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Title: A modular approach to sphingolipid analogs mediated by aziridines: Synthesis and biological studies
Author: Alcaide López, Anna
Director: Llebaria Soldevila, Amadeu
Delgado Cirilo, Antonio
Keywords: Síntesi de fàrmacs
Síntesis de fármacos
Drug synthesis
Esfingolípidos (SL)
Issue Date: 18-Dec-2012
Publisher: Universitat de Barcelona
Abstract: [eng] Sphingolipids are essential biomolecules for the physiological cell function. In addition to its structural role in cell membranes, these lipids have also crucial functions in signal transduction and cell regulation. As a consequence of the important biological roles of sphingolipids, the synthesis of their analogs and the development of chemical inhibitors of sphingolipid enzymes are the object of current interest. Furthermore, it has been reported that slight modifications on the natural C1 (phyto)sphingosine scaffold or variations in its chain lengths can potentially alter the role and bioactivity of sphingolipid analogs. On the other hand, cyclitols are an important group of compounds due to their remarkable biological activities as well as their synthetic usefulness in the synthesis of other natural compounds or pharmaceuticals. Specially, the development of carbohydrate mimetics prompted primarily by their properties as glycosidase inhibitors, has led to a wide variety of novel structures by themselves or when considering them as key synthetic precursors of more complex molecules such as glycosphingolipids. For the above‐mentioned reasons, we developed a synthetic methodology towards sphingolipid analogs based on the regioselective ring‐opening reactions of N‐acylaziridines with different nucleophiles such as thiols or beta‐glycosil thiols, amines, phosphate derivatives or phosphorothioate derivatives. This approach is a short and flexible route for the synthesis of a variety of (phyto)sphingolipid analogs from aziridine derivatives and this method leads to molecules with different groups bonded to the C‐1 position of the sphingoid backbone from common intermediate aziridines by changing the nucleophile in the ring‐opening reaction step. Moreover, the diversity of compounds obtained is extended by introducing different N‐acyl groups at the nitrogen aziridine. Once, the desired sphingolipid analogs were obtained, a representative selection of them was tested in enzyme assays to identify inhibitors of mammalian sphingolipid metabolism enzymes, such as sphingomyelin synthase (SMS) and glucosylceramide synthase (GCS). Some of the tested analogs were potent inhibitors of GCS and none of them inhibited SMS at concentrations relevant for activity. In general, the inhibitory activity was higher for phytosphingosine analogs than their corresponding sphingosine analogs and the presence of the double bond between C4 and C5 of the sphingosine backbone in analogs was important for their bioactivity, since the dihydroceramide analogs were less active. In addition, a collection of (phyto)sphingolipid analogs were tested in an assay to identify inhibitors against yeast inositol phosphorylceramide synthase (IPCS). Generally, the inhibitory activities were lower than the inhibitions against GCS. However, one analog depicted selectivity against baker’s yeast IPCS since no inhibition of mammalian SMS and GCS was observed. For that reason, this analog showed potential properties as antifungal agent. Some (phyto)sphingolipid analogs were also tested as antigens for CD1d‐restricted iNKT cells and some of them were active, although this activity was lower when comparing with the endogenous glycolipid beta‐glucosylceramide. In particular, the most active compound was a nonglycosidic phytoceramide analog, but some glycosphingolipid analogs were also active in the activation of iNKT cells. However, these compounds were considered weak antigens. Finally, in order to obtain glycolipid analogs a synthetic methodology to obtain enantio‐ and diastereomerically pure galacto‐configured aziridines based on olefin aziridination reactions was examined. This consists in the use of nitrene precursors and a galactose related cyclohexene. The results obtained with this method showed potential for the preparation of the aziridine compounds.
[spa] Los esfingolípidos (SL) son biomoléculas esenciales para las funciones fisiológicas de las células. El metabolismo anómalo o la expresión de SL específicos o glicoesfingolípidos (GSL) es el origen de diferentes enfermedades como las esfingolipidosis, causadas por la presencia de mutaciones en las enzimas que intervienen en la biosíntesis de SL o GSL. Debido a la importancia biológica de los SL, el desarrollo de inhibidores químicos de las enzimas que intervienen en el metabolismo de los SL de mamíferos y hongos, es un tema de gran interés científico. Por otro lado, cabe remarcar que los ciclitoles son un tipo de compuestos muy interesantes debido a su remarcable actividad biológica y a su utilidad como precursores sintéticos de moléculas más complejas como los GSL. Teniendo en cuenta las consideraciones comentadas anteriormente, se ha desarrollado una nueva metodología sintética para la obtención de análogos de SLs basada en las reacciones de apertura de Nacilaziridinas con diferentes nucleófilos como tioles, beta‐glicosil tioles, aminas, fosfatos y fosforotioatos. Esta aproximación es una ruta corta y flexible para la obtención de análogos lipídicos con diversidad estructural. Una selección representativa de los compuestos sintetizados se ensayó frente a la inhibición de enzimas del metabolismo de los mamíferos tales como la esfingomielin sintasa (SMS) y la glucosilceramida sintasa (GCS), y enzimas del metabolismo de los hongos como la inositol fosforilceramida sintasa (IPCS). Algunos de estos análogos resultaron ser inhibidores potentes de la GCS pero ninguno de ellos fue inhibidor de la SMS. Mientras que la inhibición frente a la IPCS en levaduras fue más baja en comparación con la inhibición de la GCS. A pesar de ello, uno de los análogos ensayados mostró selectividad frente a la IPCS ya que no se observó inhibición de la SMS y la GCS de mamíferos, mostrando así propiedades interesantes como agente antifúngico. De manera adicional, algunos análogos de (fito)esfingolípidos fueron ensayados como antígenos de células iNKT restringidas por la proteína CD1d y resultaron activos. Curiosamente, el compuesto más activo resultó ser un análogo de fitoceramida no glicosídico, aunque otros GSL también resultaron activos. Por otro lado, se desarrolló una metodología sintética para obtener aziridinas con configuración galacto (análogos de galactosa) enantiomericamente y diastereomericamente puras para obtener análogos de glicolípidos.
Note: El text dels capítols 3, 5, 6 i 7 ha estat retirat seguint instruccions de l’autora de la tesi, en existir participació d’empreses, existir conveni de confidencialitat o existeix la possibilitat de generar patents / El texto delos capítulos 3,5, 6 y 7 ha sido retirado siguiendo instrucciones de la autora, al existir participación de empresas, convenio de confidencialidad o la posibilidad de generar patentes / The text of chapters 3, 5, 6 and 7 has been withdrawn on the instructions of the author, as there is participation of undertakings, confidentiality agreement or the ability to generate patent
Appears in Collections:Tesis Doctorals - Departament - Farmacologia i Química Terapèutica

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