Exploration of head-to-tail and head-to-head isomers of a guanine quadruplex platinum-based binder

When constructed out of two identical, dissymmetrical, bidentate ligands, square planar platinum(II) complexes may take the form of two isomers, with either ‘head-to-head’ (HH) or ‘head-to-tail’ (HT) orientations. These two isomers display a different footprint which may impact their respective ability to interact with natural biomolecules. Such a platinum(II) complex composed of two 3-(pyridin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine chelates has recently been reported as an excellent guanine quadruplex (G4) binder, with a crystal structure that reveals one binder on each G4 face. However the resolution of the nucleic acid crystal structure does not allow to definitively identify which isomer resides at the 5′ G4 end. This manuscript explores the energetic, kinetic and structural aspects of the isomerization between the HH and HT isomers, using Density Functional Theory (DFT) calculations of energy and geometry, ¹H NMR and UV–visible spectroscopies, and X-ray crystallography, with the assistance of the more labile copper(II) surrogate, and using an analogous CH-containing ligand as control.