Oxidative DNA cleavage with Non-Heme iron complexes

PhD ceremony: Ms. Q. Li, 14.45 uur, Aula Academiegebouw, Broerstraat 5, Groningen

Dissertation: Oxidative DNA cleavage with Non-Heme iron complexes

Promotor(s): prof. J.G. Roelfes en prof. B.L. Feringa

Faculty: Mathematics and Natural Sciences

 

Bleomycins (BLM) are a family of natural antibiotics widely used in the clinical treatment of certain cancers. BLM are believed to prevent the growth of cancerous cells by effecting oxidative cleavage of DNA strands. Based on the structural characteristics of the metal binding domain of BLM, the pentadentate ligand N ,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)-methylamine (N4Py) was designed and synthesized. The aim of the present research project was to systematically evaluate the mono-nuclear Fe(II)N4Py complexes as synthetic mimics of Fe(II)-BLM in oxidative DNA cleavage. The studies carried out in the present thesis demonstrated that the plasmid DNA cleavage activity of Fe(II)N4Py complexes can be changed by modifying their structures and/or employing different photo irradiation conditions. The key step in DNA cleavage process was proposed to be the formation of [( N4Py)Fe^IIIOOH]²⁺, an analogy to [(BLM)Fe^IIIOOH]²⁺, as the direct active species or the precursor of direct active species. In living human cells, Fe(II)N4Py complexes induced nuclear DNA cleavage as efficiently as Fe(II)BLM, which were the first examples of synthetic BLM mimics capable of nuclear DNA cleavage. All the results together proved that Fe(II)N4Py complexes are successful synthetic mimics of Fe(II)BLM, both in the test tube and the complex intracellular environment.