Human telomeric DNA is composed of hundreds of 5’-TTAGGG repeats that end in a single-strand overhang of around 200 nucleobases. Under physiological conditions, this sequence can fold into a tetra-stranded arrangement known as G-quadruplex DNA. This secondary DNA structures has attracted significant attention due to its role in telomere maintenance, leading to cancer cell immortality. Therefore, telomeric G-quadruplex DNA represent a potential target for cancer therapy. A G-quadruplex monomer sequence is usually used as the model to screen G-quadruplex ligands. However, telomeric end can form high-order G-quadruplex structures (dimer or multimer), consisting of consecutive G-quadruplex units connected by TTA linkers. Therefore, it is more biologicals relevant to design compounds that can selectively interact with higher-order G-quadruplexes structures. Here, we report the synthesis of new dinuclear-Ruthenium(II) complexes bearing 1,10-phenanthroline (phen) or 1,4,5,8-tetraazaphenanthrene (TAP) linked by polyether linkers (Figure 1). Some of them, have shown interesting photochemical and photophysical properties. Indeed, upon light irradiation, the oxidation potential of these compounds are enhanced, leading to photocleavage and/or photoadduct formation with DNA. The affinity and selectivity of our complexes towards multimeric G-quadruplexes DNA have been extensively studied using dichroism circular (CD), melting temperature (Tm) and Bio Layer Interferometry (BLI). Finally, <i>in cellulo</i> studies revealed that our complexes have the ability to induce cell mortality upon light irradiation.

Dinuclear-ruthenium(II) complexes as binders of human telomeric dimeric G-quadruplexes

2019 Fall National Meeting

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