Photo-Cytotoxicity of New Ruthenium Complexes Targeting G-Quadruplex Telomeric DNA in Telomerase-Free Cells

The use of metal in medicine began with the serendipitous discovery of the anticancer properties of cisplatin.1 Since then, using new metals has progressively gained interest for the development of new therapeutic agents.2 Among them, polyazaaromatic complexes of Ru(II) have shown interesting photochemical and photophysical properties. Indeed, upon light irradiation, the oxidation and reduction potential of these compounds are enhanced and for some of them, photocleavage and/or photoadduct formation with DNA have been demonstrated.3 In this context, we aim at designing new photo-oxidizing complexes of Ru(II) complexes for the targeting of G-quadruplex DNA. G-quadruplex (G4) consist in particular secondary structures adopted by guanines-rich nucleic acids These structures are formed through the stacking of guanine tetrads (G-quartet), the latter resulting from the coplanar arrangement of four guanines.4 They have been found in the telomeres where they appear to play crucial biological roles. Therefore, designing ligands able to selectively target G-quadruplex versus duplex DNA is of great interest. We report therein on the synthesis of new photo-oxidizing ruthenium complexes. They are able to photo-induce oxidative damage to telomeric G-quadruplex DNA through photo-induced electron transfer (PET) with guanine. The affinity and selectivity for G-quadruplex DNA have been evidenced thanks to steady-state luminescence studies, BLI and molecular modelling. Finally, we demonstrated the cell internalization and the photo-cytotoxicity towards human osteosarcoma cells, which do not express telomerase.