Full text
| |
| Author(s): |
Tatiana Cristina de Oliveira Mac Leod
Total Authors: 1
|
| Document type: | Doctoral Thesis |
| Press: | Ribeirão Preto. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (PCARP/BC) |
| Defense date: | 2008-07-01 |
| Examining board members: |
Marilda das Dores de Assis;
Gianluca Camillo Azzellini;
Ieda Lucia Viana Rosa;
Marco Antônio Schiavon;
Ademar Alves da Silva Filho
|
| Advisor: | Marilda das Dores de Assis; Maria Eugenia Queiroz Nassur |
| Abstract | |
In this work, the catalytic activities of metalloporphyrins and the salen complex (Jacobsen catalyst) in solution and immobilized on different supports were studied in the oxidation of hydrocarbons, anticonvulsivant drugs (carbamazepine and primidone) and antidepressives (fluoxetine) by the following oxygen donors: hydrogen peroxide, terc-butyl hydroperoxide (t-BOOH), 3-chloroperoxybenzoic acid (m-CPBA), and iodosylbenzene (PhIO). The catalysts containing the salen complex immobilized on alumina, chitosan membranes and poly(dimethylsiloxane)/polyvinyl acetate membranes (PDMS/PVA) were prepared and characterized by UV-Vis spectroscopy, thermogravimetric analysis, differential thermal analysis, differential scanning calorimetry, infrared spectroscopy, scanning electron microscopy, X-ray diffraction, and surface area analysis. The activity of these materials was initially investigated in the oxidative catalysis of hydrocarbons (cyclooctene, styrene and cyclohexane). These heterogeneous systems were efficient for the oxidation of these substrates, with yields as high as 79 % for cyclooctene oxide. The selectivity for epoxide or ketone formation was high when the substrate alkenes or cyclohexane were used, respectively. The chitosan membranes and hybrid membranes PDMS/PVA were available in a triphasic system, where the membrane was located in the interface between the apolar phase (organic substrate) and the aqueous phase (containing the oxidant). The catalytic results were excellent, with turnover frequencies of 138 h-1. Drug oxidation (carbamazepine, primidone and fluoxetine) products were analyzed by High Performance Liquid Chromatography (HPLC-UV) in reverse phase, liquid chromatography coupled to mass spectrometry (LC-ESI), and gas chromatography coupled to mass spectrometry (GC-MS), for products identification. In the case of carbamazepine (CBZ) oxidation only carbamazepine 10,11- epoxide (CBZ-EP) was produced. This is to the main metabolite obtained in carbamazepine metabolism by P450 in vivo, indicating that the catalytic systems employed here are excellent biomimetic models of this enzyme. Formation of CBZEP is highly dependent on the oxidant and pH, especially in the reaction with hydrogen peroxide, resulting in homolytic and/or heterolytic cleavage, according to the pH of the reaction medium. The oxidants m-CPBA and t-BOOH showed that the presence of substituents linked to the -OOH group of the peroxide affects the catalytic activity of the studied system significantly. As for primidone oxidation, two metabolites found in the in vivo system were obtained: phenylethylmalondiamide and phenobarbital, besides three other products (2-phenylbutyramide, g-phenyl-g-butyrolactone and, a product in trace amounts, not identified). The formation of these compounds was highly dependent on the oxidant, co-catalyst, pH and presence of oxygen. These results enabled the proposition of a scheme for Mn(salen)-catalyzed primidone oxidation and the possible intermediate involved. All the studied catalytic systems used in fluoxetine oxidation generated the product obtained via the O-dealkylation mechanism, p-trifluoromethylphenol (TFMF). Norfluoxetine, the main metabolite in vivo and formed via the N-demethylation mechanism, was not obtained. This indicates that the O-dealkylation mechanism prevails and, therefore, the catalysts do not follow the biomimetical route in the case of this drug. This work demonstrated the ability of the salen complex and metalloporphyrins to mimic the action of cytochrome P450 in drug oxidation. These results showed the potential application of these biomimetic models in the synthesis of drug metabolites, which should provide samples for pharmacological and toxicological tests, as well as aid studies that pursue the elucidation of in vivo drug metabolism, being an alternative to enzymatic studies. (AU) | |