Design and synthesis of novel small molecules as anticancer agents.

Cancer is an increasing worldwide emergency, and its incidence and mortality will double in the next twenty years. Thus, it seems to be clear that we need new and more effective pharmacological therapies. This pathology is a set of evolving diseases that differently respond to treatments. It is a multifactorial process characterized by altered function of several proteins, and which involves numerous pathways of various nature. Hence, research is continuously looking for different solutions for fighting tumours. Accordingly, this PhD thesis aims at designing and developing small molecules targeting receptor or enzymes implicated in cancer. Firstly, we focused on the development of molecules capable of selectively inhibiting human Carbonic Anhydrase enzymes IX and XII, also known as the tumour-associated isoforms. Indeed, these enzymes actively support the metastatic spread of tumour cells, and they are highly overexpressed in numerous and different tumours (including renal, breast, ovarian, pancreatic colorectal, and gastrointestinal carcinoma). In addition, this PhD thesis focused on fighting specific forms of cancer, namely glioblastoma (GBM) and multiple myeloma (MM). These are rare forms of cancer, very aggressive and difficult to attack. Although therapies slow down the disease progression and symptoms, to date, the treatment of these tumours is very difficult. Finally, this work focused on immunotherapy; a revolutionary approach able to arm the patient's immune system against cancer cells. Specifically, we concentrated on the PD1-PDL1 interaction, one of the most important immune checkpoints. Indeed, PDL1 is upregulated on the surface of cancer cells, for this reason, interfering with the PD-1/PD-L1 interplay represents an attractive strategy in cancer therapy.