Design, synthesis and functional evaluation of novel heterocyclic compounds as drug candidates for the treatment of solid tumors

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. In this thesis I show the use of small molecule as inhibitor of 3 different target for the therapy of solid tumor. 1. Inhibition of Protein kinases interested in the growth and tumor vascularization (EGFR and VGFR). 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. 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.