Development of novel pyrazolo[3,4-d]pyrimidines as anticancer agents: synthesis of potent c-Src/Abl inhibitors

The interest in protein tyrosine kinases has increased in recent years, particularly since their oncogenicity in human cells has been recognized. Tyrosine kinases promote phosphorylation of many proteins involved in cellular signaling pathways and the deregulation of their normal activity leads to diseases, such as cancer. In this context, several pyrazolo[3,4-d]pyrimidines have been developed as Tyrosine Kinase Inhibitor (TKI) and some of them have revealed promising in vitro and in vivo antitumor activity. In this thesis I describe the work done during my three years of PhD, which concerns the design and synthesis of novel pyrazolo[3,4-d]pyrimidines able to inhibit the protein tyrosine kinase c-Src and Abl, involved in cancer processes. The first chapter provides a general introduction on Protein Kinases, focusing on the major non-receptor tyrosine kinases c-Src and Abl. Here, the protein activation mechanisms and some structural aspects have been described. The second chapter is dedicated to the development of potent c-Src/Abl inhibitors for the treatment of Chronic Myeloid Leukemia (CML). Optimization of molecules, through the design and synthesis of novel derivatives, has been successfully performed and new promising anticancer agents have been obtained. The third chapter describes the elaboration of five novel families of pyrazolo[3,4- d]pyrimidines designed through merge-hybridization with TKIs approved in cancer therapy. Thereby, a small library of c-Src inhibitors against Hepatocellular Carcinoma (HCC) has been developed. Finally, the last chapter illustrates the optimization process of two pyrazolo[3,4-d]pyrimidine compounds, Si306 and Si409, with the aim of improving some pharmacological properties for the treatment of Glioblastoma Multiforme (GBM) through the design and synthesis of a small set of derivatives.