Portrait of a Family of Highly Stabilizing and Selective Guanine Quadruplex Platinum(II)-Based Binders

The long-standing history of platinum coordination complexes in nucleic acid recognition attests to the unique suitability of such species for therapeutic applications. Here, we report the synthetic exploration and development of a family of di-imine ligands, and their platinum(II) complexes, elaborated on a 3-(2-pyridyl)-[1,2,4]triazolo[4,3-a]pyridine platform which, in its unsubstituted form, has recently been shown to display exceptional capabilities for guanine quadruplex (G4) targeting. The identification of facile, high-yielding synthetic methods for the derivatization of this platform for the incorporation of additional sites of interactions with guanine quadruplex loops and grooves, along with the optimization of platinum(II) complexation methods, are discussed. Gratifyingly, preliminary biophysical screening of this novel family of binders validates all but one family members as robust G4 binders and highlights enhanced selectivity for quadruplex versus duplex DNA compared to the parent compound. These results bear promise for practical developments based on this platform.