Nickel‐Catalyzed Construction of Dibenzoxathiepine and Dibenzothiazepine Frameworks as H‐Telo G‐Quadruplex DNA Binders

A series of medium-ring heterocycles, including dibenzoxathiepine and dibenzothiazepine derivatives bearing tetra-substituted exocyclic olefins, were synthesized via a ligand-free nickel-catalyzed one-pot cyclocarbonickelation-arylation cascade of functionalized bromoalkyne substrates. In this study, these synthesized ligands were evaluated for their binding affinity toward various G-quadruplex (GQ) and duplex DNA structures using biophysical such as UV-Vis absorption, fluorescence spectroscopy, fluorescence anisotropy, time-resolved decay, circular dichroism, thermal melting, thermodynamic analysis, and in silico studies (molecular docking and simulation studies). Owing to their biological significance, GQ-DNA motifs have emerged as attractive targets for anticancer drug development. Among the tested compounds, ligand 3i demonstrated high selectivity for the H-Telo GQ-DNA over other GQ forms and duplex DNA. The thermodynamic and spectroscopic data collectively reveal that hydrophobic and π-π stacking interactions drive the ligand-GQ association. This recognition suggests that ligand 3i may serve as a promising ligand and also potential candidates for further investigation in cancer cells. Overall, the findings provide valuable insights into ligand-GQ interactions and may support the development of GQ-targeted agents, contributing to the broader understanding of GQ-DNA recognition and therapeutic design. These findings also establish a structure-function relationship linking the heterocyclic framework to GQ recognition.