Dottorato in MOLECULAR DESIGN AND CHARACTERIZATION FOR THE
PROMOTION OF HEALTH AND WELL-BEING: FROM DRUG TO FOOD

Titolo della tesi: New Heterocycles as Anticancer and Anti-Infective Agents

During my three-year Ph.D. program, I contributed to multiple research projects, primarily focusing on designing and developing new compounds that target the Wnt/β-catenin signalling pathway for cancer therapy, as well as candidates active against Staphylococcus aureus for treating infectious diseases. The broader project focused on developing new chemotherapy agents that target the Wnt/β-catenin signalling pathway. My research group has extensive experience in this area, and in previous work, we successfully replaced the ester group in benzenesulfonamide derivatives with a five- or six-membered heterocyclic ring. The resulting compounds were more effective than the reference molecules, both in reducing luciferase activity and in demonstrating antitumor effects. One of these derivatives was found to interact with a previously unreported binding site, co-crystallized within the hotspot region near Lys508 of the β-catenin armadillo repeat domain. To further explore this site, we synthesized new sulfonamides, thereby expanding a promising new class of β-catenin inhibitors for potential anticancer applications. During my visiting PhD period at the University of California, San Diego, my research focused on the development of new isoxazoles that stabilize β-catenin to treat triple-negative breast cancer (TNBC). This aggressive subtype lacks targeted therapies and is often associated with poor prognosis and limited treatment options. Previous studies had identified isoxazoles for their ability to drive key differentiation programs across various normal stem cell types and biological processes. In this work, we demonstrate that these molecules can induce robust differentiation of TNBC cancer stem cells in both established cell lines and patient-derived organoid models. Then, further studies within our research group highlighted compound RS4690, which showed promising selective inhibition of DVL1 binding. This finding supported the development and synthesis of new therapeutic agents against Wnt-dependent colon cancer. In addition, we synthesized pyrrole-benzene sulfonamide derivatives acting as dual inhibitors of both the Wnt/β-catenin signalling pathway and carbonic anhydrase, which exhibited potent activity against multidrug-resistant breast cancer cells. Finally, I also contributed to two smaller projects in the anti-infective field, where, starting from docking studies, we designed and developed potential antibacterial candidates against Staphylococcus aureus and observed promising activity even against multidrug-resistant strains, supported by Rome Technopole.