Tesi di dottorato di ricerca
Design, synthesis and functional evaluation of novel heterocyclic compounds as drug candidates for the treatment of solid tumors
Settore scientifico disciplinare
Corso di studi
SCIENZA DEL FARMACO E DELLE SOSTANZE BIOATTIVE
tutor Prof.ssa La Motta, Concettina
- solid tumors
- heterocyclic compounds
- drug candidates
Data inizio appello
Data di rilascio
In my doctoral work, I have been concerned to identify new targets involved in solid tumors. That because, all solid tumors represent more than 50% of causes of death. There are several therapeutic approaches for the treatment of these tumors, chemotherapy has identified a number of targets you can hit to fight.<br>In this thesis I show the use of small molecule as inhibitor of 3 different target for the therapy of solid tumor.<br>1. Inhibition of Protein kinases interested in the growth and tumor vascularization (EGFR and VGFR).<br>2. Three novel series of 1,2-benzisothiazole derivatives have been developed as inhibitors of carbonic anhydrase isoform IX to attack the hypoxic part of the solid tumor.<br>3. Finally, a new frontier are stem cells; glioma stem-like cells (GSC) with tumor initiating activity the cellular hierarchy in glioblastoma (GBM) and engender therapeutic resistance. In this work, I show that the FOXD1-ALDH1A3 signaling axis as a determinant of the GSC. Mechanistically, FOXD1 regulates the transcriptional activity of ALDH1A3, an established functional marker for GSC. In clinical specimens of high-grade glioma, the levels of expression of both FOXD1 and ALDH1A3 are inversely correlated with patient prognosis. A novel small molecule inhibitor of ALDH we developed, termed GA11, displays potent in vivo efficacy. Later, starting from GA11, I synthetized the series of compounds to make a structure activity relationship.
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