Platinum phenanthroimidazole complexes as G-quadruplex DNA selective binders

摘要

Complexes that bind and stabilize G-quadruplex DNA structures are of significant interest due to their potential to inhibit telomerase and halt tumor cell proliferation. We here report the synthesis of the first Pt-II Gquadruplex selective molecules, containing pi-extended phenanthroimidazole ligands. Binding studies of these complexes with duplex and quadruplex d(T(4)G(4)T(4))(4) DNA were performed. Intercalation to duplex DNA was established through UV/Vis titration, CD spectroscopy, and thermal denaturation studies. Significantly stronger binding affinity of these phenanthroimidazole Pt-II complexes to G-quadruplex DNA was observed by UV/Vis spectroscopy and competitive equilibrium dialysis studies. Observed binding constants to quadruplex DNA were nearly two orders of magnitude greater than for duplex DNA. Circular dichroism studies show that an increase in;pi-surface leads to a significant increase in the thermal stability of the Pt-II/quadruplex DNA complex. The match in the pi-surface of these phenanthroimidazole Pt-II complexes with quadruplex DNA was further substantiated by molecular modeling studies. Numerous favorable pi-stacking interactions with the large aromatic surface of the intermolecular G-quadruplex, and unforeseen hydrogen bonds between the ancillary ethylenediamine ligands and the quadruplex phosphate backbone are predicted. Thus, both biological and computational studies suggest that coupling the square-planar geometry of Pt-II with pi-extended ligands results in a simple and modular method to create effective G-quadruplex selective binders, which can be readily optimized for use in telomerase-based antitumor therapy.