Bis-phenanthroline derivatives as suitable scaffolds for effective G-quadruplex recognition

Abstract

Selective recognition of DNA folding is central to multiple biological and pharmacological applications aimed at precise targeting of distinct genomic regions. Here, we focused on the recognition of physiologically relevant G-quadruplex (G-4) structures by bis-phenanthroline (bis-Phen) ligands containing two Phen moieties covalently linked through an amine or thioether bond. The transition metal ions Mn(2+), Ni(2+), Cu(2+), and the biologically relevant Mg(2+) and Zn(2+) efficiently form 1 : 1 bis-Phen complexes characterised by a large planar structure fit to successfully recognise G-quartet arrangements.Interestingly, metal ion complexation dramatically affects ligand-stabilising effects on G-quadruplex, the melting temperature of the folded structure being increased up to 30 degrees C at ligand concentrations as low as 1 microM in the presence of Ni(2+) and Cu(2+). In addition, the test complexes were able to induce G-4 formation from essentially unfolded G-rich sequences even in the absence of K(+) ions as shown by gel shift and circular dichroism experiments. In line with their G-4 stabilising properties bis-Phen complexes are effective inhibitors of telomerase activity, Ni(II) complexes being effective in the sub-micromolar range. This is combined with lack of unselective DNA-damaging activity and short-term cellular toxicity, which makes the novel compounds (above all their Ni(II) complexes) interesting antiproliferative drug leads.

Effect of G-Quadruplex Polymorphism on the Recognition of Telomeric DNA by a Metal Complex

“…In agreement with other authors [30], our investigation showed Cu(II) and Ni(II) as the most effective transition metals in providing phenanthroline complexes selective toward G-quadruplex [28], [29]. Moreover, the evaluation of several phenanthroline-based free ligands and of their Ni(II) complexes indicated the assembly of two phenanthroline moieties around the metal center as the key structural feature required to enhance such a selectivity.…”

“…In previous works, we exported this model toward G-quadruplex DNA with the idea that only selected metal ions could coordinate phenanthroline units according to geometries suitable to enhance the G-quadruplex recognition and disfavor the binding to the double helix [28], [29]. In agreement with other authors [30], our investigation showed Cu(II) and Ni(II) as the most effective transition metals in providing phenanthroline complexes selective toward G-quadruplex [28], [29].…”

Screening of candidate G-quadruplex ligands for the human c-KIT promotorial region and their effects in multiple in-vitro models

“…To further optimize the promising outcome provided by these derivatives, we set up a library of “in house” available compounds that can be clustered into five different families according to their main scaffold: anthraquinone (AQ) [23], anthracene (AN) [24], phenantroline (Phen) [25-27], naphthalene diimide (NDI) [28] and heterocyclic diamidines (HAD) [29]. Interestingly, G4 recognition properties were previously reported for at least one member of each family.…”

Interaction of metal complexes with nucleic acids

“…12b) as good quadruplex DNA binders. 79 This study shows that the quadruplex affinities of the complexes are much higher than those of the free ligands highlighting the important role played by the different metal cations. In addition, CD studies showed that the bis-phenanthroline complexes were able to induce quadruplex folding even in the absence of K + .…”