Identification of a non-planar imidazole-cored small molecule for selective telomeric G4 DNA targeting

Abstract The telomeric DNA, being guanine-rich in nature, has a high propensity to fold into a four-stranded structure named G4 via Hoogsteen H-bonding. As the telomeric DNA forming into the G4 structure has been proved able to inhibit telomerase activity, the study of its biological functions has currently become a hotspot. Therefore, selective targeting telomeric G4 DNA is the motivation of our present study. Most of the reported G4 ligands generally have planar aromatic structures which could stabilize G4 by π-π stacking. Herein, we focused on a non-planer tetraaryl imidazole derivative AI9 featuring a G4 groove binder analogue side chain. In solution, AI9 prefers binding to hybrid telomeric G4 DNA rather than to other G4s and non-G4s with turn-on effect. We have characterized the interactions by using UV–Vis, fluorimetric titration, circular dichroism and molecular docking studies. Analysis indicated that partial intercalation and groove binding might play major roles in the stability of the AI9-22AG complex in a 1:1 stoichiometry. Furthermore, AI9 was applicable to visualize the cellular nucleus in cells. These results have shown that planar structures are not essential for G4 binding, representing a new class of G4-targeted agents.