Identification and development of new antitumor agents with multi-target action

My research work has been focused on the design, synthesis, and evaluation of new antitumor agents with particular attention to their potential multi-target activity. Tumor is a multifactorial disease characterised by inflammation and hypoxic environment and both these conditions lead to an altered extracellular pH that favour cancer invasion of adjacent tissues. Tumor cells modify their energy metabolic activity to have advantages for the tumorigenesis. A promising approach to obtain anticancer agents could be represented by the identification of new small molecules capable to inhibit more than one enzyme involved in in tumoral growth. Between these enzymes, Cyclooxygenase, Carbonic Anhydrase and Kinase are attractive from the poli-pharmacological point of view. Indeed, both the design of isozyme selective COX and CA inhibitors, and the design of dual Abl/c-Src Kinase inhibitors are promising approaches to the identification of new anti-cancer agents. Different libraries of coumarin and their psoralen analogues EMAC10155, EMAC10156, EMAC10157, EMAC10158, EMAC10159, EMAC10160, EMAC10161 and EMAC10162 have been designed and synthesised with the purpose to further explore the influences of structural modifications on the coumarin and the psoralen core on the activity and selectivity towards CA I, II, IX and XII. None of the new compounds exhibited activity towards the off-targets hCA I and II isozymes. Conversely, both coumarin and psoralen derivates were active against the tumour associated isoforms IX and XII. Different series of potential multi-target agents to investigate on the structural requisites for the selective inhibition of tumor overexpressed hCAs and COX-2 enzymes has been synthetized: EMA10190 and EMAC10191. They present a benzene-sulphonamide group, efficient for the inhibition of COX-2 enzyme, and capable to coordinate the hCAs zinc cofactor in the catalytic site. This essential moiety binds a differently substituted central heterocyclic core either through a hydrazine or a thiazole spacer. Substitutions of the phenyl ring bonded to the hydrazine spacer or to the thiazole spacer is determinant to the selectivity toward the CA tumoral isoform, in particular toward the isoform IX. During my stay at the Lead Discovery Siena, I have designed and synthetized new pyrazolo[3,4-d]pyrimidine compounds substituted in position N-1, C-4 and C-6 to investigate on their inhibition potential towards tyrosine kinase Src and for T315I mutant cells. Significantly, all of the compounds of this library were micromolar inhibitors of Abl and c-Src.