Aproximacions a la síntesi de 2"-fluoro, 2--metilencarboxilat i/o 3", 4"-dimetilencarboxilat anàlegs de l'Adenofostina A.
inositol Triphosphate is a second messenger that releases calcium stored in the endoplasmatic reticulum, providing several cell responses depending on the cell where the process is done. Adenophostin A and B are two potent glyconucleotides triphosphate that were isolated from a penicillium brevicomp...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2007 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/9015 |
| Acceso en línea: | http://www.tdx.cat/TDX-0612107-112357 http://hdl.handle.net/10803/9015 |
| Access Level: | acceso abierto |
| Palabra clave: | Productes naturals Carbohidrats Nucleòsids Fluoro-carbohidrats Síntesi Adenofostina 54 547 |
| Sumario: | inositol Triphosphate is a second messenger that releases calcium stored in the endoplasmatic reticulum, providing several cell responses depending on the cell where the process is done. Adenophostin A and B are two potent glyconucleotides triphosphate that were isolated from a penicillium brevicompactum culture in 1993. They are the powerful agonist described up to now for the IP3 receptor, with affinities 10-100 higher than IP3.<br/>The replacement of a phosphate group by an isoster methylencarboxilate group in biological active molecules doesn't altered the recognition of their specific receptors, being more stable to the phosphatases hydrolisis. On the other hand, the introduction of a fluorine atom in a biological active molecule involves a significant change in their activity, enhancing the stability of the nearby positions of the molecule at the same time.<br/>This thesis is the beginning of a wide investigation project where the target is synthesize different analogues of Adenophostin A. In these analogues phosphate groups have been replaced systematically by isoster methylencarboxilate groups. On the other hand, another analogue with a fluorine atom in the 2" position would be synthesized in order to determine the function of the replaced essential hydroxil group and, at the same time, enhance the neighbour glycosidic bond. <br/>First of all, we have done three different synthesis towards the glucose 3,4-dialquilated derivative. <br/>We obtain the adenosine 2'-allyl derivative in six synthetic stages. After doing a study of the glycosidic reaction with three different glycosil donors (glucose fluoride, phosphite and tricloroacethimidate derivatives), we found that the best result was with the glycosil tricloroacethimidate with tert-buthyldimethylsilil as activator. <br/>The yield of this reaction weren't brilliant, so we decide to investigate a second synthetic way, where the functionalities of the target molecule were included in the glycosil donor and acceptor before the glycosilation reaction. Firstly, the glucopyranoside with two phosphate groups in the positions 3 and 4 was synthesized, being this a new interesting way to obtain adenophostin derivatives. But it was not possible to obtain the 2'-methylencarboxilate derivative of adenosine because of an unexpected lactonization. <br/>The Selectfluor treatment of different protected glycals lead to four glycosil 2-deoxy-2-fluoro-glucopyranoside donors with estereoselectivity and yields good. The glycosilation reaction was performed with a protected adenosine derivative as glycosil acceptor, which had been synthesized before. The best result was obtained with glycosil bromide and silver triflate and silver carbonate activation system. Subsequent deprotection steps led us to a very close synthetic precursor of the target molecule. <br/>This work has opened the synthetic route to the different target molecules and, nowadays, there is another doctoral thesis which is developing this project in the laboratory. |
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