Cationic side chain-functionalized heteroarene-fused anthraquinones as selective G-quadruplex stabilizers.

G-quadruplexes (G4s) are non-canonical nucleic acid structures involved in transcription, genome stability, and telomere maintenance, and represent attractive targets for anticancer therapy. Anthraquinone derivatives are privileged G4 ligands owing to their rigid planar π-conjugated cores, which promote end-stacking interactions with G-tetrads and confer selectivity over duplex DNA. In this study, we synthesized a series of indole-, thiazole-, quinoline-, and quinoxaline-fused anthraquinones bearing three terminal cationic side chains to investigate structure-activity relationships. FRET-melting and fluorescence assays showed that the heterocyclic core critically determines G4 stabilization and selectivity. Thiazole-fused derivatives exhibited the strongest stabilization of telomeric and c-Myc promoter G-quadruplexes while showing minimal interaction with duplex DNA and imperfect G4 structures, whereas the other scaffolds were less effective. These compounds also displayed the highest antiproliferative activity against K562 leukemia and HCT116 colon carcinoma cells with favorable selectivity toward cancer cells. Molecular modelling revealed preferential binding of the thiazole ligands to G-quadruplex DNA over duplex DNA, and confocal fluorescence microscopy confirmed efficient cellular uptake and nuclear accumulation. Moreover, compounds 7b and 9b significantly downregulated c-Myc expression, supporting G4-mediated modulation of oncogene transcription as a contributor to their antiproliferative activity.