New strategies to address cancer via diverse mechanisms and targets

During my PhD tenure I have worked on several projects, regarding different biological targets. My principal focus has been the development of small molecules, with potential pharmacological activities as new anticancer agents. These act through different mechanisms of actions, depending on the scaffold carried by the compounds. A first project regarded the carbonic anhydrases (CAs), enzymes with a main role in various physiological processes, but that can be involved in different pathological conditions, such as glaucoma, epilepsy, and Parkinson’s disease above all. The primary goal was to synthesize small molecules capable of inhibiting different isoforms of CAs. My research group has worked on these targets for many years and has reported different types of inhibitors. Based on different scaffolds, primarily pyrrole and indole scaffolds, I designed and synthesized a new series of CAs inhibitors bearing a sulfonamide moiety, pivotal group for the inhibitions of these metalloenzymes. A second project regarded the Wnt/β-catenin pathway. This is an essential signaling pathway for the homeostasis of colorectal tissue, but its abnormal activation could lead to cancer. This double aspect requires particular attention in the development of small organic molecules that can target the WNT/β-catenin pathway. I designed and synthesized novel analogue able to inhibit β-catenin, an elusive but essential target that plays an essential role in this pathway. Among the different projects, a particular attention was given to ferroptosis. It is a programmed iron-dependent cell death, which is increasingly been investigated in recent years. My group has a solid experience in the synthesis of tubulin polymerization inhibitors, characterized by a specific pyrrole scaffold, namely ARDAP: 3-ARoyl-1,4-DiAryl Pyrrole. The ARDAP structure ignites the apoptosis, a programmed cell death recognized as critical for sustained tumor suppression following anticancer treatments. We recently reported a new congener of the ARDAP series, with a different substituent on the nitrogen atom of the pyrrole, that is a heterocyclic ring. Interestingly, this new analogue, which still works as a tubulin polymerization inhibitor, shows the hallmarks of ferroptosis rather than the conventional apoptosis. Therefore, we have decided to develop a new series of pyrroles, called ARDHEP (3-Aroyl-1,4- DiHEterocyclic Pyrrole), with the aim of inducing ferroptosis in various tumor cell lines. In conclusion, this thesis has the aim of finding new possible strategies to target cancer, through the design and synthesis of small organic molecules, that work with different mechanisms and target diverse biological component of various pathways, nonetheless all with the same final outcome, which is finding a possible cure for cancer.