Bioinorganic strategies for the development of metal-enzymes inhibitors and compounds with antitumor activity

Abstract

This PhD thesis is centred on two main research areas within the bioinorganic strategies for the development of bioactive compounds. The first one regards the synthesis and characterization of water-soluble thiosemicarbazones (TSCs) copper complexes as compounds with anticancer activity. Promising results were previously obtained in this research group with salicylaldehyde TSCs Cu(II) complexes that, nevertheless, showed that their application could be improved enhancing their water solubility. Therefore, the first project focused on the synthesis of some sulfonated salicylaldehyde TSC ligands and of their copper(II) complexes. The synthesis of structurally modified ligands and complexes was carried out to have insights on the structure-activity relationship in this class of compounds. Another way to improve solubility brought to the synthesis of a panel of glyco-conjugate TSCs ligands and their copper(II) complexes. The second subject concerns the synthesis and characterization of chelating compounds as inhibitors of viral metal-dependent enzymes, by using the validated strategy of the metal chelation of the ion cofactors within the active site of the target enzymes. The synthesis of different chelating compounds targeting the metal-dependent RNA-dependent RNA polymerase in viruses of the Bunyavirales order was undertaken. Several bunyaviruses represent emerging zoonotic pathogens and the therapeutic options for the treatment of these infections are very limited, thus the identification of effective antiviral compounds is of vital importance. Finally, due to the arrival of the COVID-19 pandemic, an in-house library of chelating compounds and metal complexes has been completed to be used in a screening targeting PLpro, a specific zinc-dependent enzyme of SARS-COV-2.