The Cu(II) complexes of cyclen and two of its heterosubstituted analogues were shown to be efficient oxidative DNA cleavers. The reactivity strongly depends on the heteroatom inserted into the macrocycle (O > S > N).
Keywords: DNA cleavage / Copper / Macrocyclic ligands / Cyclen / Cyclic voltammetryMacrocyclic Cu II complexes with [N X O Y ] donor sets of different N/O ratios were synthesised resulting in a series ranging from cyclen (X = 4, Y = 0: 1) to 12-crown-4 (X = 0, Y = 4: 6) complexes. In order to elucidate the structure of the complexes UV/Vis spectroscopy and X-ray crystallography were applied, focusing especially on the literature-unknown compounds with regioisomeric [N 2 O 2 ] and [NONO] donor sets (3, 4). The complexes were subjected to DNA cleavage experiments under reducing conditions and were also tested in the [a]
Many drugs that are applied in anticancer therapy such as the anthracycline doxorubicin contain DNA-intercalating 9,10-anthraquinone (AQ) moieties. When Cu(II) cyclen complexes were functionalized with up to three (2-anthraquinonyl)methyl substituents, they efficiently inhibited DNA and RNA synthesis resulting in high cytotoxicity (selective for cancer cells) accompanied by DNA condensation/aggregation phenomena. Molecular modeling suggests an unusual bisintercalation mode with only one base pair between the two AQ moieties and the metal complex as a linker. A regioisomer, in which the AQ moieties point in directions unfavorable for such an interaction, had a much weaker biological activity. The ligands alone and corresponding Zn(II) complexes (used as redox inert control compounds) also exhibited lower activity.
A simple approach towards efficient artificial proteases based on the cyclen ligand is presented. We thus achieved an increase of the proteolytic activity of two orders of magnitude when compared to the unsubstituted cyclen complex. Amphiphilic Cu(ii) and Co(iii) complexes cut BSA and myoglobin as model substrates at μM concentrations. MALDI-ToF MS is used to identify the cleavage fragments.
Bridging organic and inorganic chemistry as well as molecular biology, this undergraduate experiment deals with the synthesis of ligands for metal complexes that can cleave DNA. Students gain theoretical and experimental expertise about metal−DNA interactions and the mechanisms behind DNA cleavage. This experiment lays a basis for the understanding and the rational design of artificial DNA scissors and provides insight into interdisciplinary research in the field of bioinorganic chemistry.
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