Water-Soluble Heptacyclic Oligo-Heteroaryls Targeting G‑Quadruplex DNA via Groove-Binding Interactions.

G-quadruplexes (G4s) are noncanonical nucleic acid structures involved in the regulation of key biological processes and represent attractive targets for therapeutic intervention. In this study, we report the design, synthesis, and biophysical evaluation of a new family of water-soluble heptacyclic oligo-heteroaryl ligands tailored for G4 recognition. The synthetic route, based on a modular and convergent approach, enables late-stage functionalization and overcomes common limitations of macrocyclic scaffolds such as low yields and poor tractability. The new compounds incorporate 1,2,4-oxadiazole and 1,2,3-triazole units as bioisosteric replacements for oxazole and systematically vary the nature of the central atoms (C vs N) and pendant groups to investigate their effect on G4 binding. All derivatives displayed high aqueous solubility under physiological conditions and selective stabilization of G4 structures, particularly the parallel LTR-IV motif. Biophysical studies and docking calculations indicate that these ligands operate primarily through groove-binding interactions. Notably, no substantial differences were observed between nitrogen- and carbon-substituted analogues, suggesting a conserved binding profile across the series. These findings identify a versatile class of G4 binders with favorable solubility and structural tunability, laying the groundwork for the development of functionalized derivatives for chemical biology and therapeutic applications.