Design, Preparation, and Characterization of Zn and
Cu Metallopeptides Based On Tetradentate Aminopyridine Ligands Showing
Enhanced DNA Cleavage Activity
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Abstract
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
(<sup>Me2</sup>PyTACN) and (2<i>S</i>,2<i>S</i>′)-1,1′-bis(pyrid-2-ylmethyl)-2,2′-bipyrrolidine
((<i>S,S</i>′)-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 <b>1</b><sub><b>Cu</b></sub> and <b>2</b><sub><b>Cu</b></sub> show an enhanced activity compared to the parent complexes,
[Cu(PyTACN)]<sup>2+</sup> and [Cu(BPBP)]<sup>2+</sup>, respectively.
Under optimized conditions, <b>1</b><sub><b>Cu</b></sub> displays an apparent pseudo first-order rate constant (<i>k</i><sub>obs</sub>) of ∼0.16 min<sup>–1</sup> with a supercoiled
DNA half-life time (<i>t</i><sub>1/2</sub>) of ∼4.3
min. On the other hand, <i>k</i><sub>obs</sub> for <b>2</b><sub><b>Cu</b></sub> has been found to be ∼0.11
min<sup>–1</sup> with <i>t</i><sub>1/2</sub> ≈
6.4 min. Hence, these results point out that the DNA cleavage activities
promoted by the metallopeptides <b>1</b><sub><b>Cu</b></sub> and <b>2</b><sub><b>Cu</b></sub> 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