Xanthone derivatives as potential telomeric G-quadruplex stabilizing and cytotoxic agents: Effects of substitution on quadruplex binding affinity and cytotoxicity

• A novel series of xanthone derivatives were designed, synthesized and evaluated. • Compound 2a might be used as a potent quadruplex stabilizer and antitumor agent. • Effects of substitution on quadruplex binding and cytotoxicity have been discussed. A series of xanthone derivatives (2a-2e) as telomeric quadruplex stabilizing ligands were designed, synthesized and evaluated by molecular docking, drug-likeness prediction, spectroscopy assay, melting profiles, PCR stop analysis. The ligands possessed the rigid aromatic xanthone scaffold and the flexible basic side chain with the appropriate length. Molecular docking and quadruplex binding property studies revealed that the ligands could stack on the external G-quartets, and the basic side chain could contribute to the stabilizing ability. Introduction of a tertiary amine group with high p K a value and small steric hinderance was favorable for improving the binding ability. Such as bis-dimethylamine derivative (2a), exhibited stronger binding ability and higher affinity towards G-quadruplex than duplex DNA. Cytotoxicity assay showed that the xanthone derivatives could inhibit the viabilities of HeLa, MCF-7, SGC-7901 and A549 cells in different degrees. AO/EB staining and flow cytometry assay indicated that the cytotoxicity of xanthones was related to induced apoptosis. These results suggested that the ligands could be further studied as potential new G-quadruplex stabilizers and potent antitumor agents, especially 2a.