Síntesis danàlegs de BEL i de substrat com a nous potencials inhibidors de la fosfolipasa independent de calci(grup VIA)
SUMMARY: In last decades, researchers have demonstrated that lipids are not only structural compounds of cellular membranes. These compounds have several functions in cell metabolism, specifically, phospholipids are cleaved by phospholipases, and their metabolites are secondary messengers in inflammation pathways. Moreover calcium-independent phospholipase A2 (iPLA2) might be linked to schizophrenia. Synthesis of new inhibitors of this enzyme has been the main aim of this work. In our group we have designed different analogues of the only inhibitor of this enzyme (BEL). We introduced several modifications and functional groups, like trifluoroketones, in BELs structure. Unfortunately, any of these compounds could not inhibit the activity of the enzyme. Some compounds that have an ariloxigroup in alpha position of ketone increase activity of iPLA2 and not produce the same effect in cPLA2. Then, we have synthesized analogues of the natural substrate of phospholipases with several modifications; thioether group in sn-1 position, phosphorilcholine group in sn-3 position and different functional groups (amide, carbamate, sulfonamide) in sn-2 position. Some of these compounds show inhibition of iPLA2, moreover, they also inhibit cPLA2. To know more information about catalytic mechanism of this phospholipase and design new inhibitors we have cloned and expressed two fragments of catalytic site of the enzyme. However these proteins are not soluble and its levels of expression were very small, and we could not do structural studies like X-ray crystallization. Furthermore, we have designed and synthesized analogues of ceramide. Biological assays of these compounds in several enzymes of sphingolipid metabolism proved that this family opens a new research line in sphingolipid field.
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Advisor:Montaña Pedrero, Ángel; Llebaria Soldevila, Amadeu
School:Universitat de Barcelona
Source Type:Master's Thesis
Date of Publication:12/21/2006