A phosphate-targeted dinuclear Cu(II) complex combining major groove binding and oxidative DNA cleavage

Zara Molphy, Diego Montagner, Satish S Bhat, Creina Slator, Conor Long, Andrea Erxleben and Andrew Kellett.

Nucleic Acids Research, accepted, 2018.

We have recently reported the rational design and DNA binding interactions of a novel di-Cu(II) artificial metallonuclease [Cu2(tetra-(2-pyridyl)-NMe-naphthalene)Cl4] (Cu2TPNap) in the Oxford University press journal Nucleic Acids Research. Cu2TPNap is a high-affinity binder of duplex DNA with an apparent binding constant (Kapp) of 107 M(bp)−1. The agent binds non-intercalatively in the major groove causing condensation and G-C specific destabilization. Artificial metallonuclease activity occurs in the absence of exogenous reductant, is dependent on superoxide and hydrogen peroxide, and gives rise to single strand DNA breaks. Pre-associative molecular docking studies with the 8-mer d(GGGGCCCC)2, a model for poly[d(G-C)2], identified selective major groove incorporation of the complex with ancillary Cu2+-phosphate backbone binding. Molecular mechanics methods then showed the d(GGGGCCCC)2 adduct to relax about the complex and this interaction is supported by UV melting experiments where poly[d(G-C)2] is selectively destabilized.

[Open Access]