , Animais , Anti-Inflamatórios não Esteroides/toxicidade , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Cistationina gama-Liase/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Humanos , Concentração de Íons de Hidrogênio , Interleucina-6/metabolismo , Masculino , Camundongos , Estrutura Molecular , Organotiofosfonatos/química , Organotiofosfonatos/metabolismo , Substâncias Protetoras/química , Substâncias Protetoras/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
3.
Environ Toxicol Pharmacol ; 47: 62-78, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27636985

RESUMO

In this paper, the carcinogenic potential and mammalian toxicity on rodents, based on the quantitative relationship models between structure and biological activity (QSAR), were evaluated. The carcinogenicity and acute toxicity were evaluated by docking molecular physicochemical descriptors, on a series of 33 thiophosphonates. These properties, mainly hydrophobicity, electronic distribution, hydrogen bonding characteristics, molecule size and flexibility, and the presence of various pharmacophoric features, influence the behavior of molecule in a living organism, including bioavailability, transport properties, affinity to proteins, reactivity, toxicity, metabolic stability and many others. The model was validated using linear regression methods: principal component analysis (PCA), partial least squares (PLS) and multiple linear regression (MLR); non-linear regression methods: cluster analysis (CA) and discriminant analysis (DA); and neural network analysis: probabilistic neural network (PNN), identifying the best predictor.


Assuntos
Carcinógenos/toxicidade , Organotiofosfonatos/toxicidade , Praguicidas/toxicidade , Relação Quantitativa Estrutura-Atividade , Animais , Teorema de Bayes , Carcinógenos/química , Análise por Conglomerados , Análise Discriminante , Mamíferos , Simulação de Acoplamento Molecular , Organotiofosfonatos/química , PPAR alfa , Praguicidas/química , Reprodutibilidade dos Testes , Roedores
4.
Chirality ; 26(10): 614-9, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24706407

RESUMO

An improved method, which is highly reproducible, was developed for the enantioseparation of racemic O-ethyl phenylphosphonothioic acid (1a) with brucine by introducing seeding to a supersaturated solution of the diastereomeric salt mixture. The present method gave both diastereomeric salts in high yields with a diastereomeric ratio of >99.5:0.5 upon choosing the crystallization solvent (MeOH for the (R)-1a salt and MeOH/H2 O for the (S)-1a salt). The enantiopure acid showed a good chirality recognition ability for not only strong bases, such as amines and amino alcohols, but also weakly basic alcohols and was applicable as a solvating agent to the (1) H NMR determination of the enantiomeric excess of chiral amines, amino alcohols, and alcohols, including aliphatic substrates.


Assuntos
Fracionamento Químico/métodos , Organotiofosfonatos/química , Organotiofosfonatos/isolamento & purificação , Solventes/química , Estereoisomerismo
5.
Eur J Med Chem ; 63: 869-81, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23603046

RESUMO

9-[2-(Thiophosphonomethoxy)ethyl]adenine [S-PMEA, 8] and (R)-9-[2-(Thiophosphonomethoxy)propyl]adenine [S-PMPA, 9] are acyclic nucleoside thiophosphonates we described recently that display the same antiviral spectrum (DNA viruses) as approved and potent phosphonates PMEA and (R)-PMPA. Here, we describe the synthesis, antiviral activities in infected cell cultures and decomposition study of bis(pivaloyloxymethoxy)-S-PMEA [Bis-POM-S-PMEA, 13] and bis(isopropyloxymethylcarbonyl)-S-PMPA [Bis-POC-S-PMPA, 14] as orally bioavailable prodrugs of the S-PMEA 8 and S-PMPA 9, in comparison to the equivalent "non-thio" derivatives [Bis-POM-PMEA, 11] and [Bis-POC-PMPA, 12]. Compounds 11, 12, 13 and 14 were evaluated for their in vitro antiviral activity against HIV-1-, HIV-2-, HBV- and a broad panel of DNA viruses, and found to exhibit moderate to potent antiviral activity. In order to determine the decomposition pathway of the prodrugs 11, 12, 13 and 14 into parent compounds PMEA, PMPA, 8 and 9, kinetic data and decomposition pathways in several media are presented. As expected, bis-POM-S-PMEA 13 and bis-POC-S-PMPA 14 behaved as prodrugs of S-PMEA 8 and S-PMPA 9. However, thiophosphonates 8 and 9 were released very smoothly in cell extracts, in contrast to the release of PMEA and PMPA from "non-thio" prodrugs 11 and 12.


Assuntos
Antivirais/farmacologia , Organofosfonatos/farmacologia , Organotiofosfonatos/farmacologia , Pró-Fármacos/farmacologia , Antivirais/síntese química , Antivirais/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Vírus de DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ésteres/síntese química , Ésteres/química , Ésteres/farmacologia , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Vírus da Hepatite B/efeitos dos fármacos , Humanos , Modelos Químicos , Estrutura Molecular , Nucleosídeos/química , Organofosfonatos/síntese química , Organofosfonatos/química , Organotiofosfonatos/síntese química , Organotiofosfonatos/química , Pró-Fármacos/síntese química , Pró-Fármacos/química
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