Design, Preparation, and Characterization of Zn and Cu Metallopeptides Based On Tetradentate Aminopyridine Ligands Showing Enhanced DNA Cleavage Activity

Article abstract of DOI:10.1021/acs.inorgchem.5b01680

The conjugation of redox-active complexes that can function as chemical nucleases to cationic tetrapeptides is pursued in this work in order to explore the expected synergistic effect between these two elements in DNA oxidative cleavage. Coordination complexes of biologically relevant first row metal ions, such as Zn(II) or Cu(II), containing the tetradentate ligands 1,4-dimethyl-7-(2-pyridylmethyl)-1,4,7-triazacyclononane (^Me2PyTACN) and (2S,2S′)-1,1′-bis(pyrid-2-ylmethyl)-2,2′-bipyrrolidine ((S,S′)-BPBP) have been linked to a cationic LKKL tetrapeptide sequence. Solid-phase synthesis of the peptide-tetradentate ligand conjugates has been developed, and the preparation and characterization of the corresponding metallotetrapeptides is described. The DNA cleavage activity of Cu and Zn metallopeptides has been evaluated and compared to their metal binding conjugates as well as to the parent complexes and ligands. Very interestingly, the oxidative Cu metallopeptides 1_Cu and 2_Cu show an enhanced activity compared to the parent complexes, [Cu(PyTACN)]²⁺ and [Cu(BPBP)]²⁺, respectively. Under optimized conditions, 1_Cu displays an apparent pseudo first-order rate constant (k_obs) of ～0.16 min^-1 with a supercoiled DNA half-life time (t_1/2) of ～4.3 min. On the other hand, k_obs for 2_Cu has been found to be ～0.11 min^-1 with t_1/2 ≈ 6.4 min. Hence, these results point out that the DNA cleavage activities promoted by the metallopeptides 1_Cu and 2_Cu render ～4-fold and ～23 rate accelerations in comparison with their parent Cu complexes. Additional binding assays and mechanistic studies demonstrate that the enhanced cleavage activities are explained by the presence of the cationic LKKL tetrapeptide sequence, which induces an improved binding affinity to the DNA, thus bringing the metal ion, which is responsible for cleavage, in close proximity.