Cytotoxic activity and G-quadruplex stabilization of Ir(III) complexes with phenanthroimidazole derivative ligands

Metal complexes are playing an important role over the last few years in the design of new fluorophores with potential application in cell imaging and cancer therapy. Focusing on DNA as the cellular target, G-quadruplex DNA-forming sequences have attracted great attention because they are involved in several biological processes, from chromosome protection to senescence process. In fact, the higher prevalence of these structures in cancer cells than in normal cells, link G4 structures with cancer. So a growing interest is devoted to drugs with a good affinity for G4-DNA and selectivity towards G-quadruplex over duplex DNA to enhance and/or promote quadruplex-related biological effects.
Bearing in mind the above-mentioned, we have synthesized a couple of Ir(III) biscyclometallated phosphorescent complexes, [Ir1]Cl and [Ir2]Cl, which incorporate two different imidazolephenanthroline ligands, L1 and L2, where L1 holds an acidic N-H group, while L2 is decorated with a N-Ph group. As shown in this work, such a trivial functional change influences the acidbase and redox chemistry of [Ir1]Cl and [Ir2]Cl, and what is more interesting, it also affects the subcellular localization of these derivatives, their cytotoxic behaviour and their mechanism of action. Finally, both complexes are able to stabilize a battery of G4 structures with preference for antiparallel two-tetrads G4 (Bom17 and TBA). In addition, [Ir1]Cl exhibits selectivity for G-quadruplex even in the presence of a DNA double helix as competitor revealing the potential of this complex for specifically target G4 structures.