Development of new macrocyclic ligands for Cu(II) complexes with potential DNA cleavage properties

Abstract

According to the World Health Organization, cancer is among the second leading death cause globally, and cancer treatment is a challenge in the field of medicinal chemistry. The DNA cleavage activity of a metallonuclease is related to its capability to generate toxic reactive oxygen species (ROS) in a reductive environment. In this scenario, 1,4,7,10-tetraazacyclododecane is a fully exploited ligand, thanks to the good stability constants towards many metal centres. Exploiting Cu(II) as metal core, the heteroatom substitution together with a coupling of this macrocyclic ligand with the DNA targeting function anthraquinone were already performed, in order to improve the efficacy. The aim of the present thesis was to synthesise new ligands for Cu(II) metallonucleases, where the ligand itself could be redox active, in order to enhance the ROS concentration and consequently the catalytic activity of the nuclease. Therefore 1-thia-4,7,10-triazacyclodedecane-1-oxide and 1-thia-7-oxa-4,10-diazacyclodedecane-1-oxide were synthesised and fully characterised. Their Cu(II) complexes [Cu([12]aneN3SO)NO3]NO3 and [Cu([12]aneN2SO2)NO3]NO3 were also synthesised and characterised. Their DNA cleavage activity was tested, in comparison with the known complexes [Cu([12]aneN3S)NO3]NO3 and [Cu([12]aneN2SO)NO3]NO3. Moreover, the ligands under study were functionalised by an anthraquinone moiety, and these compounds were tested towards DNA intercalation, alone and after incubation with Cu(II) salt.