SYNTHESIS OF NEW SULFURATED DERIVATIVES OF NATURAL AND SYNTHETIC SYSTEMS AS MULTITARGET ANTICANCER AGENTS AND DEVELOPMENT OF NEW DRUG DISCOVERY METHODOLOGIES

This PhD thesis is divided in two parts. The former, entitled "Design and synthesis of new derivatives of natural and synthetic systems endowed with anticancer activity, through a multitarget mechanism", has been carried out at the Universitá degli Studi di Milano under the supervision of Professor Anna Sparatore. This project treats the synthesis of new sulfurated compounds with the aim of obtaining anticancer agents acting through a multitarget mechanism. On one hand, we explored the potentialities of new sulfurated chemical scaffolds, such as dithiolethiones, methanethiosulfonates and allyldisulfides to evaluate their antiproliferative activity, as well as their ability to inhibit STAT3 and NfkB, and to design new anticancer agents. On the other hand, we evaluated the possibility of creating hybrid molecules, combining moieties with different mechanism of action, which could carry out a synergistic antitumor effect. In particular, the sulfurated compounds synthetized have been combined with different STAT3 and/or NfkB inhibiting structures such as natural products (curcumin, phenolic acids and celastrol), semi-synthetic and synthetic systems (rosmaricine and heterocyclic compounds). Some of them exhibited very interesting inhibitory activity on both transcription factors in the micromolar range and antiproliferative activity. The second part, entitled "Optimized reaction conditions for amide bond formation in DNA-encoded combinatorial libraries", has been developed at Swiss Federal Institute of Technology in Zurich (ETH Zurich) in the research group of Professor Dario Neri. This project is focused on the advantages of using DNA-encoded chemical libraries (DECLs) in drug discovery process. In particular, since in the majority of cases DECLs require at least one-step of amide bond formation between amino modified DNA and a carboxylic acid, we optimized a new methodology of synthesis in order to facilitate the construction of single-pharmacophore libraries (DECLs).