Importance of Metal-Ion Exchange for the Biological Activity of Coordination Complexes of the Biomimetic Ligand N4Py

Metal coordination complexes can display interesting biological activity, as illustrated by the bleomycins (BLMs), a family of natural antibiotics that when coordinated to a redox-active metal ion, show antitumor activity. Yet, which metal ion is required for the activity in cells is still subject to debate. In this study, we described how different metal ions affect the intracellular behavior and activity of the synthetic BLM-mimic N, N-bis(2-pyridylmethyl)- N-bis(2-pyridyl)methylamine (N4Py). Our study shows that a mixture of iron(II), copper(II), and zinc(II) complexes can be generated when N4Py is added to cell cultures but that the metal ion can also be exchanged by other metal ions present in cells. Moreover, the combination of chemical data, together with the performed biological experiments, shows that the active complex causing oxidative damage to cells is the FeII-N4Py complex and not per se the metal complex that was initially added to the cell culture medium. Finally, it is proposed that the high activity observed upon the addition of the free N4Py ligand is the result of a combination of scavenging of biologically relevant metals and oxidative damage caused by the iron(II) complex

Redox-active N4Py-metal complexes in human cell cultures

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

Folic acid conjugates of a bleomycin mimic for selective targeting of folate receptor positive cancer cells

A major challenge in the application of cytotoxic anti-cancer drugs is their general lack of selectivity, which often leads to systematic toxicity due to their inability to discriminate between malignant and healthy cells. A particularly promising target for selective targeting are the folate receptors (FR) that are often over-expressed on cancer cells. Here, we report on a conjugate of the pentadentate nitrogen ligand N4Py to folic acid, via a cleavable disulphide linker, which shows selective cytotoxicity against folate receptor expressing cancer cells

Importance of Metal-Ion Exchange for the Biological Activity of Coordination Complexes of the Biomimetic Ligand N4Py

Metal coordination complexes can display interesting biological activity, as illustrated by the bleomycins (BLMs), a family of natural antibiotics that when coordinated to a redox-active metal ion, show antitumor activity. Yet, which metal ion is required for the activity in cells is still subject to debate. In this study, we described how different metal ions affect the intracellular behavior and activity of the synthetic BLM-mimic <i>N</i>,<i>N</i>-bis­(2-pyridylmethyl)-<i>N</i>-bis­(2-pyridyl)­methylamine (N4Py). Our study shows that a mixture of iron­(II), copper­(II), and zinc­(II) complexes can be generated when N4Py is added to cell cultures but that the metal ion can also be exchanged by other metal ions present in cells. Moreover, the combination of chemical data, together with the performed biological experiments, shows that the active complex causing oxidative damage to cells is the Fe^II-N4Py complex and not per se the metal complex that was initially added to the cell culture medium. Finally, it is proposed that the high activity observed upon the addition of the free N4Py ligand is the result of a combination of scavenging of biologically relevant metals and oxidative damage caused by the iron­(II) complex

CCDC 1820683: Experimental Crystal Structure Determination

Related Article: Arjan Geersing, Nathalie Ségaud, Monique G. P. van der Wijst, Marianne G. Rots, Gerard Roelfes|2018|Inorg.Chem.|57|7748|doi:10.1021/acs.inorgchem.8b00714,An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.