Conformational rearrangements of G-quadruplex topology promoted by Cu(II) 12-MCCu(II)PyrAcHA-4 metallacrown

Abstract

Cu(II) 12-MC_{Cu(II)PyrAcHA}-4 metallacrown was studied by several spectroscopic techniques as an interacting ligand with G-quadruplex DNA structures. Investigations were performed on oligonucleotides bearing human telomeric and protooncogenic c-myc sequences in buffered solution mimicking ionic conditions in cellular environment. The planar square-based Cu(II) 12-MC-4 metallacrown interacts with GQ via an end-stacking mode with 1:1 stoichiometry. Circular dichroism (CD) titration revealed capability of this metallacrown to induce transformation of the GQ hybrid topology into the parallel form. Thermal melting experiment indicated higher thermal stability of both antiparallel (ΔT_m = +15 °C) and parallel (ΔT_m = ≥27 °C) G-quadruplexes in the presence of Cu (II) 12-MC-4. Indirect GQ FID assay let to determine high binding affinity of the Cu(II) 12-MC-4 to antiparallel 22Htel/Na⁺ GQ (K_MC = 3.9 (±0.4) x 10⁶ M^-1). Comparing with lower binding constants previously reported for Ln (III) 15-MC-5 and Sm (III) 12-MC-4, one can conclude that the square planar geometry and the positive charge of metallacrown play an important role in MC/GQ interactions.

Keywords: Copper(II) 12-MC-4 metallacrown; G-quadruplex conformational rearrangement; G-quadruplex thermal stabilization.