The synthetic iron complex Fe(N4Py) has previously shown to be an excellent catalyst in the aerobic oxidation of DNA in cell-free systems. Since various anticancer drugs depend upon breakdown of DNA, it became clear that the exploration of N4Py in a cellular environment could open up an entirely new field of research. The aim of this thesis was to determine the chemical nature and localization of N4Py in living cells, as well as to further manipulate its structure in order to enhance its favorable properties in a cellular environment, since this could ultimately lead to the development of new anticancer drugs based on the induction of oxidative stress. The results indicate that it is clearly not one N4Py metal species that can be present in a cell. Instead, a mixture of Fe(II)-, Cu(II)- and Zn(II)-N4Py complexes is proposed, of which the iron complex seems to be responsible for the observed activity of N4Py in the cell. In addition, conjugation of a fluorophore to N4Py for tracking purposes revealed that, even though conjugation had little effect on the intrinsic DNA cleavage activity of N4Py, the cellular behavior was greatly affected: it can change both its cellular localization as well as the mode of cell death. Furthermore, conjugation of N4Py to a molecule of folate resulted in selective delivery of N4Py to high folate receptor expressing cancer cells, emphasizing the potential for obtaining an N4Py derivative with good potency and reduced toxicity compared to the generic working of N4Py itself.
|Qualification||Doctor of Philosophy|
|Place of Publication||[Groningen]|
|Publication status||Published - 2017|