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Tesi etd-09232013-094759


Thesis type
Tesi di laurea specialistica LC5
Author
BACI, REINHOLD
URN
etd-09232013-094759
Title
Rational design, synthesis and evaluation of heterocyclic derivatives as inhibitors of serine palmitoyltransferase
Struttura
FARMACIA
Corso di studi
CHIMICA E TECNOLOGIA FARMACEUTICHE
Commissione
relatore Dott.ssa Del Carlo, Sara
relatore Dott. Saccomanni, Giuseppe
correlatore Prof.ssa Manera, Clementina
Parole chiave
  • inhibitors
  • SPT
Data inizio appello
09/10/2013;
Consultabilità
completa
Riassunto analitico
Sphingolipid metabolites have crucial roles in cell pathway like apoptosis, proliferation and differentiation. Inhibition of late steps of sphingolipid biosynthesis causes accumulation of intermediate products which are death effectors whereas serine palmitoyltrasferase (SPT) inhibition prevents accumulation of toxic intermediates. <br>Recently different studies have demonstrated that some neurodegenerative disease are caused by alteration of SPT activity. Mutation of the gene encoding for LCB1 subunit causes a shift in the substrate specificity leading to the production of atypical deoxysphingoid bases. These intermediates couldn’t be metabolized and they are accumulated in cells producing neurotoxic effects. Moreover higher levels of de novo synthesized ceramide has been related to photoreceptor death in retinitis pigmentosa and inhibition of SPT causes a reduction of ceramide levels reducing apoptotic events. Moreover inhibition of SPT could be a safe therapeutic strategy to ameliorate the Alzheimer’s disease.3 Thereby inhibitors of SPT could exert neuroprotective activity. <br>Few inhibitors of SPT are known. Several natural products have been identified as potent SPT inhibitors (such as myriocin and cycloserine) but few complete investigations into the exact mechanism of inhibition by each have been undertaken. <br>The only data reported in literature about aromatic SPT inhibitors are represented by a patent of Pfizer. In this patent a lot of compound are reported whose general structure is mainly represented by 2-oxo-imidazole.<br>On the basis of aromatic compound developed in the research lab where I performed my thesis, new aromatic SPT inhibitors has been designed and synthesized in order to obtain SAR information.
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